Color Textbook of Histology - Gartner - Hiatt, 3E

Leslie P.
Gartner
James L. Hiatt
THIRD l:DITlON
SAUNDl
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Color Textbook of
Histology
Third Edition
LESLIE P. GARTNER, PhD
Professor of Anatomy
Department of Biomedical Sciences
Baltimore College of Dental Surgery
Dental School
University of Maryland
Baltimore, Maryland
JAMES L. HIATT, PhD

Professor Emeritus
Department of Biomedical Sciences
Baltimore College of Dental Surgery
Dental School
University of Maryland
Baltimore, Maryland
1600 John F. Kennedy Blvd.
Ste 1800
Philadelphia, PA 19103-2899
COLOR TEXTBOOK OF HISTOLOGY ISBN-13: 978-1-4160-2945-8

ISBN-10: 1-4160-2945-1
International Edition ISBN-13: 978-0-8089-2356-5
ISBN-10: 0-8089-2356-0
Copyright © 2007, 2001, 1997 by Saunders, an imprint of Elsevier Inc.
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Notice
Neither the Publisher nor the Authors assume any responsibility for any loss or injury and/or damage
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The Publisher
Library of Congress Control Number: 2006930093
Cover: Top image used with permission of Nature Publishing Group; from Smith CJ, Grigorieff N, Pearse
BM: Clathrin coats at 21 Å resolution: A cellular assembly designed to recycle multiple membrane
receptors. EMBO J 17:4943–4953, 1998. Middle image courtesy of Alexey Khodjakov, Wadsworth Center,
Albany, New York. Bottom image courtesy of Drs. Gartner and Hiatt.
Reg. ISBN-13: 978-1-4160-2945-8

Reg. ISBN-10: 1-4160-2945-1
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Last digit is the print number: 9 8 7 6 5 4 3 2

To my wife Roseann,
my daughter Jennifer,
and my mother Mary
LPG
To my grandchildren
Nathan David,
James Mallary,
Hanna Elisabeth,
Alexandra Renate,
Eric James,
and Elise Victoria
JLH
䡲䡲䡲
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䡲䡲䡲
Preface
Once again, we are gratified to release a new edition of permits the purchaser of this book to view the entire
a histology textbook that is well established not only in text plus all images online. The website also provides
its original language but also in several other languages. seamless integration to related content in other Elsevier
The place of histology has changed as the biological sci- books that the reader has purchased, if that book is a
ences have progressed in the last half of the 20th century. title that has been selected to be a Student Consult title.
It evolved from the purely descriptive science of micro- As in the first two editions, we have conveyed infor-
scopic anatomy to its current position as the linchpin mation as efficiently as possible. Tables and figures
between functional anatomy and molecular and cell summarize complex topics to promote acquisition of
biology. knowledge. The text is punctuated by bulleted sections
This third edition, coming only a few short years after that not only organize important aspects of functional
the second edition reached bookshelves, has been histology but also alert the reader to their significance.
revised to reflect new information in cell and molecu- Important terms appear in bold type to permit rapid
lar biology that pertains to histology. While incorporat- review as the student prepares for examinations. Clini-
ing much new material we were mindful of the time cal Correlation boxes illustrate the relevance of histol-
constraints that students face due to an ever-expanding ogy to students of the health professions. We believe
curriculum and an exponentially increasing information that these features emphasize an important tenet of
glut. We labored diligently to maintain readability and modern day histology—that structure and function are
brevity. We revised many illustrations and added detail intimately related.
to figure legends. Although we have made every effort to present a
The most visible, and we believe most valuable, addi- complete and accurate account of the subject matter,
tion for the student to this revision is the inclusion of a we realize that there are omissions and errors in any
CD-ROM containing 21 brief PowerPoint presenta- undertaking of this magnitude. Therefore, we continue
tions that give overviews of each chapter. They offer the to encourage and welcome suggestions, advice, and crit-
student keys by which he or she can quickly form a basic icism that will facilitate the improvement of this text.
understanding of the material.
The third edition of this textbook is bundled not only Leslie P. Gartner
with the CD but also with access to Student Consult, a James L. Hiatt
website developed by Elsevier publishing company that lgartner@umaryland.edu
vii
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Acknowledgments
We would like to thank the following individuals for the Histology is a visual subject; therefore, excellent
help and support they provided in the preparation of graphic illustrations are imperative. For that we are
this book. At the University of Maryland, special thanks indebted to Todd Smith for his careful attention to
go to Ms. Lyndsay C. Bare, a third-year dental student, detail in revising and creating new illustrations. We also
for her many suggestions that helped to improve the thank our many colleagues from around the world and
presentation of the material. their publishers who generously permitted us to borrow
We are truly grateful to Dr. Robert A. Bloodgood illustrative materials.
for providing us with an extensive list of sugges- Finally, our thanks go to the project team at Elsevier
tions for improvement. We also wish to thank Drs. for all their help, namely Inta Ozols, Jacqueline Mahon,
Felipe A. Roberio and Joel Schechter for their helpful and Joan Nikelsky.
comments on topics related to their fields of expertise.
ix
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1 䡲䡲䡲
Introduction to Histology
and Basic Histological
Techniques
Histology is that branch of anatomy that studies tissues is responsible for the kidney’s ability to perform its func-
of animals and plants. This textbook, however, discusses tion. Alterations of the kidney’s structure are responsi-
only animal, and more specifically human, tissues. In its ble for a great number of life-threatening conditions.
broader aspect, the word histology is used as if it were The remainder of this chapter discusses the methods
a synonym for microscopic anatomy, because its subject used by histologists to study the microscopic anatomy
matter encompasses not only the microscopic structure of the body.
of tissues but also that of the cell, organs, and organ
systems.
The body is composed of cells, intercellular matrix, LIGHT MICROSCOPY
and a fluid substance, extracellular fluid (tissue fluid), Tissue Preparation
which bathes these components. Extracellular fluid,
which is derived from plasma of blood, carries nutrients, Steps required in preparing tissues for light microscopy
oxygen, and signaling molecules to cells of the body. include (1) fixation, (2) dehydration and clearing, (3)
Conversely, signaling molecules, waste products, and embedding, (4) sectioning, and (5) mounting and
carbon dioxide released by cells of the body reach blood staining the sections.
and lymph vessels by way of the extracellular fluid.
Extracellular fluid and much of the intercellular matrix Various techniques have been developed to prepare
are not visible in routine histological preparations, yet tissues for study so that they closely resemble their
their invisible presence must be appreciated by the natural, living state. The steps involved are fixation,
student of histology. dehydration and clearing, embedding in a suitable
The subject of histology no longer merely deals with medium, sectioning into thin slices to permit viewing by
the structure of the body; it also concerns itself with the transillumination, mounting sections onto a surface for
body’s function. In fact, histology has a direct relation- ease of handling, and staining them so that the various
ship to other disciplines and is essential for their under- tissue and cell components may be differentiated.
standing. This textbook, therefore, intertwines the
disciplines of cell biology, biochemistry, physiology,
embryology, gross anatomy, and, as appropriate, pathol-
Fixation
ogy. Students will recognize the importance of this Fixation refers to treatment of the tissue with chemical
subject as they refer to the text later in their careers. An agents that not only retard the alterations of tissue sub-
excellent example of this relationship will be evident sequent to death (or after removal from the body) but
when the reader learns about the histology of the kidney also maintain its normal architecture. The most
and realizes it is the intricate and almost sublime struc- common fixative agents used in light microscopy are
ture of that organ (down to the molecular level) that neutral buffered formalin and Bouin’s fluid. Both of
1
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2 䡲䡲䡲 Chapter 1 䡲 Introduction to Histology and Basic Histological Techniques
these substances cross-link proteins, thus maintaining a rehydrated and stained. After staining, the section is
lifelike image of the tissue. again dehydrated so that the coverslip may be perma-
nently affixed by the use of a suitable mounting
Dehydration and Clearing medium. The coverslip not only protects the tissue from
damage but also is necessary for viewing the section
Because a large fraction of the tissue is composed of
with the microscope.
water, a graded series of alcohol baths, beginning with
Various types of stains have been developed for visu-
50% alcohol and progressing in graded steps to 100%
alization of the many components of cells and tissues;
alcohol, are used to remove the water (dehydration).
they may be grouped into three classes:
The tissue is then treated with xylene, a chemical that
is miscible with melted paraffin. This process is known 䡲 Stains that differentiate between acidic and basic
as clearing, because the tissue becomes transparent in components of the cell
xylene. 䡲 Specialized stains that differentiate the fibrous com-
ponents of the extracellular matrix
Embedding 䡲 Metallic salts that precipitate on tissues, forming
metal deposits on them
In order to distinguish the overlapping cells in a tissue
and the extracellular matrix from one another, the his- The most commonly used stains in histology are
tologist must embed the tissues in a proper medium and hematoxylin and eosin (H&E). Hematoxylin is a base
then slice them into thin sections. For light microscopy, that preferentially colors the acidic components of the
the usual embedding medium is paraffin. The tissue is cell a bluish tint. Because the most acidic components
placed in a suitable container of melted paraffin until it are deoxyribonucleic acid (DNA) and ribonucleic acid
is completely infiltrated. Once the tissue is infiltrated (RNA), the nucleus and regions of the cytoplasm rich
with paraffin, it is placed into a small receptacle, in ribosomes stain dark blue; these components are
covered with melted paraffin, and allowed to harden, referred to as basophilic. Eosin is an acid that dyes the
forming a paraffin block containing the tissue. basic components of the cell a pinkish color. Because
many cytoplasmic constituents have a basic pH, regions
Sectioning of the cytoplasm stain pink; these elements are said
to be acidophilic. Many other stains are also used
After the blocks of tissue are trimmed of excess embed- in preparation of specimens for histological study
ding material, they are mounted for sectioning. This (Table 1-1).
task is performed using a microtome, a machine Molecules of some stains, such as toluidine blue,
equipped with a blade and an arm that advances the polymerize with each other when exposed to high con-
tissue block in specific equal increments. For light centrations of polyanions in tissue. These aggregates
microscopy, the thickness of each section is about 5 to differ in color from their individual molecules. For
10 µm. example, toluidine blue stains tissues blue except for
Sectioning also can be performed on specimens those that are rich in polyanions (e.g., cartilage matrix
frozen either in liquid nitrogen or on the rapid-freeze
and granules of mast cells), which stain purple. A tissue
bar of a cryostat. These sections are mounted by the use
or cell component that stains purple with this stain is
of a quick-freezing mounting medium and sectioned at
said to be metachromatic, and toluidine blue is said to
subzero temperatures by means of a pre-cooled steel
exhibit metachromasia.
blade. The sections are placed on pre-cooled glass
slides, permitted to come to room temperature, and
stained with specific dyes (or treated for histochemical Light Microscopes
or immunocytochemical studies).
Compound microscopes are composed of a specific
Mounting and Staining arrangement of lenses that permit a high magnification
and good resolution of the tissues being viewed.
Paraffin sections are mounted (placed) on glass slides
and then stained by water-soluble stains that permit dif- The present-day light microscope uses a specific
ferentiation of the various cellular components. arrangement of groups of lenses to magnify an image
The sections for conventional light microscopy, cut (Fig. 1-1). Because this instrument uses more than just
by stainless steel blades, are mounted on adhesive- a single lens, it is known as a compound microscope.
coated glass slides. Because many tissue constituents The light source is an electric bulb with a tungsten fil-
have approximately the same optical densities, they ament whose light is gathered into a focused beam by
must be stained for light microscopy, usually with water- the condenser lens.
soluble stains. Therefore, the paraffin must first be The light beam is located below and is focused on
removed from the section, after which the tissue is the specimen. Light passing through the specimen
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Chapter 1 䡲 Introduction to Histology and Basic Histological Techniques ■ ■ ■ 3
objects are separated by a distance. The quality of a lens

Table 1–1 Common Histological Stains depends on how close its resolution approaches the the-
and Reactions oretical limit of 0.25 µm, a restriction that is determined
by the wavelength of visible light.
Reagent Result There are several types of light microscopes, distin-
guished by the type of light used as a light source and
Hematoxylin Blue: nucleus; acidic regions the manner in which they use the light source.
of the cytoplasm; cartilage However, most students of histology are required to rec-
matrix
ognize only images obtained from compound light
Eosin Pink: basic regions of the microscopy, transmission electron microscopy, and
cytoplasm; collagen fibers scanning electron microscopy; therefore, the other
types of light microscopes are not discussed.
Masson’s trichrome Dark blue: nuclei
Red: muscle, keratin, cytoplasm
Light blue: mucinogen, Digital Imaging Techniques
collagen
Digital imaging techniques employ computer technology
Orcein’s elastic stain Brown: elastic fibers to capture and manipulate histologic images.
Weigert’s elastic stain Blue: elastic fibers The advent of computer technology has provided a
means of capturing images digitally, without the use of
Silver stain Black: reticular fibers
film. Although this method of image capturing cannot
Iron hematoxylin Black: striations of muscle, yet compete with film technology, it has several advan-
nuclei, erythrocytes tages that make it a valuable tool:
Periodic acid–Schiff Magenta: glycogen and 䡲 Immediate visualization of the acquired image
carbohydrate-rich molecules 䡲 Digital modification of the image
䡲 Capability of enhancing the image by the use of com-
Wright’s and Giemsa Pink: erythrocytes, eosinophil mercially available software
stains (used for granules
differential staining Blue: cytoplasm of monocytes In addition, because these images are stored in a
of blood cells) and lymphocytes digital format, hundreds of them may be archived on
a single CD-ROM disk and their retrieval is almost
instantaneous. Finally, their digital format permits the
electronic transmission of these images by e-mail or dis-
tribution via the Internet.
enters one of the objective lenses; these lenses sit on
a movable turret located just above the specimen. Interpretation of
Usually four objective lenses are available on a single Microscopic Sections
turret, providing low, medium, high, and oil magnifica-
tions. Generally, in most microscopes the first three One of the most difficult, frustrating, and time-
lenses magnify 4, 10, and 40 times, respectively, and are consuming skills needed in histology is interpreting
used without oil; the oil lens magnifies the image 100 what a two-dimensional section looks like in three
times. dimensions. If you imagine a coiled garden hose and
The image from the objective lens is gathered and then take thin sections from that hose, you will see that
further magnified by the ocular lens of the eyepiece. the three-dimensional object is not necessarily dis-
This lens usually magnifies the image by a factor of 10— cerned from any one of the two-dimensional sections
for total magnifications of 40, 100, 400, and 1000—and (Fig. 1-2). However, by viewing all of the sections drawn
focuses the resulting image on the retina of the eye. from the coiled tube, you can mentally reconstruct the
Focusing of the image is performed by the use of correct three-dimensional image.
knurled knobs that move the objective lenses up or
down above the specimen. The coarse-focus knob Advanced Visualization Procedures
moves it in larger increments than the fine-focus knob
does. It is interesting that the image projected on the Histochemistry
retina is reversed from right to left and is upside down.
Histochemistry is a method of staining tissue that
The quality of an image depends not only on the
provides information about the presence and location of
capability of a lens to magnify but also on its resolu-
intracellular and extracellular macromolecules.
tion—the ability of the lens to show that two distinct
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Image in eye
Cathode
Anode
Ocular lens
Anode
Condenser
lens
Condenser
lens
Specimen Scanning
coil
Scanning
beam
Objective
lens
Specimen Electron Electronic
detector amplifier
Condenser Viewing window

lens
Projection
lens
Lamp Mirror Image on Specimen Image on Television

viewing screen viewing screen screen
Light microscope Transmission electron Scanning electron
microscope microscope
Figure 1–1 Comparison of light, transmission electron, and scanning electron microscopes.
Cross
section Longitudinal
section
Oblique
section
Figure 1–2 Histology requires

a mental reconstruction of two-
dimensional images into the three-
dimensional solid from which they
were sectioned. Here, a curved tube
Diagram showing the different is sectioned in various planes to illus-
appearances of sections cut through
trate the relationship between a series
a curved tube at different levels
of two-dimensional sections and their
three-dimensional structure.
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Add fluoresceinated
anti-antibody
Figure 1–3 Direct and indirect Fluoresceinated
methods of immunocytochemistry. antibody
Left, An antibody against the antigen Antibody
was labeled with a fluorescent dye and
viewed with a fluorescent microscope. Antigen Antigen
The fluorescence occurs only over the
location of the antibody. Right, Fluo-
rescent-labeled antibodies are pre- Tissue section
pared against an antibody that reacts
with a particular antigen. When
viewed with fluorescent microscopy, Wash
the region of fluorescence represents
the location of the antibody. Direct Indirect
Specific chemical constituents of tissues and cells can There are two methods of antibody labeling: direct
be localized by the methods of histochemistry and cyto- and indirect. In the direct method (Fig. 1-3) the
chemistry. These methods capitalize on the enzyme antibody against the macromolecule is labeled with
activity, chemical reactivity, and other physicochemical a fluorescent dye. The antibody is then permitted to
phenomena associated with the constituent of interest. react with the macromolecule, and the resultant
Reactions of interest are monitored by the formation of complex may be viewed with a fluorescent microscope
an insoluble precipitate that takes on a certain color. (Fig. 1-4).
Frequently, histochemistry is performed on frozen In the indirect method (see Fig. 1-3) a fluorescent-
tissues and can be applied to both light and electron labeled antibody is prepared against the primary anti-
microscopy. body specific for the macromolecule of interest. Once
A common histochemical reaction uses the periodic the primary antibody has reacted with the antigen, the
acid–Schiff (PAS) reagent, which forms a magenta pre- preparation is washed to remove unbound primary anti-
cipitate with molecules rich in glycogen and carbohy- body; the labeled antibody is then added and reacts with
drate-rich molecules. To ensure that the reaction is the original antigen-antibody complex, forming a sec-
specific for glycogen, consecutive sections are treated ondary complex visible by fluorescent microscopy (Fig.
with amylase. Thus, sections not treated with amylase 1-5). The indirect method is more sensitive than the
display a magenta deposit, whereas amylase-treated sec- direct method because numerous labeled anti-antibod-
tions display a lack of staining in the same region. ies bind to the primary antibody, making them easier to
Although enzymes can be localized by histochemical visualize. In addition, the indirect method does not
procedures, the product of enzymatic reaction rather require labeling of the primary antibody, which often is
than the enzyme itself is visualized. The reagent is available only in limited quantities.
designed so that the product precipitates at the site of Immunocytochemistry can be used with specimens
the reaction and is visible either as a metallic or a for electron microscopy by labeling the antibody with
colored deposit. ferritin, an electron-dense molecule, instead of with a
fluorescent dye. Ferritin labeling can be applied in both
Immunocytochemistry the direct and indirect methods.
Immunocytochemistry uses fluoresceinated antibodies Autoradiography
and anti-antibodies to provide more precise intracellular
and extracellular localization of macromolecules than is Autoradiography is a method that uses the
possible with histochemistry. incorporation of radioactive isotopes into
macromolecules, which are then visualized by the use of
Although histochemical procedures permit relatively an overlay of film emulsion.
good localization of some enzymes and macromolecules
in cells and tissues, more precise localization can be Autoradiography (or radioautography) is a particularly
achieved by the use of immunocytochemistry. This pro- useful method for localizing and investigating a specific
cedure requires developing an antibody against the par- temporal sequence of events. The method requires
ticular macromolecule to be localized and labeling the incorporation of a radioactive isotope—most commonly
antibody with a fluorescent dye such as fluorescein or tritium (3H)—into the compound being studied (Fig.
rhodamine. 1-6). An example is the use of tritiated amino acid to
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Figure 1–4 Example of direct immunocytochemistry. Cultured

neurons from rat superior cervical ganglion were immunostained with
Figure 1–5 Indirect immunocytochemistry. Fluorescent anti-
bodies were prepared against primary antibodies against type IV col-
fluorescent-labeled antibody specific for the insulin receptor. The
lagen, to demonstrate the presence of a continuous basal lamina at
bright areas correspond to sites where the antibody has bound to
the interface between malignant clusters of cells and the surrounding
insulin receptors. The staining pattern indicates that receptors are
connective tissue. (From Kopf-Maier P, Schroter-Kermani C: Distri-
located throughout the cytoplasm of the soma and processes but
bution of type VII collagen in xenografted human carcinomas. Cell
are missing from the nucleus. (From James S, Patel N, Thomas P,
Tissue Res 272:395-405, 1993.)
Burnstock G: Immunocytochemical localisation of insulin receptors
on rat superior cervical ganglion neurons in dissociated cell culture.
J Anat 182:95-100, 1993.)
scope. The silver grains are positioned over the regions

of the specimen that incorporated the radioactive
track the synthesis and packaging of proteins. After the compound.
radiolabeled compound is injected into an animal, tissue Autoradiography has been used to follow the time
specimens are taken at selected time intervals. The course of incorporation of tritiated proline into the
tissue is processed as usual and placed on a glass slide; basement membrane underlying endodermal cells of
however, instead of the tissue being sealed with a cov- the yolk sac (see Fig. 1-6). An adaptation of the autora-
erslip, a thin layer of photographic emulsion is placed diography method of electron microscopy has been
over it. The tissue is placed in a dark box for a few used to show that the tritiated proline first appears in
days or weeks, during which time particles emitted from the cytosol of the endodermal cells, then travels to the
the radioactive isotope expose the emulsion over the rough endoplasmic reticulum, then to the Golgi appa-
cell sites where the isotope is located. The emulsion ratus, then into vesicles, and finally into the extracellu-
is developed and fixed by means of photographic lar matrix (Fig. 1-7). In this manner, the sequence of
techniques, and small silver grains are left over the events occurring in the synthesis of type IV collagen—
exposed portions of the emulsion. The specimen then the main protein in the lamina densa of the basal
is sealed with a coverslip and viewed with a light micro- lamina—was visually demonstrated.
Ch001-X2945.qxd 12/8/06 3:17 PM Page 7
In confocal microscopy, a laser beam passes through a

dichroic mirror to be focused on the specimen by two
motorized mirrors whose movements are computer-
controlled to scan the beam along the sample. Because
the sample is treated by fluorescent dyes, the impinging
laser beam causes the emission of light from the dyes. The
emitted light follows the same path taken by the laser
A beam, but in the opposite direction, and the dichroic
mirror focuses this emitted light on a pinhole in a plate. A
photomultiplier tube collects the emitted light passing
through the pinhole while the plate containing the
pinhole blocks all the extraneous light that would create a
fuzzy image. It must be remembered that the light
emerging from the pinhole at any particular moment in
time represents a single point in the sample, and as the
laser beam scans across the sample additional individual
B points are collected by the photomultiplier tube. All of
these points gathered by the photomultiplier tube are
then compiled by a computer, forming a composite image
one pixel at a time (Fig. 1-8). Since the depth of field is
very small (only a thin layer of the sample is observed at
any one scan), the scanning may be repeated at deeper
and deeper levels in the sample, allowing the compilation
of a very good three-dimensional image (Fig. 1-9).
C
ELECTRON MICROSCOPY
The use of electrons as a light source in electron

microscopy permits the achievement of much greater
magnification and resolution than that realized by light
microscopy.
In light microscopes, optical lenses focus visible light

D
(a beam of photons). In electron microscopes, electro-
magnets serve the function of focusing a beam of elec-
trons. Because the wavelength of an electron beam is
Figure 1–6 Autoradiography. Light microscopic examination
of tritiated proline incorporation into the basement membrane as a much shorter than that of visible light, electron micro-
function of time subsequent to tritiated proline injection (scale scopes theoretically are capable of resolving two objects
bar = 10 µ). In light micrographs A to C, the silver grains (black dots) separated by 0.005 nm. In practice, however, the resolu-
are localized mostly in the endodermal cells; after 8 hours (light tion of the transmission electron microscope is about
micrograph D), however, the silver grains are also localized in the
basement membrane. The presence of silver grains indicates the loca-
0.2 nm, which is still more than a thousand-fold greater
tion of tritiated proline. (From Mazariegos MR, Leblond CP, van der than the resolution of the compound light microscope.
Rest M: Radioautographic tracing of 3H-proline in endodermal cells The resolution of the scanning electron microscope is
of the parietal yolk sac as an indicator of the biogenesis of basement about 10 nm, considerably less than that of the transmis-
membrane components. Am J Anat 179:79-93, 1987.) sion electron microscope. Moreover, modern electron
microscopes can magnify an object as much as 150,000
times; this magnification is powerful enough to see indi-
CONFOCAL MICROSCOPY vidual macromolecules such as DNA and myosin.
Confocal microscopy relies on a laser beam for the light Transmission Electron Microscopy
source and a pinhole screen to eliminate undesirable
reflected light from being observed. Thus, the only light Transmission electron microscopy (TEM) uses much
that can be observed is that which is located at the focal thinner sections compared with light microscopy and
point of the objective lens, making the pinhole requires heavy metal precipitation techniques rather
conjugate of the focal point. than water-soluble stains to stain tissues.
Ch001-X2945.qxd 12/8/06 3:17 PM Page 8
Figure 1–7 Autoradiography. In this

electron micrograph of a yolk sac endodermal
cell, silver grains (similar to those in Figure
1-6), representing the presence of tritiated
proline, are evident overlying the rough
endoplasmic reticulum (RER), Golgi appara-
tus (G), and secretory granules (SG). Type IV
collagen, which is rich in proline, is synthe-
sized in endodermal cells and released into
the basement membrane. The tritiated
proline is most concentrated in organelles
involved in protein synthesis. M, mitochon-
dria; N, nucleus. (From Mazariegos MR,
Leblond CP, van der Rest M: Radioauto-
graphic tracing of 3H-proline in endodermal
cells of the parietal yolk sac as an indicator of
the biogenesis of basement membrane com-
ponents. Am J Anat 179:79-93, 1987.)
Scanning Pinhole Photomultiplier

mirror aperture detector
Scanning
mirror
Pinhole
aperture
Laser with
laser light
Specimen
Figure 1–8 Confocal microscopy. A laser beam passes through a dichroic mirror to be focused on the specimen by two motorized mirrors
whose movements are computer-controlled to scan the beam along the sample. The light emerging from the pinhole at any particular moment
in time represents a single point in the sample, and as the laser beam scans across the sample additional individual points are collected by the
photomultiplier tube. All the points are computer-assembled to produce the final confocal image.
Ch001-X2945.qxd 12/8/06 3:17 PM Page 9
electrons that pass through the hole in the anode have

high kinetic energy.
The electron beam is focused on the specimen by
the use of electromagnets, which are analogous to the
condenser lens of a light microscope (see Fig. 1-1).
Because the tissue is stained with heavy metals that
precipitate preferentially on lipid membranes, the
electrons lose some of their kinetic energy as they
interact with the tissue. The heavier the metal encoun-
tered by an electron, the less energy the electron will
retain.
The electrons leaving the specimen are subjected to
the electromagnetic fields of several additional electro-
magnets, which focus the beam on a fluorescent plate.
As the electrons hit the fluorescent plate, their kinetic
energy is converted into points of light, whose intensity
is a direct function of the electron’s kinetic energy. You
can make a permanent record of the resultant image by
substituting an electron-sensitive film in place of the
fluorescent plate and by producing a negative from
which a black and white photomicrograph can be
printed.
Figure 1–9 Confocal image of a metaphase Kangaroo rat cell
(PtK2) stained with FITC-phalloidin for F-actin (green) and propid-
ium iodide for chromosomes (red). (Courtesy of Dr. Matthew Schi- Freeze-Fracture Technique
bler, University of California Brain Research Institute, Los Angeles,
California.) The macromolecular structure of the internal aspects
of membranes is revealed by the freeze-fracture tech-
nique (Fig. 1-10). Quick-frozen specimens that have
been treated with cryopreservatives do not develop
Preparation of tissue specimens for TEM involves the ice crystals during the freezing process; hence, the
same basic steps as in light microscopy. Special fixa- tissue does not suffer mechanical damage. As the
tives have been developed for use with transmission frozen specimen is hit by a super-cooled razor blade,
light microscopy, because the greater resolving power it fractures along cleavage planes, which are regions of
of the electron microscope requires finer and more least molecular bonding; in cells, fracture frequently
specific cross-linking of proteins. These fixatives, occurs between the inner and outer leaflets of
which include buffered solutions of glutaraldehyde, membranes.
paraformaldehyde, osmium tetroxide, and potas- The fracture face is coated at an angle by evaporated
sium permanganate, not only preserve fine structural platinum and carbon, forming accumulations of plat-
details but also act as electron-dense stains, which inum on one side of a projection and no accumulation
permit observation of the tissue with the electron on the opposite side next to the projection, thus gener-
beam. ating a replica of the surface. The tissue is then digested
Because these fixatives penetrate fresh tissues even away, and the replica is examined by TEM. This method
less than fixatives for light microscopy, relatively small allows display of the transmembrane proteins of cellu-
pieces of tissues are infiltrated in large volumes of fixa- lar membranes.
tives. Tissue blocks for TEM are usually no larger than
1 mm3. Suitable embedding media have been devel-
oped, such as epoxy resin, so that plastic-embedded Scanning Electron Microscopy
tissues may be cut into extremely thin (ultra-thin) sec-
tions (25 to 100 nm) that do not absorb the beam of Scanning electron microscopy (SEM) provides a three-
electrons. dimensional image of the specimen.
Electron beams are produced in an evacuated
chamber by heating a tungsten filament, the cathode. Unlike TEM, SEM is used to view the surface of a
The electrons then are attracted to the positively solid specimen. Using this technique, you can view a
charged anode, a donut-shaped metal plate with a three-dimensional image of the object. Usually, the
central hole. With a charge differential of about 60,000 object to be viewed is prepared in a special manner
volts placed between the cathode and the anode, the that permits a thin layer of heavy metal, such as gold
Ch001-X2945.qxd 12/8/06 3:17 PM Page 10
Figure 1-10 Cytochemistry and freeze-

fracture. Fracture-label replica of an acinar cell
of the rat pancreas. N-acetyl-D-galactosamine
residues were localized by the use of Helix
pomatia lectin-gold complex, which appears as
black dots in the image. Arrowheads indicate
cell membranes. The nucleus (Nu) appears as a
depression, the rough endoplasmic reticulum
(RER) as parallel lines, and secretory granules as
small elevations or depressions. The elevations
(G) represent the E-face half, and the depressions
(asterisks) represent the P-face of the membrane
of the secretory granule. m, mitochondria. (From
Kan FWK, Bendayan M: Topographical and
planar distribution of Helix pomatia lectin-
binding glycoconjugates in secretory granules and
plasma membrane of pancreatic acinar cells of the
rat: Demonstration of membrane heterogeneity.
Am J Anat 185:165-176, 1989.)
or palladium, to be deposited on the specimen’s captured by electron detectors that are interpreted,
surface. collated, and displayed on a monitor as a three-
As a beam of electrons scans the surface of the dimensional image (see Fig. 1-1). You can make the
object, some (backscatter electrons) are reflected and image permanent either by photographing it or digitiz-
others (secondary electrons) are ejected from the heavy ing it for storage in a computer.
metal coat. The backscatter and secondary electrons are
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2 䡲䡲䡲
Cytoplasm
Cells are the basic functional units of complex organ- constituents of the organelles, cytoskeleton, and
isms. Cells that are related or are similar to each other inclusions.
as well as cells that function in a particular manner or
serve a common purpose are grouped together to form
tissues. The four basic tissues (epithelium, connective ORGANELLES
tissues, muscle, and nervous tissue) that compose the
body are assembled to form organs which, in turn, are Organelles are metabolically active cellular structures
collected into organ systems. The task of each organ that execute specific functions.
system is specific, in that it performs a collection of
associated functions, such as digestion, reproduction, Although some organelles were discovered by light
and respiration. microscopists, their structure and function were not
Although the human body is composed of more than elucidated until the advent of electron microscopy, sep-
200 different types of cells, each performing a different aration techniques, and sensitive biochemical and his-
function, all cells possess certain unifying characteris- tochemical procedures. As a result of the application of
tics and thus can be described in general terms. Every these methods, it is now known that the membranes of
cell is surrounded by a bilipid plasma membrane, pos- organelles are composed of a phospholipid bilayer,
sesses organelles that permit it to discharge its func- which not only partitions the cell into compartments but
tions, synthesizes macromolecules for its own use or for also provides large surface areas for the biochemical
export, produces energy, and is capable of communi- reactions essential for the maintenance of life.
cating with other cells (Figs. 2-1 to 2-4).
Protoplasm, the living substance of the cell, is sub- Cell Membrane
divided into two compartments: cytoplasm, extending
from the plasma membrane to the nuclear envelope, The cell membrane forms a selectively permeable barrier
and karyoplasm, the substance forming the contents between the cytoplasm and the external milieu.
of the nucleus. The cytoplasm is detailed in this chapter;
Each cell is bounded by a cell membrane (also known
the nucleus is discussed in Chapter 3.
as the plasma membrane or plasmalemma) that
The bulk of the cytoplasm is water, in which various
functions in:
inorganic and organic chemicals are dissolved and/or
suspended. This fluid suspension is called the cytosol. 䡲 Maintaining the structural integrity of the cell
The cytosol contains organelles, metabolically active 䡲 Controlling movements of substances in and out of
structures that perform distinctive functions (Figs. 2-5 the cell (selective permeability)
and 2-6). Additionally, the shapes of cells, their ability 䡲 Regulating cell–cell interactions
to move, and the intracellular pathways within cells are 䡲 Recognizing, via receptors, antigens and foreign cells
maintained by a system of tubules and filaments known as well as altered cells
as the cytoskeleton. 䡲 Acting as an interface between the cytoplasm and the
Finally, cells contain inclusions, which consist of external milieu
metabolic by-products, storage forms of various nutri- 䡲 Establishing transport systems for specific molecules
ents, and inert crystals and pigments. The following 䡲 Transducing extracellular physical or chemical signals
topics discuss the structure and functions of the major into intracellular events.
11
Ch002-X2945.qxd 12/8/06 3:19 PM Page 12
12 䡲䡲䡲 Chapter 2 䡲 Cytoplasm
L
N
Figure 2–1 Light micrograph

of typical cells from the renal cortex
of a monkey (×975). Note the blue
nucleus (N) and the pink cytoplasm.
The boundaries of individual cells
may be easily distinguished. The
white area in the middle of the field
is the lumen (L) of a collecting
tubule.
D
A
PC
Figure 2-2 Purkinje cells (PC)
from the cerebellum of a monkey
(×540). Observe the long, branching
processes, dendrites (D), and axon
(A), of these cells. The nucleus is
located in the widest portion of the
cell.
Cell membranes are not visible with the light micro- Molecular Composition
scope. In electron micrographs, the plasmalemma is
about 7.5 nm thick and appears as a trilaminar structure The plasmalemma is composed of a phospholipid bilayer
of two thin, dense lines with an intervening light area. and associated integral and peripheral proteins.
Each layer is about 2.5 nm in width, and the entire
structure is known as the unit membrane (Fig. 2-7). Each leaflet is composed of a single layer of phospho-
The inner (cytoplasmic) dense line is its inner leaflet; lipids and associated proteins, usually in a 1:1 propor-
the outer dense line is its outer leaflet. tion by weight. In certain cases, such as myelin sheaths,
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Chapter 2 䡲 Cytoplasm ■ ■ ■ 13
however, the lipid component outweighs the protein

component by a ratio of 4 : 1. The two leaflets, com-
posing a lipid bilayer in which proteins are sus-
pended, constitute the basic structure of all membranes
of the cell (Fig. 2-8).
Ng Each phospholipid molecule of the lipid bilayer is
composed of a polar head, located at the surface of the
membrane, and two long nonpolar fatty acyl tails pro-
jecting into the center of the plasmalemma (see Fig. 2-
N
8). The nonpolar fatty acyl tails of the two layers face
each other within the membrane and form weak non-
covalent bonds with each other, holding the bilayer
together. Because the phospholipid molecule is com-
posed of a hydrophilic head and a hydrophobic tail,
the molecule is said to be amphipathic.
N The polar heads are composed of glycerol, to which
a positively charged nitrogenous group is attached by a
negatively charged phosphate group. The two fatty
acyl tails, only one of which is usually saturated, are cova-
lently bound to glycerol. Other amphipathic molecules,
such as glycolipids and cholesterol, are also present in
the cell membrane. The unsaturated fatty acyl mole-
cules increase membrane fluidity, whereas cholesterol
Figure 2–3 Motor neurons from the human spinal cord (×540). decreases it (although cholesterol concentrations much
These nerve cells have numerous processes (axons and dendrites). lower than normal increase membrane fluidity).
The centrally placed nucleus and the single large nucleolus are clearly The protein components of the plasmalemma either
visible. The Nissl bodies (N; rough endoplasmic reticulum) are the
most conspicuous features of the cytoplasm. Observe also the small span the entire lipid bilayer as integral proteins or are
nuclei of the neuroglia cells (Ng). attached to the cytoplasmic aspect (and at times the
extracellular aspect) of the lipid bilayer as peripheral
proteins. Because most integral proteins pass through
Ma
G L
Figure 2–4 Goblet cells (G)
from the monkey colon (×540).
Some cells, such as goblet cells, spe-
cialize in secreting materials. These
cells accumulate mucinogen, which
occupies much of the cells’ volume,
and then release it into the lumen
(L) of the intestine. During the pro-
cessing of the tissue, the mucinogen
is extracted, leaving behind empty
spaces. Observe the presence of a
mast cell (Ma).
Ch002-X2945.qxd 12/8/06 3:19 PM Page 14
Centrioles
Secretion granule
Microtubules
Microfilaments
Nucleolus
Microvilli Rough
endoplasmic
reticulum
Plasma
membrane Golgi
apparatus
Smooth
endoplasmic
reticulum
Nuclear
envelope
Mitochondrion
Lysosome
Figure 2–5 Three-dimensional illustration of an idealized cell, as visualized by transmission electron microscopy. Various organelles and
cytoskeletal elements are displayed.
the thickness of the membrane, they are also referred lipids, this model is referred to as the fluid mosaic
to as transmembrane proteins. Those regions of model of membrane structure. However, the integral
transmembrane proteins that project into the cytoplasm proteins frequently possess only limited mobility, espe-
or the extracellular space are composed of hydrophilic cially in polarized cells, in which particular regions of
amino acids, whereas the intramembrane region con- the cell serve specialized functions.
sists of hydrophobic amino acids. Transmembrane pro- Peripheral proteins do not usually form covalent
teins frequently form ion channels and carrier proteins bonds with either the integral proteins or the phospho-
that facilitate the passage of specific ions and molecules lipid components of the cell membrane. Although
across the cell membrane. they are usually located on the cytoplasmic aspect of the
Many of these transmembrane proteins are quite cell membrane, they may also be on the extracellular
long and are folded so that they make several passes surface. These proteins may form bonds either with the
through the membrane and thus are known as multi- phospholipid molecules or with the transmembrane
pass proteins. The cytoplasmic and extracytoplasmic proteins. Frequently, they are associated with the sec-
aspects of these proteins commonly possess receptor ondary messenger system of the cell (see below) or with
sites that are specific for particular signaling mole- the cytoskeletal apparatus.
cules. Once these molecules are recognized at these Using freeze-fracture techniques, you can cleave the
receptor sites, the integral proteins can alter their con- plasma membrane into its two leaflets in order to view
formation and can perform a specific function. the hydrophobic surfaces (Figs. 2-9 and 2-10). The outer
Because the same integral membrane proteins have surface of the inner leaflet is referred to as the
the ability to float like icebergs in the sea of phospho- P-face (closer to the protoplasm); the inner surface of
Ch002-X2945.qxd 12/8/06 3:19 PM Page 15
CM
RER
G
SG
Figure 2–6 Electron micro-

graph of an acinar cell from the ure-
thral gland of a mouse illustrating
the appearance of some organelles
(×11,327). CM, cell membrane; G,
Golgi apparatus; M, mitochondria;
N, nucleus; RER, rough endoplas-
mic reticulum; SG, secretory gran-
ules; U, nucleolus. (From Parr MB,
Ren HP, Kepple L, et al: Ultrastruc-
ture and morphometry of the ure-
thral glands in normal, castrated,
and testosterone-treated castrated
mice. Anat Rec 236:449-458, 1993.)

graph showing a junction between
two cells that demonstrates the
trilaminar structures of the two
cell membranes (×240,000). (From
Leeson TS, Leeson CR, Papparo AA:
Text/Atlas of Histology. Philadelphia,
WB Saunders, 1988.)
Ch002-X2945.qxd 12/8/06 3:19 PM Page 16
Extracellular space
Glycoprotein Glycolipid
Outer
leaflet
Cholesterol Inner
leaflet
Fatty acid
tails Integral
Peripheral protein
Channel
protein
Polar head
Cytoplasm
Figure 2–8 A fluid mosaic model of the cell membrane.
membrane. This coat is usually composed of carbohy-

Outer leaflet drate chains that are covalently attached to transmem-
brane proteins and/or phospholipid molecules of the
outer leaflet (see Fig. 2-8). Additionally, some of the
E-face
extracellular matrix molecules, adsorbed to the cell
surface, also contribute to its formation. Its intensity
Integral protein
and thickness vary, but it may be as thick as 50 nm on
some epithelial sheaths, such as those lining regions of
P-face
the digestive system.
Because of its numerous negatively charged sulfate
and carboxyl groups, the glycocalyx stains intensely with
Inner leaflet
lectins as well as with dyes such as ruthenium red
and Alcian blue, permitting its visualization with light
microscopy. The most important function of the glyco-
Figure 2–9 The E-face and the P-face of the cell membrane. calyx is protection of the cell from interaction with inap-
propriate proteins, from chemical injury, and from
physical injury. Other cell coat functions include
the outer leaflet is known as the E-face (closer to the cell–cell recognition and adhesion, as occurs between
extracellular space). Electron micrographs of freeze- endothelial cells and neutrophils, in blood clotting, and
fractured plasma membranes show that the integral in inflammatory responses.
proteins, visualized by shadowing replica, are more
numerous on the P-face than on the E-face (see Fig. 2-10). Membrane Transport Proteins
Glycocalyx Membrane transport proteins are of two types, channel
proteins and carrier proteins; they facilitate the
Glycocalyx, composed usually of carbohydrate chains, movement of aqueous molecules and ions across the
coats the cell surface. plasmalemma.
A fuzzy coat, referred to as the cell coat, or glycocalyx, Although the hydrophobic components of the plasma
is often evident in electron micrographs of the cell membrane limit the movement of polar molecules
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Figure 2–10 Freeze-fracture rep-

lica of a cell membrane (×168,000).
The E-face (right) is closer to the
extracellular space, and the P-face
(left) is closer to the protoplasm. Note
that the integral proteins are more
numerous on the P-face than on the
E-face side. (From Leeson TS, Leeson
CR, Papparo AA: Text/Atlas of His-
tology. Philadelphia, WB Saunders,
1988.)
across it, the presence and activities of specialized malemma. In order to form hydrophilic channels, the
transmembrane proteins facilitate the transfer of these proteins are folded so that the hydrophobic amino acids
hydrophilic molecules across this barrier. These trans- are positioned peripherally, interacting with the fatty
membrane proteins and protein complexes form acyl tails of the phospholipid molecules of the lipid
channel proteins and carrier proteins, which are bilayer, whereas the hydrophilic amino acids face
specifically concerned with the transfer of ions and inward, forming a polar inner lining for the channel.
small molecules across the plasma membrane. There are more than 100 different types of ion chan-
A few nonpolar molecules (e.g., benzene, oxygen, nels; some of these are specific for one particular ion
nitrogen) and uncharged polar molecules (e.g., water, but others permit the passage of several different ions
glycerol) can move across the cell membrane by simple and small water-soluble molecules. Although these ions
diffusion down their concentration gradients. Even and small molecules follow chemical or electrochemi-
when driven by a concentration gradient, however, cal concentration gradients for the direction of their
movement of most ions and small molecules across a passage, cells have the capability of preventing these
membrane requires the aid of membrane transport pro- substances from entering these hydrophilic tunnels by
teins, either channel proteins or carrier proteins. This means of controllable gates that block their opening.
process is known as facilitated diffusion. Because both Most channels are gated channels; only a few are
types of diffusion occur without any input of energy ungated. Gated channels are classified according to the
other than that inherent in the concentration gradient, control mechanism required to open the gate.
they represent passive transport (Fig. 2-11). By
expending energy, cells can transport ions and small mol- VOLTAGE-GATED CHANNELS
ecules against their concentration gradients. Only carrier
proteins can mediate such energy-requiring active These channels go from the closed to the open position,
transport. The several channel proteins involved in permitting the passage of ions from one side of the
facilitated diffusion are discussed first, and the more membrane to the other. The most common example is
versatile carrier proteins are considered afterward. depolarization in the transmission of nerve impulses. In
some channels, such as Na+ channels, the open position
Channel Proteins is unstable and the channel goes from an open to an
inactive position, in which the passage of the ion is
Channel proteins may be gated or ungated; they are blocked and for a short time (a few milliseconds) the
incapable of transporting substances against a gate cannot be opened again. This is the refractory
concentration gradient. period (see Chapter 9 on the nervous tissue). The
velocity of response to depolarization may also vary,
Channel proteins participate in the formation of and some of those channels are referred to as
hydrophilic pores, called ion channels, across the plas- velocity-dependent.
Ch002-X2945.qxd 12/8/06 3:19 PM Page 18
A Passive Transport
Extracellular space
Uniport Plasma
membrane
Simple diffusion Ion channel-mediated Carrier-mediated

of lipids diffusion diffusion
Facilitated diffusion
Cytoplasm
B Active Transport
Extracellular space
Symport Antiport
Figure 2–11 Types of transport.

A, Passive transport: facilitated diffu-
sion, which includes ion channel-medi-
ated diffusion and carrier-mediated
Cytoplasm Coupled transport diffusion. B, Active transport: coupled
transport.
LIGAND-GATED CHANNELS guanosine monophosphate [cGMP] in rods of the

retina) that binds to a site on the protein and, by alter-
Channels that require the binding of a ligand (signal-
ing the conformation of the protein complex, permits
ing molecule) to the channel protein to open their gate
the flow of a particular ion through the ion channel.
are known as ligand-gated channels. Unlike voltage-
gated channels, these channels remain open until the MECHANICALLY-GATED CHANNELS
ligand dissociates from the channel protein; they are
referred to as ion channel–linked receptors. Some of In these channels, an actual physical manipulation is
the ligands controlling these gates are neurotransmit- required to open the gate. An example of this mecha-
ters, whereas others are nucleotides. nism is found in the hair cells of the inner ear. These
Neurotransmitter-gated channels are usually cells, located on the basilar membrane, possess stere-
located on the postsynaptic membrane. The neuro- ocilia that are embedded in a matrix known as the tec-
transmitter binds to a specific site on the protein, alter- torial membrane. Movement of the basilar membrane
ing its molecular conformation, and thus opening the causes a shift in the positions of the hair cells, resulting
channel or gate and permitting the influx of a specific in the bending of the stereocilia. This physical distor-
ion into the cell. Some neurotransmitters are excita- tion opens the mechanically-gated channels of the
tory, whereas others are inhibitory. Excitatory neuro- stereocilia located in the inner ear, permitting the entry
transmitters (e.g., acetylcholine) facilitate depolarization; of cations into the cell, depolarizing it. This event gen-
inhibitory neurotransmitters facilitate hyperpolarization erates impulses that the brain interprets as sound.
of the membrane. G-PROTEIN–GATED ION CHANNELS
In nucleotide-gated channels, the signal molecule
is a nucleotide (e.g., cyclic adenosine monophos- Certain gated ion channels (e.g., muscarinic acetyl-
phate [cAMP] in olfactory receptors and cyclic choline receptors of cardiac muscle cells) require the
Ch002-X2945.qxd 12/8/06 3:19 PM Page 19
interaction between a receptor molecule and a G- brane, the carrier protein returns to its previous
protein complex (discussed later) with the resultant conformation.
activation of the G protein. The activated G protein As stated previously, transport by carrier proteins
then interacts with the channel protein, modulating the may be passive—along an electrochemical concentra-
ability of the channel to open or close. tion gradient—or active—against a gradient. Transport
may be uniport—a single molecule moving in one
UNGATED CHANNELS direction—or coupled—two different molecules
moving in the same (symport) or opposite (antiport)
One of the most common forms of an ungated channel
directions (see Fig. 2-11). Coupled transporters convey
is the potassium (K+) leak channel, which permits the
the solutes either simultaneously or sequentially.
movement of K+ across it and is instrumental in the cre-
ation of an electrical potential (voltage) difference
between the two sides of the cell membrane. Because PRIMARY ACTIVE TRANSPORT BY
this channel is ungated, the transit of K+ ions is not THE NA+-K+ PUMP
under the cell’s control; rather, the direction of ion Normally, the concentration of Na+ is much greater
movement reflects its concentration on the two sides of outside the cell than inside, and the concentration of K+
the membrane. is much greater inside the cell than outside. The cell
maintains this concentration differential by expending
AQUAPORINS adenosine triphosphate (ATP) to drive a coupled
Currently, twelve different types of aquaporins have antiport carrier protein known as the Na+-K+ pump.
been identified. They are a family of multipass proteins This pump transports K+ ions into and Na+ ions out of
that form channels designed for the passage of water the cell, each against a steep concentration gradient.
from one side of the cell membrane to the other. Some Because this concentration differential is essential for
of these channels are pure water transporters (e.g., the survival and normal functioning of practically every
AqpZ) whereas others transport glycerol (GlpF). These animal cell, the plasma membrane of all animal cells
aquaporins discriminate in the transport of the two possesses a large number of these pumps.
molecules by restricting the pore sizes in such a fashion The Na+-K+ pump possesses two binding sites for K+
that glycerol is too large to pass through pores of the on its extracellular aspect and three binding sites for
AqpZ channel. An interesting property of aquaporins is Na+ on its cytoplasmic aspect; thus, for every two K+
that they are completely impermeable to protons, so ions conveyed into the cell, three Na+ ions are trans-
that streams of protons cannot traverse the channel ported out of the cell.
even though they readily pass through water molecules Na+,K+-ATPase has been shown to be associated with
via the process of donor-acceptor configurations. Aqua- the Na+-K+ pump. When three Na+ ions bind on the
porins interfere with this donor-acceptor model by cytosolic aspect of the pump, ATP is hydrolyzed to
forcing the water molecules to flip-flop halfway along adenosine diphosphate (ADP) and the released phos-
the channel, so that water molecules enter the channel phate ion is used to phosphorylate the ATPase, resulting
face up (hydrogen side up and oxygen side down) and in alteration of the conformation of the pump, with the
leave the channel face down (oxygen side up and hydro- consequent transfer of Na+ ions out of the cell. Binding of
gen side down). Properly functioning aquaporins in the two K+ ions on the external aspect of the pump causes
kidney may transport as much as 20 L of water per hour, dephosphorylation of the ATPase with an ensuing return
whereas improperly functioning aquaporins may result of the carrier protein to its previous conformation, result-
in diseases such as diabetes insipidus and congenital ing in the transfer of the K+ ions into the cell.
cataracts of the eye. The constant operation of this pump reduces the
intracellular ion concentration, resulting in decreased
Carrier Proteins intracellular osmotic pressure. If the osmotic pressure
within the cell were not reduced by the Na+-K+ pump,
Carrier proteins can utilize ATP-driven transport water would enter the cell in large quantities, causing
mechanisms to ferry specific substances across the the cell to swell and eventually to succumb to osmotic
plasmalemma against a concentration gradient. lysis (i.e., burst). Hence it is through the operation of
this pump that the cell is able to regulate its osmolarity
Carrier proteins are multipass membrane transport and, consequently, its volume. Additionally, this pump
proteins that possess binding sites for specific ions or assists the K+ leak channels in the maintenance of the
molecules on both sides of the lipid bilayer. When a cell membrane potential.
solute binds to the binding site, the carrier protein Because the binding sites on the external aspect of
undergoes reversible conformational changes; as the the pump bind not only K+ but also the glycoside
molecule is released on the other side of the mem- ouabain, this glycoside inhibits the Na+-K+ pump.
Ch002-X2945.qxd 12/8/06 3:19 PM Page 20
SECONDARY ACTIVE TRANSPORT BY vicinity. Occasionally, the signaling cell is also the target
COUPLED CARRIER PROTEINS cell, resulting in a specialized type of paracrine signal-
ing known as autocrine signaling. The most wide-
The ATP-driven transport of Na+ out of the cell estab-
spread form of signaling is endocrine signaling; in this
lishes a low intracellular concentration of that ion. The case, the signaling molecule enters the bloodstream to
energy reservoir inherent in the sodium ion gradient be ferried to target cells situated at a distance from the
can be utilized by carrier proteins to transport ions or signaling cell.
other molecules against a concentration gradient. Fre-
quently, this mode of active transport is referred to as
secondary active transport, distinct from the primary Signaling Molecules
active transport, which utilizes the energy released from
Signaling molecules bind to extracellular or intracellular
the hydrolysis of ATP.
receptors to elicit a specific cellular response.
The carrier proteins that participate in secondary
active transport are either symports or antiports. As a Most signaling molecules are hydrophilic (e.g., acetyl-
Na+ ion binds to the extracellular aspect of the carrier choline) and cannot penetrate the cell membrane.
protein, another ion or small molecule (e.g., glucose) Therefore, they require receptors on the cell surface.
also binds to a region on the same aspect of the carrier Other signaling molecules are either hydrophobic, such
protein, inducing in it a conformational alteration. The as steroid hormones, or are small nonpolar molecules,
change in conformation results in the transfer and sub- such as nitric oxide (NO), which have the ability to
sequent release of both molecules on the other side of diffuse through the lipid bilayer. These ligands require
the membrane. the presence of an intracellular receptor. Hydrophilic
ligands have a very short life span (a few milliseconds
Cell Signaling to minutes at most), whereas steroid hormones last for
extended time periods (several hours to days).
Cell signaling is the communication that occurs when Signaling molecules often act in concert, in that
signaling cells release signaling molecules that bind to several different ligands are required before a specific
cell surface receptors of target cells. cellular response is elicited. Moreover, the same ligand
or combination of ligands may elicit different responses
When cells communicate with each other, the one that from different cells. For instance, acetylcholine causes
sends the signal is called the signaling cell; the cell skeletal muscle cells to contract, cardiac muscle cells to
receiving the signal is called the target cell. Transmis- relax, endothelial cells of blood vessels to release nitric
sion of the information may occur either by the secre- oxide, and parenchymal cells of some glands to release
tion or presentation of signaling molecules, which the contents of their secretory granules.
contact receptors on the target cell membrane (or Binding of signaling molecules to their receptors
intracellularly either in the cytosol or in the nucleus), or activates an intracellular second messenger system,
by the formation of intercellular pores known as gap initiating a cascade of reactions that result in the
junctions, which permit the movement of ions and required response. A hormone, for example, binds to its
small molecules (e.g., cAMP) between the two cells. receptors on the cell membrane of its target cell. The
(Gap junctions are discussed in Chapter 5.) receptor alters its conformation, with the resultant acti-
The signaling molecule, or ligand, may be either vation of adenylate cyclase, a transmembrane protein,
secreted and released by the signaling cell or may whose cytoplasmic region catalyzes the transformation
remain bound to its surface and be presented by the sig- of ATP to cAMP, one of the most common second
naling cell to the target cell. A cell-surface receptor messengers.
usually is a transmembrane protein, whereas an intra- cAMP activates a cascade of enzymes within the cell,
cellular receptor is a protein that resides in the cytosol thus multiplying the effects of a very few molecules of
or in the nucleus of the target cell. Ligands that bind to hormones on the cell surface. The specific intracellular
cell-surface receptors usually are polar molecules; event depends on the enzymes located within the cell;
those that bind to intracellular receptors are hydropho- thus, cAMP activates one set of enzymes within an
bic and thus can diffuse through the cell membrane. endothelial cell and another set of enzymes within a fol-
In the most selective signaling process, synaptic sig- licular cell of the thyroid gland. Therefore, the same
naling, the signaling molecule, a neurotransmitter, is molecule can have a different effect in different cells.
released so close to the target cell that only a single cell The system is known as a second messenger system
is affected by the ligand. A more generalized but still because the hormone is the first messenger that acti-
local form of signaling, paracrine signaling, occurs vates the formation of cAMP, the second messenger.
when the signaling molecule is released into the inter- Other second messengers include calcium (Ca2+),
cellular environment and affects cells in its immediate cGMP, inositol triphosphate (IP3), and diacylglycerol.
Ch002-X2945.qxd 12/8/06 3:19 PM Page 21
Steroid hormones (e.g., cortisol) can also diffuse 䡲 Pertussis toxin–insensitive (GBq)
through the cell membrane. Once in the cytosol, they 䡲 Transducin (Gt)
bind to steroid hormone receptors (members of
G proteins act by linking receptors with enzymes that
the intracellular receptor family), and the ligand-
modulate the levels of the intracellular signaling mole-
receptor complex activates gene expression, or tran-
cules (second messengers) cAMP or Ca2+.
scription (the formation of messenger ribonucleic
acid [mRNA]). Transcription may be induced directly,
Signaling via G and G Proteins
resulting in a fast primary response, or indirectly, bring- S I
ing about a slower, secondary response. In the second- Gs proteins (Fig. 2-12) are usually present in the inac-
ary response, the mRNA codes for the protein that is tive state, in which a GDP molecule is bound to the a
necessary to activate the expression of additional genes. subunit. When a ligand binds to the G-protein–linked
receptor, it alters the receptor’s conformation, permit-
Cell-Surface Receptors ting it to bind to the a subunit of the Gs protein, which
in turn exchanges its GDP for GTP. The binding of GTP
Cell-surface receptors are of three types: ion channel- causes the a subunit to dissociate not only from the
linked, enzyme-linked, and G-protein–linked. receptor but also from the other two subunits and to
bind with adenylate cyclase, a transmembrane
Most cell-surface receptors are integral glycoproteins protein. This binding activates adenylate cyclase to form
that function in recognizing signaling molecules and
in transducing the signal into an intracellular action.
The three main classes of receptor molecules are ion Extracellular space
Signaling
channel-linked receptors (see earlier), enzyme-linked molecule
receptors, and G-protein–linked receptors.
Receptor
ENZYME-LINKED RECEPTORS
These receptors are transmembrane proteins whose
extracellular regions act as receptors for specific ligands.
When a signaling molecule binds to the receptor site,
the receptor’s intracellular domain becomes activated so
that it now possesses enzymatic capabilities. These
enzymes then either induce the formation of second γ
messengers, such as cGMP, or permit the assembly of β α Adenylate
intracellular signaling molecules that relay the signal cyclase
G protein GDP
intracellularly. This signal then elicits the required
response by activating additional enzyme systems or by GTP
Cytoplasm
stimulating gene regulatory proteins to initiate the tran-
scription of specific genes. Activated
adenylate cyclase
G-PROTEIN–LINKED RECEPTORS
These receptors are multipass proteins whose extracel-
lular domains act as receptor sites for ligands. Their
intracellular regions have two separate sites, one that
binds to G proteins and another that becomes phosphor-
ylated during the process of receptor desensitization.
Most cells possess two types of GTPases (monomeric
γ α
and trimeric), each of which has the capability of
binding guanosine triphosphate (GTP) and guano- β GTP
sine diphosphate (GDP). Trimeric GTPases, or G Activated ATP cAMP

proteins, are composed of a large α subunit and two Gα-subunit + PPi
small β and γ subunits, and can associate with G-
protein–linked receptors. There are several types of G Figure 2–12 G-protein–linked receptor. When the signaling
proteins, including: molecule contacts its receptor, the a subunit dissociates from the G
protein and contacts and activates adenylate cyclase, which converts
䡲 Stimulatory (Gs) adenosine triphosphate (ATP) to cyclic adenosine monophosphate
䡲 Inhibitory (Gi) (cAMP). GDP, guanosine disphosphate; GTP, guanosine triphos-
䡲 Pertussis toxin–sensitive (Go) phate; PPi, pyrophosphate.
Ch002-X2945.qxd 12/8/06 3:19 PM Page 22
many molecules of cAMP from ATP molecules. As the the plasma membrane and, with the assistance of Ca2+,
activation of adenylate cyclase is occurring, the ligand activates the enzyme protein kinase C (C-kinase).
uncouples from the G-protein–linked receptor, return- C-kinase, in turn, initiates a phosphorylation cascade,
ing the receptor to its original conformation without whose end result is the activation of gene regulatory
affecting the activity of the a subunit. Within a few proteins that initiate transcription of specific genes.
seconds, the a subunit hydrolyzes its GTP to GDP, IP3 is rapidly inactivated by being dephosphorylated,
detaches from adenylate cyclase (thus deactivating it), and diacylglycerol is catabolized within a few seconds
and reassociates the β and γ subunits. after its formation. These actions ensure that responses
Gi behaves similarly to Gs, but instead of activating to a ligand are of limited duration.
adenylate cyclase, it inhibits it, so that cAMP is not Note that because cytosolic Ca2+ acts as an important
being produced. The lack of cAMP prevents the phos- second messenger, its cytosolic concentration must be
phorylation, and thus activation, of enzymes that would carefully controlled by the cell. These control mecha-
elicit a particular response. Hence, a particular ligand nisms include the sequestering of Ca2+ by the endo-
binding to a particular receptor may activate or inacti- plasmic reticulum, specific Ca2+-binding molecules in
vate the cell, depending on the type of G protein that the cytosol and mitochondria, and the active transport
couples it to adenylate cyclase. of this ion out of the cell.
When IP3 causes elevated cytosolic Ca2+ levels, the
Cyclic Adenosine Monophosphate As a excess ions bind to calmodulin, a protein found in
Second Messenger high concentration in most animal cells. The Ca2+-
calmodulin complex activates a group of enzymes
cAMP is an intracellular signaling molecule that acti-
known as Ca2+-calmodulin–dependent protein kinases
vates cAMP-dependent protein kinase (A-kinase) by
(CaM-kinases). CaM-kinases have numerous regula-
binding to it. The activated A-kinase dissociates into its
tory functions in the cell, such as initiation of
regulatory component and two active catalytic sub-
glycogenolysis, synthesis of catecholamines, and con-
units. The active catalytic subunits phosphorylate other
traction of smooth muscle.
enzymes in the cytosol, thus initiating a cascade of phos-
phorylations and resulting in a specific response. Ele-
Protein Synthetic and Packaging
vated levels of cAMP in some cells result in the
transcription of those genes whose regulatory regions Machinery of the Cell
possess cAMP response elements (CREs). A-kinase The primary components of the protein synthetic
phosphorylates, and thus activates, a gene regulatory machinery of the cell are ribosomes (and polyribosomes),
protein known as CRE-binding protein (CREB) rough endoplasmic reticulum, and the Golgi apparatus.
whose binding to the CRE stimulates the transcription
of those genes.
As long as cAMP is present at a high enough con- Ribosomes
centration, a particular response is elicited from the
Ribosomes are small particles, approximately 12 nm
target cell. In order to prevent responses of unduly
wide and 25 nm long, composed of proteins and ribo-
long duration, cAMP is quickly degraded by cAMP
somal RNA (rRNA). They function as a surface for the
phosphodiesterases to 5′-AMP, which is unable to
synthesis of proteins. Each ribosome is composed of a
activate A-kinase. Moreover, the enzymes phosphory-
large subunit and a small subunit, both of which are
lated during the cascade of phosphorylations become
manufactured or assembled in the nucleolus and
deactivated by becoming dephosphorylated by another
released as separate entities into the cytosol. The small
series of enzymes (serine/threonine phosphoprotein
subunit has a sedimentation value of 40S and is com-
phosphatases).
posed of 33 proteins and an 18S rRNA. The sedimen-
Signaling via G Protein tation value of the large subunit is 60S, and it consists
O
of 49 s and 3 rRNAs. The sedimentation values of the
When a ligand becomes bound to Go-protein–linked RNAs are 5S, 5.8S, and 28S.
receptor, the receptor alters its conformation and binds The small subunit has a site for binding mRNA, a P-
with Go. This trimeric protein dissociates, and its subunit site for binding peptidyl transfer ribonucleic acid
activates phospholipase C, the enzyme responsible (tRNA), an A-site for binding aminoacyl tRNA, and an
for cleaving the membrane phospholipid phosphatidyl- E-site where the tRNA that gave up its amino acid exits
inositol bisphosphate (PIP2) into IP3 and diacylglyc- the ribosome. Some of the rRNAs of the large subunit are
erol. IP3 leaves the membrane and diffuses to the referred to as ribozymes since they have enzymatic
endoplasmic reticulum, where it causes the release of activity and catalyze peptide bond formation. The small
Ca2+—another second messenger—into the cytosol. and large subunits are present in the cytosol individually
Diacylglycerol remains attached to the inner leaflet of and do not form a ribosome until protein synthesis begins.
Ch002-X2945.qxd 12/8/06 3:19 PM Page 23
Endoplasmic Reticulum with that of the rough endoplasmic reticulum. Except

for cells active in synthesis of steroids, cholesterol, and
Endoplasmic reticulum (ER) is the largest membranous triglycerides, and cells that function in detoxification of
system of the cell, comprising approximately half of the toxic materials (e.g., alcohol and barbiturates), most
total membrane volume. It is a system of intercon- cells do not possess an abundance of SER. SER has
nected tubules and vesicles whose lumen is referred to become specialized in some cells (e.g., skeletal muscle
as the cistern. ER has two components: smooth cells), where it is known as sarcoplasmic reticulum.
endoplasmic reticulum (SER) and rough endoplas- Here, it functions in sequestering calcium ions from the
mic reticulum (RER). Although only the RER partic- cytosol, assisting in the control of muscle contraction.
ipates in protein synthesis, the SER is also discussed at
this point, but only as an aside, and the reader should Rough Endoplasmic Reticulum
keep in mind that distinction.
Cells that function in the synthesis of proteins that are
to be exported are richly endowed with RER (see Fig.
Smooth Endoplasmic Reticulum
2-6). The membranes of this organelle are somewhat
A system of anastomosing tubules and occasional flat- different from those of its smooth counterpart, because
tened membrane-bound vesicles constitute SER (Fig. it possesses integral proteins that function in recogniz-
2-13). The lumen of SER is assumed to be continuous ing and binding ribosomes to its cytosolic surface and
Figure 2–13 Electron micrograph of the

smooth endoplasmic reticulum of the human
suprarenal cortex. (From Leeson TS, Leeson CR,
Papparo AA: Text/Atlas of Histology, Philadelphia,
WB Saunders, 1988.)
Ch002-X2945.qxd 12/8/06 3:19 PM Page 24
also maintains the flattened morphology of the RER. It is interesting that the approximate time of synthe-
For the purposes of this textbook, the integral proteins sis of a protein composed of 400 amino acids is about
of interest are (1) signal recognition particle recep- 20 seconds. Because a single strand of mRNA may have
tor (docking protein), (2) ribosome receptor as many as 15 ribosomes translating it simultaneously, a
protein (ribophorin I and ribophorin II), and (3) pore large number of protein molecules may be synthesized
protein. Their functions are discussed later. in a short period of time. This conglomeration of an
RER participates in the synthesis of all proteins that mRNA-ribosome complex, which usually has a spiral or
are to be packaged or delivered to the plasma mem- long hairpin form, is referred to as a polyribosome, or
brane. It also performs post-translational modifications polysome (Fig. 2-14).
of these proteins, including sulfation, folding, and gly-
cosylation. Additionally, lipids and integral proteins of Synthesis of Cytosolic Proteins
all membranes of the cell are manufactured by the
The general process of protein synthesis in the cytosol
RER. The cisterna of RER is continuous with the peri-
is outlined in Figure 2-15.
nuclear cistern, the space between the inner and outer
nuclear membranes. STEP 1
䡲 The process begins when the P-site of the small ribo-
Polyribosomes
somal subunit is occupied by an initiator tRNA
Proteins to be packaged are synthesized on the RER whose anticodon recognizes the triplet codon AUG,
surface, whereas proteins destined for the cytosol are coding for the amino acid methionine.
manufactured within the cytosol. The information for 䡲 An mRNA binds to the small subunit.
the primary structure of a protein (sequence of amino 䡲 The small subunit assists the anticodon of the tRNA
acids) is housed in the deoxyribonucleic acid (DNA) molecule to recognize the start codon AUG on the
of the nucleus. This information is transcribed into a mRNA molecule. This step acts as a registration step
strand of mRNA, which leaves the nucleus and enters so that the next three nucleotides of the mRNA mol-
the cytoplasm. The sequence of codons of the mRNA ecule may be recognized as the next codon.
thus represents the chain of amino acids, in which each
codon is composed of three consecutive nucleotides. STEP 2
Because any three consecutive nucleotides constitute a The large ribosomal subunit binds to the small subunit
codon, it is essential that the protein synthetic machin- and the ribosome moves along the mRNA chain, in a 5′
ery recognizes the beginning and the end of the message; to 3′ direction, until the next codon lines up with the A-
otherwise, an incorrect protein will be manufactured. site of the small subunit.
The three types of RNA play distinctive roles in
protein synthesis. mRNA carries the coded instructions STEP 3
specifying the sequence of amino acids. tRNA forms An acylated tRNA (tRNA bearing an amino acid) com-
covalent bonds with amino acids, forming aminoacyl pares its anticodon with the codon of the mRNA; if they
tRNA. These enzyme-catalyzed reactions are specific; match, the tRNA binds to the A-site.
that is, each tRNA reacts with its own corresponding
amino acid. Each tRNA also contains the anticodon STEP 4
that recognizes the codon in mRNA corresponding to 䡲 The amino acids at the A-site and the P-site form a
the amino acid it carries. Finally, several rRNAs asso- peptide bond.
ciate with a large number of proteins to form the small 䡲 The tRNA on the P-site yields its amino acid to the
and large ribosomal subunits. tRNA at the A-site, which now has two amino acids
attached to it. These reactions are catalyzed by the
Protein Synthesis (Translation) rRNA-based enzyme of the large subunit known as
peptidyl transferase.
Protein synthesis (translation) occurs on ribosomes in the
cytosol or on the surface of the rough endoplasmic STEP 5
reticulum. The deaminated tRNA leaves the P-site and binds to
the E-site; the tRNA with its two amino acids attached
The requirements for protein synthesis are: moves from the A-site to the P-site. Concurrently, the
䡲 An mRNA strand ribosome moves along the mRNA chain until the next
䡲 tRNAs, each of which carries an amino acid and pos- codon lines up with the A-site of the small ribosomal
sesses the anticodon that recognizes the codon of the subunit and the tRNA from the E-site is ejected. The
mRNA coding for that particular amino acid energy required by this step is derived from the hydrol-
䡲 Small and large ribosomal subunits ysis of GTP.
Ch002-X2945.qxd 12/8/06 3:19 PM Page 25
Figure 2–14 Electron micrograph of bound

polysome. Arrowheads indicate rough endoplasmic
reticulum; arrows indicate ribosomes; asterisks
indicate cisternae; M, mitochondrion; mt, micro-
tubule. (From Christensen AK, Bourne CM: Shape
of large bound polysomes in cultured fibroblasts
and thyroid epithelial cells. Anat Rec 255: 116-129,
1999.)
STEP 6 Synthesis of Proteins on the Rough

䡲 Steps 3 through 5 are repeated, elongating the Endoplasmic Reticulum
polypeptide chain until the stop codon is reached. Proteins that need to be packaged either for delivery to
䡲 There are three stop codons (UAG, UAA, and
the outside of the cell or merely isolated from the
UGA), each one of which may halt translation. cytosol must be identified and be delivered cotransla-
STEP 7 tionally (during the process of synthesis) into the RER
䡲 When the A-site of the small ribosomal subunit cistern. The mode of identification resides in a small
reaches a stop codon, a release factor binds to the segment of the mRNA, located immediately following
A-site. the start codon, which codes for a sequence of amino
䡲 This factor is responsible for releasing the newly acids known as the signal peptide.
formed polypeptide chain from the tRNA of the P- Employing the sequence just outlined for the syn-
site into the cytosol. thesis of protein in the cytosol, the mRNA begins to
be translated, forming the signal peptide (Fig. 2-16).
STEP 8 This peptide is recognized by a protein-RNA complex
The tRNA moves from the P-site to the E-site, the located in the cytosol, the signal recognition particle
release factor is released from the A-site, and the small (SRP). The SRP attaches to the signal peptide and
and large ribosomal subunits leave the mRNA. by occupying the P-site on the small subunit of the
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Large
ribosomal
subunit
Small Amino
ribosomal tRNA acid
subunit
P site
E site E site A site
A site
mRNA
P site
Initiation begins when the small The large subunit joins the initial A second aminoacyl-tRNA, A peptide bond is formed
ribosomal subunit binds with complex. The empty A site is bearing an amino acid, binds to between the two amino acids.
messenger RNA (mRNA). The now ready to receive an the empty A site. This bond formation brings the
initiator transfer RNA (tRNA) aminoacyl-tRNA. acceptor end of the A site tRNA
binds with its associated amino into the P site as it picks up the
acid, methionine, to the P site. peptidyl chain.
Termination
Polypeptide signal complex
chain
The P site tRNA moves to the Polypeptide synthesis continues The terminal signal complex, a Once protein synthesis is
E site and the A site tRNA, until the ribosome encounters a release factor which promotes completed, the two ribosomal
with the attached peptidyl chain, “stop” or “nonsense codon” polypeptide release, docks at subunits dissociate from the
moves to the vacated P site. As a which signals the end of the the A site. The polypeptide mRNA, and return to the
new aminoacyl-tRNA bearing an polypeptide chain. chain is released. cytosol.
amino acid occupies the A site,
the spent tRNA on the E site
drops off the ribosome. A peptide
bond is formed, and the ribosome
moves down the mRNA. The
cycle of adding to the forming
protein chain continues.
Figure 2–15 Protein synthesis in the cytosol.
ribosome halts translation; it then directs the polysome 4 As translation resumes, the nascent protein continues
to migrate to the RER. to be channeled into the cistern of the RER.
The SRP receptor protein (docking protein) in the 5 An enzyme attached to the cisternal aspect of the
RER membrane contacts the SRP, and the ribosome RER membrane, known as signal peptidase,
receptor protein contacts the large subunit of the ribo- cleaves the signal peptide from the forming protein.
some, attaching the polysome to the cytosolic surface The signal peptide becomes degraded into its amino
of the RER. The following events then occur almost acid components.
simultaneously: 6 As detailed previously, when the stop codon is
reached, protein synthesis is completed, and the small
1 The pore proteins assemble, forming a pore through and large ribosomal subunits dissociate and reenter
the lipid bilayer of the RER. the cytosol to join the pool of ribosomal subunits.
2 The signal peptide contacts the pore protein and 7 The newly formed proteins are folded, glycosylated,
begins to be translocated (amino terminus first) into and undergo additional post-translational modifica-
the cistern of the RER. tions within the RER cisternae.
3 The SRP is dislodged, reenters the cytosol, and frees 8 The modified proteins leave the cistern via small
the P-site on the small ribosomal subunit. The ribo- transport vesicles (without a clathrin coat) at
some remains on the RER surface. regions of the RER devoid of ribosomes.
Ch002-X2945.qxd 12/8/06 3:19 PM Page 27
Ribosome
Protein synthesis dissociates
continues to completion
Protein Signal
synthesis Protein Protein sequence
mRNA 5′ begins synthesis synthesis removed
3′
inhibited resumes
Ribosome
Signal C
sequence
Signal N
recognition N
Cleaved Carbohydrate Completed
particle protein
signal
SRP Signal sequence
receptor peptidase Rough endoplasmic reticulum
Figure 2–16 Protein synthesis on the rough endoplasmic reticulum. C, carboxyl terminus; mRNA, messenger RNA; N, amino terminus;
SRP, signal recognition particle.
Golgi Apparatus There are two additional compartments of interest,

one associated with the cis-face and the other with the
The Golgi apparatus functions in the synthesis of trans-face. Located between the RER and the cis-face
carbohydrates and in the modification and sorting of of the Golgi apparatus is an intermediate compartment
proteins manufactured on the RER. of vesicles, or endoplasmic reticulum/Golgi inter-
mediate compartment (ERGIC) and the trans
Proteins manufactured and packaged in the RER follow Golgi network (TGN), located at the distal side of the
a default pathway to the Golgi apparatus for post- Golgi apparatus. The ERGIC, also known as the
translational modification and packaging. Proteins des- tubulovesicular complexes, is a collection of vesicles and
tined to remain in the RER or to go to a compartment tubules formed from the fusion of transfer vesicles
other than the Golgi apparatus possess a signal that will derived from the final cisterna of the RER, known as
divert them from the default pathway. transitional endoplasmic reticulum (TER). These
The Golgi apparatus is composed of one or more transfer vesicles bud off the TER and contain nascent
series of flattened, slightly curved membrane-bounded proteins synthesized on the surface and modified within
cisternae, the Golgi stack, which resemble a stack of the cisternae of the RER.
pita breads that do not quite contact each other (Figs. Vesicles derived from the ERGIC make their way to
2-17 to 2-19). The periphery of each cisterna is dilated and fuse with the periphery of the cis-face of the Golgi
and is rimmed with vesicles that are in the process apparatus, thus delivering the protein to this compart-
of either fusing with or budding off that particular ment for further modification. The modified proteins
compartment. are transferred from the cis to the medial and finally to
Each Golgi stack has three levels of cisternae: the trans cisternae via vesicles that bud off and fuse with
䡲 The cis-face (or cis Golgi network) the rims of the particular compartment (Fig. 2-20). As
䡲 The medial face (intermediate face) the proteins pass through the Golgi apparatus, they are
䡲 The trans-face modified within the Golgi stack. Proteins that form the
cores of glycoprotein molecules become heavily glyco-
The cis-face is closest to the RER. It is convex in sylated, whereas other proteins acquire or lose sugar
shape and is considered to be the entry face, because moieties.
newly formed proteins from the RER enter the cis-face Mannose phosphorylation occurs within the cis-face
before they are permitted to enter the other cisternae cisterna, whereas the removal of mannose from certain
of the Golgi apparatus. The trans-face is concave in proteins takes place within the cis and medial compart-
shape and is considered to be the exit face, because the ments of the Golgi stack. N-acetylglucosamine is added
modified protein is ready to be packaged and to be sent to the protein within the medial cisternae. Addition of
to its destination from here. sialic acid (N-acetylneuraminic acid) and galactose, as
Ch002-X2945.qxd 12/8/06 3:19 PM Page 28
ER
Transitional ER
Transport
vesicles
ERGIC
cis-face
Medial face
trans-face Figure 2–17 Rough endoplas-

mic reticulum (ER) and the Golgi
apparatus. Transfer vesicles contain
trans Golgi newly synthesized protein and are
network ferried to the endoplasmic reticu-
Secretory lum/Golgi intermediate compart-
granules ment (ERGIC) and from there to
the Golgi apparatus. The protein is
Smooth and modified in the various faces of the
coated vesicles Golgi complex and enters the trans
Golgi network for packaging.
Figure 2–18 Electron micrograph of the Golgi

apparatus of the rat epididymis. ER, endoplasmic
reticulum; m, mitochondrion; TGN, trans Golgi net-
work. Numbers represent the saccules of the Golgi
apparatus. (From Hermo L, Green H, Clermont Y:
Golgi apparatus of epithelial principal cells of the
ependymal initial segment of the rat: Structure, rela-
tionship with endoplasmic reticulum, and role in the
formation of secretory vesicles. Anat Rec 229:159-
176, 1991.)
well as phosphorylation and sulfation of amino acids, aspect of the organelle. Three types of coat proteins
occurs in the trans-face. (COPs), or coatamers, are known to elicit the forma-
tion of cargo-bearing vesicles: coatomer I (COP I),
Golgi- and Rough Endoplasmic coatomer II (COP II), and clathrin. At the site of
Endothelium–Associated Vesicles future vesicle formation, these proteins coalesce, attach
to the membrane, draw out the vesicle, and coat its
Vesicles associated with the RER and Golgi apparatus cytosolic surface. Thus, there are COP I–coated, COP
possess a protein coat as well as surface markers. II–coated, and clathrin-coated vesicles.
Transport vesicles leaving the transitional ER are
Vesicles that transport proteins (cargo) between always COP II–coated until they reach the ERGIC, where
organelles and regions of organelles, must have a way they shed their COP II coat, which is recycled. Vesicles
of budding off the organelle and must be labeled as to that arise from the ERGIC to carry recently delivered
their destination. The process of budding is facilitated cargo to the cis-face require the assistance of COP I, as do
by the assembly of a proteinaceous coat on the cytosolic all other vesicles that proceed through the medial to the
Ch002-X2945.qxd 12/8/06 3:19 PM Page 29
Figure 2–19 A, Face view of the cis Golgi network in a step 6 spermatid. The cis-most saccule is a regular network of anastomotic mem-
branous tubules, capped by the endoplasmic reticulum. Some of the medial saccules with fewer but larger and more irregular pores are visible
under the cis Golgi saccule. B, Face view of another cis Golgi network in a step 6 spermatid. Note the fenestration at the edges of the irregu-
lar trans Golgi saccules. (From Ho HC, Tang CY, Suarez SS: Three-dimensional structure of the Golgi apparatus in mouse spermatids: A scan-
ning electron microscopic study. Anat Rec 256:189-194, 1999.)
trans-face and the trans Golgi network. Most of the vesi- extend to the cell periphery. The major MTOC of the
cles that arise from the trans Golgi network, however, cell is known as the centrosome and it houses a pair of
require the presence of clathrin for their formation. centrioles embedded in a matrix of proteins rich in γ-
The transport mechanism has a quality control tubulin ring complexes.
aspect, in that if RER (or transitional ER) resident pro- The MTOC is located in the vicinity of the Golgi
teins are packaged in vesicles and these “stowaway” complex, and these ends of the microtubules, each ema-
molecules reach the ERGIC, they are returned to the nating from a γ-tubulin ring complex, are referred to as
RER in COP I–coated vesicles. This is referred to as the minus end; the other end of each microtubule, near
retrograde transport, in contrast to anterograde the periphery of the cell, is the plus end. The molecu-
transport of cargo, described earlier. lar motor that drives vesicles to the minus end (toward
Because these vesicles are formed at a particular site the MTOC) is dynein and its accessory protein complex.
in the cell and must reach their destination, an addi- The molecular motor that drives vesicles toward the
tional set of information should be considered; namely, positive end (away from the MTOC) is kinesin and its
how the vesicles are transported to their destination. associated protein complex. Thus, vesicles derived from
Although these are interesting concepts to contemplate, the ER as well as from the ERGIC are driven toward
the complexity of the mechanism precludes a complete the MTOC and are driven by dynein, whereas vesicles
discussion here; instead, a cursory overview is pre- that leave the Golgi complex in a retrograde direction to
sented. (For more information, consult a textbook on the ERGIC or to the RER are driven by kinesin.
cell biology.)
As the cargo-containing vesicles form, they possess Sorting in the Trans Golgi Network
not only a coatomer or clathrin coat but also other
surface markers and receptors. Some of these receptors The trans Golgi network is responsible for the sorting of
interact with microtubules and the motor protein com- proteins to their respective pathways so that they reach
plexes that are responsible for vesicle movement. As the plasma membrane, secretory granules, or lysosomes.
discussed later (see Cytoskeleton), microtubules are
long, straight, rigid, tubule-like structures that originate Cargo that leaves the TGN is enclosed in vesicles that
in the microtubule organizing center (MTOC) and may do one of the following (see Fig. 2-20):
Ch002-X2945.qxd 12/8/06 3:19 PM Page 30
ER
TER (transitional ER)
Phosphorylation of mannose
Removal of mannose
Protein synthesis
Terminal glycosylation
Plasma membrane
proteins Sulfation and phosphorylation
of amino acids
Lysosomal
proteins Sorting of proteins
Secretory
Secretory granule
proteins
Clathrin Clathrin
COP II
coat triskelions
coated
vesicles
Non-clathrin
coated vesicle
COP I Mannose 6-phosphate

coated transport receptor
vesicles
trans Golgi network
CIS MEDIAL TRANS Late endosome
TER ERGIC
Lysosome Plasma
GOLGI
membrane
Figure 2–20 The Golgi apparatus and packaging in the trans Golgi network. ER, endoplasmic reticulum; ERGIC, endoplasmic reticu-
lum/Golgi intermediate compartment; COP, coat protein (coatomer).
䡲 Insert into the cell membrane as membrane proteins immediate release into the extracellular space nor inser-
and lipids tion into the cell membrane requires a particular regula-
䡲 Fuse with the cell membrane such that the protein tory process; thus, both processes are said to follow the
they carry is immediately released into the extracel- constitutive secretory pathway (default pathway). In
lular space contrast, the pathways to lysosomes and to secretory vesi-
䡲 Congregate in the cytoplasm near the apical cell cles are known as the regulated secretory pathway.
membrane as secretory granules (vesicles), and,
upon a given signal, fuse with the cell membrane for TRANSPORT OF LYSOSOMAL
eventual release of the protein outside the cell PROTEINS
䡲 Fuse with late endosomes (see later), releasing their
The sorting process begins with the phosphorylation of
content into that organelle, which then becomes a
mannose residues of the lysosomal proteins (lysosomal
lysosome
hydrolases) in the cis cisterna of the Golgi stack. When
The first three processes are known as exocytosis, these proteins reach the trans Golgi network, their
because material leaves the cytoplasm proper. Neither mannose-6-phosphate (M6P) is recognized as a signal,
Ch002-X2945.qxd 12/8/06 3:19 PM Page 31
mation of clathrin-coated vesicles. The signal for their

formation is not known; however, the mechanism is
believed to be similar to that for lysosomal proteins.
Unlike vesicles that ferry lysosomal enzymes, secre-
tory granules are quite large and carry many more pro-
teins than there are receptors on the vesicle surface.
Additionally, the contents of the secretory granules
become condensed with time as a result of the loss of
fluid from the secretory granules (see Figs. 2-6 and 2-
20). During this process of increasing concentration,
these vesicles are frequently referred to as condensing
vesicles. Moreover, secretory granules of polarized
cells remain localized in a particular region of the cell.
They remain as clusters of secretory granules that, in
reaction to a particular signal (e.g., neurotransmitter or
hormone), fuse with the cell membrane to release their
contents into the intercellular space.
TRANSPORT ALONG THE
CONSTITUTIVE PATHWAY
All vesicles that participate in nonselective transport,
Figure 2–21 A map of clathrin coat at 21 Å resolution. To allow such as those passing between the RER and the cis
a clear view of the path of the triskelion legs, the amino-terminal Golgi network or among the cisternae of the Golgi stack
domain and most of the linker have been removed from this map. or utilizing the constitutive pathway between the TGN
(From Smith CJ, Grigorieff N, Pearse BM: Clathrin coats at 21 Å res- and the plasma membrane, also require a coated vesicle
olution: A cellular assembly designed to recycle multiple membrane (see Fig. 2-20). However, the coating is composed of a
receptors. EMBO J 17:4943-4953, 1998.)
seven-unit protein (coatomer) complex instead of
clathrin. Each protein of the coatomer complex is
and they become bound to mannose-6-phosphate re- referred to as a coat protein (COP) subunit, whose
ceptors, transmembrane proteins of the TGN membrane. assembly, unlike that of clathrin, is energy-requiring and
A small pit is formed with the assistance of clathrin remains with the vesicle until it reaches its intended
triskelions, protein complexes composed of three heavy target. As indicated previously, there are two types of
and three light chains forming a structure with three coatomers, COP I and COP II.
arms that radiate from a central point (Fig. 2-21; also see Vesicles derived from the TGN are driven along
Fig. 2-20). The triskelions self-assemble, coating the microtubule tracts by the use of kinesin and its associ-
cytoplasmic aspect of the TGN rich in M6P receptors to ated protein complex. However, these vesicles also use
which M6P is bound. As the pit deepens, it pinches off an alternative, and perhaps their primary, pathway of
the TGN and forms a clathrin-coated vesicle. The actin filaments. The motor that drives these vesicles is
clathrin coat is also referred to as the clathrin basket. myosin II; it is believed that myosin II is brought to the
The clathrin-coated vesicle quickly loses its clathrin trans Golgi network subsequent to, or in conjunction
coat, which, unlike the formation of the clathrin basket, with, the recruitment of the clathrin triskelions to the
is an energy-requiring process. The uncoated vesicle site of vesicle formation.
reaches, fuses with, and releases its contents into the
late endosome (endosomes are discussed later). Alternative Concept of the
Because clathrin coats are utilized for many other Golgi Apparatus
types of vesicles, an intermediary protein, adaptin, is
interposed between the cytoplasmic aspect of the An alternative concept of the Golgi apparatus suggests
receptor molecule and the clathrin. Many different the occurrence of cisternal maturation instead of
types of adaptins exist. Each has a binding site for a par- anterograde vesicle transport.
ticular receptor as well as a binding site for clathrin.
The two predominant theories of anterograde vesicle
transport (already described) and cisternal matura-
TRANSPORT OF REGULATED
tion are mutually incompatible, and ample evidence
SECRETORY PROTEINS
exists to support both theories. The theory of cisternal
Proteins that are to be released into the extracellular maturation suggests that instead of the cargo being
space in a discontinuous manner also require the for- ferried through the various regions of the Golgi
Ch002-X2945.qxd 12/8/06 3:19 PM Page 32
apparatus, it remains stationary and the various enzyme regions) of antibodies and a blood-borne series of
systems of the Golgi are transported in a retrograde proteins known as complement. Because the variable
fashion in the correct sequence and at the designated region of the antibody binds to the surface of a micro-
time, so that a given sedentary cisterna matures into the organism, the Fc region projects away from its surface.
subsequent cisternae. Macrophages and neutrophils possess Fc receptors
At first glance, the cisternal maturation theory may that bind the Fc regions of the antibody upon contact.
appear to be dubious; however, it may be illustrated by This relationship acts as a signal for the cell to extend
a commonly observed phenomenon. If one is sitting in pseudopods, surround the microorganism, and inter-
a stationary train and watches another stationary train nalize the microorganism by forming a phagosome.
on the neighboring railroad track when one of the trains Complement on the surface of the microorganism
begins to move, it is difficult initially to determine which probably assists phagocytosis in a similar manner,
train is moving, and without external visual aids we because macrophages also possess complement recep-
cannot make a reasonable determination. The current tors on their surface. Interaction between complement
state of research cannot determine which of the two and its receptor presumably activates the cell to form
theories is correct, but most histology and cell biology pseudopods and engulf the offending microorganism.
textbooks favor the anterograde vesicle transport theory.
Pinocytosis
Endocytosis, Endosomes,
Because most cells export substances into the intercel-
and Lysosomes lular space, they continually add the membranes of vesi-
Endocytosis, endosomes, and lysosomes are involved in cles that transport those substances from the trans Golgi
the ingestion, sequestering, and degradation of network to the plasma membrane. These cells, in order
substances internalized from the extracellular space. to maintain their shape and size, must continually
remove the excess membrane and return it for recycling.
The process whereby a cell ingests macromolecules, This cycle of membrane shuffling during exocytosis and
particulate matter, and other substances from the extra- endocytosis is known as membrane trafficking, the
cellular space is referred to as endocytosis. The endo- movement of membranes to and from various compart-
cytosed material is engulfed in a vesicle appropriate for ments of the cell. In most cells, pinocytosis is the most
its volume. If the vesicle is large (>250 nm in diame- active transporting process and contributes most to the
ter), the method is called phagocytosis (cell eating) recapturing of membranes (Fig. 2-22).
and the vesicle is a phagosome. If the vesicle is small
(<150 nm in diameter), the type of endocytosis is called RECEPTOR-MEDIATED
pinocytosis (cell drinking) and the vesicle is a pinocy- ENDOCYTOSIS
totic vesicle. Many cells specialize in the pinocytosis of several types
of macromolecules. The most efficient form of captur-
Endocytotic Mechanisms ing these substances depends on the presence of recep-
tor proteins (cargo receptors) in the cell membrane.
Endocytosis is divided into two categories: phagocytosis Cargo receptors are transmembrane proteins that
and pinocytosis. become associated with the particular macromolecule
(ligand) extracellularly and with a clathrin coat intra-
Phagocytosis cellularly (see Fig. 2-20).
The assembly of clathrin triskelions beneath the
The process of engulfing larger particulate matter, such cargo receptors pulls on the plasma membrane, forming
as microorganisms, cell fragments, and cells (e.g., a clathrin-coated pit (Figs. 2-23 and 2-24), which even-
defunct red blood cells), is usually performed by spe- tually becomes a pinocytotic vesicle, enclosing the
cialized cells known as phagocytes. The most common ligand as a droplet of fluid about to drip from a surface.
phagocytes are the white blood cells, the neutrophils, To release this pinocytotic vesicle, several molecules of
and the monocytes. When monocytes leave the blood- dynamin, a GTPase, surround the constricted neck of
stream and enter the connective tissue domain to the vesicle, pinch its neck closed, and the pinocytotic
perform their task of phagocytosis, they become known vesicle is released from its membrane origin into the
as macrophages. cytoplasm. This method of endocytosis permits the cell
Phagocytes can internalize particulate matter because to increase the concentration of the ligand (e.g., low-
they possess receptors that recognize certain surface fea- density lipoprotein) within the pinocytotic vesicle.
tures of the material to be engulfed. Two of the better A typical pinocytotic vesicle may have as many as
understood of these surface features come from the 1000 cargo receptors of several types, for they may bind
study of immunology and are the constant regions (Fc different macromolecules. Each cargo receptor is
Ch002-X2945.qxd 12/8/06 3:19 PM Page 33
Nucleus
Rough
endoplasmic
reticulum
9
Golgi
4 8
10
3
5 11
6
Clathrin-
12
coated pit 7
1
2
1 Ligand
in solution
2 Ligand attaches
to receptors
3 Clathrin-coated 8 Clathrin-coated vesicles
endocytotic vesicle containing lysosomal hydrolases
4 Clathrin triskelions or lysosomal membrane proteins
recycle to plasma 9 Late endosome
membrane pH = 5.5
5 Uncoated endocytotic 10 Multivesicular body
vesicle (type of lysosome)
6 Early endosome / recycling 11 Degradation products
endosome (CURL) pH = 6.0 within residual body
7 Recycling of receptors 12 Residual body fuses with cell membrane
to plasma membrane and contents eliminated from cell
Figure 2–22 The endosomal pathways. CURL, compartment for uncoupling of receptor and ligand.
linked to its own adaptin, the protein with a binding site

for the cytoplasmic aspect of the receptor, as well as a
binding site for the clathrin triskelion.
Endosomes
Endosomes are divided into two compartments: early
endosomes, near the periphery of the cell, and late
endosomes, situated deeper within the cytoplasm.
Shortly after their formation, pinocytotic vesicles lose

their clathrin coats (which return to the pool of clathrin
triskelions in the cytosol) and fuse with early endo-
somes (Fig. 2-25; also see Fig. 2-22), a system of vesi-
Figure 2–23 Electron micrograph of endocytosis in a capillary. cles and tubules located near the plasma membrane. If
(From Hopkins CR: Structure and Function of Cells. Philadelphia, the entire contents of the pinocytotic vesicle require
WB Saunders, 1978.)
degradation, the material from the early endosome is
transferred to a late endosome. This similar set of
Ch002-X2945.qxd 12/8/06 3:19 PM Page 34
Figure 2–24 Electron micrographs of trans-

port of microperoxidase, a trace molecule, across
the endothelial cell of a capillary (×35,840). A, The
lumen of the capillary is filled with the tracer; note
its uptake of pinocytotic vesicles on the luminal
aspect. Arrows indicate the extracellular space.
B, One minute later, the tracer has been conveyed
across the endothelial cell and exocytosed on the
connective tissue side into the extracellular space
(arrows). Note the region of fused vesicles (C),
forming a temporary channel between the lumen of
the capillary and the extracellular space. (From
Hopkins CR: Structure and Function of Cells.
Philadelphia, WB Saunders, 1978.)
tubules and vesicles, located deeper in the cytoplasm transcytosis. Some authors refer to this type of early
near the Golgi apparatus, helps to prepare its contents endosome as a CURL (compartment for uncoupling of
for eventual destruction by lysosomes. receptor and ligand) or, more recently, as a recycling
Early and late endosomes, collectively, constitute the endosome (see Figs. 2-22 and 2-25).
endosomal compartment. The membranes of all endo- Within 10 to 15 minutes of entering the early endo-
somes contain ATP-linked H+ pumps that acidify the some, the ligand either is transferred to a late endosome
interior of the endosomes by actively pumping H+ ions (as in the case of low-density lipoprotein) or is packaged
into the interior of the endosome so that the early endo- to be returned to the cell membrane, where it is
some has a pH of 6.0 and the late endosome a pH of 5.5. released (e.g., transferrin) into the extracellular space.
Material entering the early endosome may be Occasionally, both the receptor and the ligand (e.g., epi-
retrieved from that compartment and returned to its dermal growth factor and its receptor) are transferred
earlier location, as occurs with cargo receptors that need to the late endosome, and then to a lysosome, for even-
to be recycled. When the pinocytotic vesicle fuses with tual degradation.
the early endosome, the acidic environment causes an The transport between early and late endosomes has
uncoupling of the ligand from its receptor molecule. not been elucidated. Some authors suggest that early
The ligand remains within the lumen of the early endo- endosomes migrate along microtubule pathways into a
some, whereas the receptor molecules (e.g., low-density deeper location within the cell and become late endo-
lipoprotein receptors) are returned to the plasma mem- somes. Others postulate that early and late endosomes
brane where they originated, or to the plasma mem- are two separate compartments and that specific endo-
brane of another region of the cell, a process known as somal carrier vesicles ferry material from early to late
Ch002-X2945.qxd 12/8/06 3:19 PM Page 35
possess proton pumps that actively transport H+ ions

into the lysosome, maintaining its lumen at a pH of 5.0
(see Fig. 2-22).
Lysosomes aid in digesting not only macromolecules,
phagocytosed microorganisms, cellular debris, and cells
but also excess or senescent organelles, such as mito-
chondria and RER. The various enzymes digest the
engulfed material into small, soluble end products that
are transported by carrier proteins in the lysosomal
membrane from the lysosomes into the cytosol and are
either reused by the cell or exported from the cell into
the extracellular space.
Formation of Lysosomes
Lysosomes receive their hydrolytic enzymes as well as
their membranes from the trans Golgi network (TGN);
however, they arrive in different vesicles. Although both
types of vesicles possess a clathrin coat as they pinch
off the TGN, the clathrin coat is lost shortly after
formation. The uncoated vesicles then fuse with late
endosomes.
Vesicles ferrying lysosomal enzymes possess mannose-
6-phosphate receptors, to which these enzymes are
bound. In the acidic environment of the late endosome,
the lysosomal enzymes dissociate from their receptors,
their mannose residue becomes dephosphorylated, and
the receptors are recycled by being returned to the
Figure 2–25 Endocytotic vesicles (Tu) of the proximal tubule TGN. It should be understood that the dephosphory-
cell of the kidney cortex (×25,000). Note the presence of microvilli
(Bb), lysosomes (Ly), mitochondria (Mi), rough endoplasmic reticu- lated lysosomal hydrolases can no longer bind to the
lum (Re), free ribosomes (Ri), and, possibly, early endosomes (Va). mannose-6-phosphate receptors and therefore stay in
(From Rhodin JAG: An Atlas of Ultrastructure. Philadelphia, WB the late endosome (see Figs. 2-20 and 2-22).
Saunders, 1963.) When late endosomes possess both enzymatic and
membrane components, some authors hypothesize that
the late endosome fuses with a lysosome. However,
endosomes. These are believed to be large vesicles con- others suggest that it matures to become a lysosome.
taining numerous small vesicles that have been noted as
multivesicular bodies in electron micrographs. Both Transport of Substances into Lysosomes
theories recognize the presence of a system of micro-
tubules along which either the early endosome or the Substances destined for degradation within lysosomes
endosomal carrier vesicle negotiates its way to the late reach these organelles in one of three ways: through
endosome. phagosomes, pinocytotic vesicles, or autophagosomes
(see Fig. 2-22).
Lysosomes Phagocytosed material, contained within phago-
somes, moves toward the interior of the cell. The
Lysosomes have an acidic pH and contain hydrolytic phagosome joins either a lysosome or a late endosome.
enzymes. The hydrolytic enzymes digest most of the contents of
the phagosome, especially the protein and carbohydrate
The contents of late endosomes are delivered for enzy- components. Lipids, however, are more resistant to
matic digestion into the lumina of specialized organelles complete digestion, and they remain enclosed within
known as lysosomes (Fig. 2-26; also see Fig. 2-25). Each the spent lysosome, now referred to as a residual body.
lysosome is round to polymorphous in shape. Its average Senescent organelles such as mitochondria and
diameter is 0.3 to 0.8 µm, and it contains at least 40 organelles no longer required by the cell, or the RER
different types of acid hydrolases, such as sulfatases, of a quiescent fibroblast, need to be degraded. The
proteases, nucleases, lipases, and glycosidases, among organelles in question become surrounded by elements
others. Because all of these enzymes require an acid of the endoplasmic reticulum and are enclosed in vesi-
environment for optimal function, lysosomal membranes cles called autophagosomes. These structures fuse
Ch002-X2945.qxd 12/8/06 3:19 PM Page 36
Figure 2–26 Lysosomes of

rat cultured alveolar macrophages
(×45,000). (From Sakai M, Araki N,
Ogawa K: Lysosomal movements
during heterophagy and autophagy:
With special reference to nema-
tolysosome and wrapping lysosome.
J Electron Microsc Tech 12:101-131,
1989.)
either with late endosomes or with lysosomes and share Peroxisomes

the same subsequent fate as the phagosome.
Peroxisomes are self-replicating organelles that contain
oxidative enzymes.
CLINICAL CORRELATIONS Peroxisomes (microbodies) are small (0.2 to 1.0 µm in

diameter), spherical to ovoid membrane-bound organ-
Certain individuals with hereditary enzyme defi- elles that contain more than 40 oxidative enzymes,
ciencies are incapable of completely degrading especially urate oxidase, catalase, and D-amino acid
various macromolecules into soluble by-products. oxidase (Fig. 2-27). They are present in almost all animal
A lysosomal storage disorder generally results. cells and function in the catabolism of long-chained fatty
As the insoluble intermediaries of these sub- acids (beta oxidation), forming acetyl coenzyme A
stances become amassed within the lysosomes of (CoA) as well as hydrogen peroxide (H2O2) by com-
their cells, the size of these lysosomes increases bining hydrogen from the fatty acid with molecular
sufficiently to interfere with the abilities of these oxygen. Acetyl CoA is used by the cell for its own meta-
cells to perform their function (Table 2-1). bolic needs or is exported into the intercellular space to
Probably the most commonly known of these be used by neighboring cells. Hydrogen peroxide detox-
conditions is Tay-Sachs disease, occurring ifies various noxious agents (e.g., ethanol) and kills micro-
mostly in children of Northeast European Jewish organisms. Excess hydrogen peroxide is degraded into
ancestry and in certain individuals of Cajun water and molecular oxygen by the enzyme catalase.
ancestry in Louisiana. These children display a Proteins destined for peroxisomes are not manufac-
deficiency in the enzyme hexosaminidase and tured on the RER but in the cytosol and are transported
cannot catabolize GM2 gangliosides. Although into the peroxisomes by two specific peroxisome tar-
most cells in these children accumulate GM2 geting signals that direct the protein from the cytosol
ganglioside in the lysosomes, it is the neurons in to the peroxisome, where they recognize membrane-
their central and peripheral nervous systems that bound import receptors unique to the targeting signal.
are the most problematic. Lysosomes of these However, some peroxisomal membrane proteins may
cells become so engorged that they interfere with be manufactured on and targeted to the peroxisomes
neuronal function, causing the children to via the RER. Similar to mitochondria, peroxisomes
become vegetative within the first year or two increase in size and undergo fission to form new peroxi-
and to die by the third year of life. somes; however, they possess no genetic material of
their own.
Ch002-X2945.qxd 12/8/06 3:19 PM Page 37
TABLE 2–1 Major Lysosomal Storage Diseases
Type Specific Disease Enzyme Deficiency Metabolite Buildup
Glycogenosis Pompe’s disease (glycogen Lysosomal glucosidase Glycogen

storage disease, type II)
Sphingolipidosis GM1 gangliosidoses GM1 ganglioside beta- GM1 ganglioside;

galactosidase oligosaccharides containing
galactose
GM2 gangliosidoses
Tay-Sachs disease Hexosaminidase A GM2 ganglioside
Gaucher’s disease Glucocerebrosidase Glucocerebroside
Niemann-Pick disease Sphingomyelinase Sphingomyelin
Mucopolysaccharidosis
(MPS)
MPS I Hurler’s syndrome α-L-Iduronidase Heparan sulfate, dermatan
sulfate
MPS II Hunter’s syndrome L-Iduronosulfate sulfatase Heparan sulfate, dermatan
sulfate
Glycoproteinosis Enzymes that degrade Several, depending on

polysaccharide side enzyme
chains of glycoproteins
Modified from Kumar V, Cotran RS, Robbins SL: Basic Pathology, 5th ed. Philadelphia, WB Saunders, 1992.
Proteasomes plexes that have a molecular weight in excess of 2

million daltons. During proteolysis, the ubiquitin mol-
Proteasomes are small organelles composed of protein ecules are released and reenter the cytosolic pool. The
complexes that are responsible for proteolysis of mechanism of ubiquitination requires:
malformed and ubiquitin-tagged proteins.
䡲 The cooperation of a series of enzymes, including
The protein population of a cell is in a constant flux as ubiquitin-activating enzyme
a result of the continuous synthesis, export, and degra- 䡲 A family of ubiquitin-conjugating enzymes
dation of these macromolecules. Frequently, proteins, 䡲 A number of ubiquitin ligases each of which rec-
such as those that act in metabolic regulation, have to ognizes one or more substrate proteins
be degraded to ensure that the metabolic response to a Ubiquitination, the release of ubiquitin from the
single stimulus is not prolonged. Additionally, proteins candidate protein, and the mechanism of protein degra-
that have been denatured, damaged, or malformed have dation by the proteasome are all energy-requiring
to be eliminated; moreover, antigenic proteins that have processes. An average cell may have as many as 30,000
been endocytosed by antigen-presenting cells (APCs) proteasomes
have to be cleaved into small polypeptide fragments
(epitopes) so that they can be presented to T lympho- Mitochondria
cytes for recognition and the mounting of an immune
response. Mitochondria possess their own DNA and perform
The process of cytosolic proteolysis is carefully con- oxidative phosphorylation and lipid synthesis.
trolled by the cell, and it requires that the protein be
recognized as a potential candidate for degradation. Mitochondria are flexible, rod-shaped organelles, about
This recognition involves ubiquination, a process 0.5 to 1 µm in girth and sometimes as much as 7 µm in
whereby several ubiquitin molecules (a 76-amino acid length. Most animal cells possess a large number of
long polypeptide chain) are attached to a lysine residue mitochondria (as many as 2000 in each liver cell)
of the candidate protein to form a polyubiquinated because, via oxidative phosphorylation, they produce
protein. Once a protein has been thus tagged, it is ATP, a stable storage form of energy that can be used
degraded by proteasomes, multisubunit protein com- by the cell for its various energy-requiring activities.
Ch002-X2945.qxd 12/8/06 3:19 PM Page 38
Figure 2-27 Peroxisomes in hepatocytes

(×10,700). The cells were treated with 3′,3′-
diaminobenzidine and osmium tetroxide,
yielding a black reaction product caused by
the enzyme catalase located within peroxi-
somes. (From Hopkins CR: Structure and
Function of Cells. Philadelphia, WB Saun-
ders, 1978.)
Each mitochondrion possesses a smooth outer mem- matrix space (intercristal space). The contents of the
brane and a folded inner membrane (Fig. 2-28; also see two spaces differ somewhat and are discussed later.
Fig. 2-6). The folds of the inner membrane, known as
cristae, greatly increase the surface area of the membrane. Outer Mitochondrial Membrane
The number of cristae possessed by a mitochondrion is
related directly to the energy requirement of the cell; thus,
and Intermembrane Space
a cardiac muscle cell mitochondrion has more cristae than The outer mitochondrial membrane possesses a large
an osteocyte mitochondrion has. The narrow space (10 to number of porins, multipass transmembrane proteins.
20 nm in width) between the inner and outer membranes Each porin forms a large aqueous channel through
is called the intermembrane space, whereas the large which water-soluble molecules, as large as 10 kD, may
space enclosed by the inner membrane is termed the pass. Because this membrane is relatively permeable to
Ch002-X2945.qxd 12/8/06 3:19 PM Page 39
Matrix space
H+ H+
ATP ATP
Cristae
ADP + Pi ADP + Pi
(folds)
H+ H+ +
2H +1/2 O2 H2O
Outer Inner e– H+
membrane membrane
H+
Intermembrane
space H+ H+ H+
ATP H+
synthase H+ H+
Matrix ATP H+
H+ H+ H+
space synthase H+
Intermembrane space
A C
Matrix
space
Intermembrane
space Inner
Outer membrane
B membrane
Figure 2–28 The structure and function of mitochondria. A, Mitochondrion sectioned longitudinally to demonstrate its outer and folded
inner membranes. B, Enlarged region of the mitochondrion, displaying the inner membrane subunits and ATP synthase. C, Two ATP synthase
complexes and three of the five members of the electron transport chain that also function to pump hydrogen (H+) from the matrix into the
intermembrane space. ADP, adenosine diphosphate; ATP, adenosine triphosphate; Pi, inorganic phosphate.
small molecules, including proteins, the contents of the In certain regions, the outer and inner mitochondrial
intermembrane space resemble the cytosol. Addi- membranes contact each other; these contact sites act
tional proteins located in the outer membrane are as pathways for proteins and small molecules to enter
responsible for the formation of mitochondrial lipids. and leave the matrix space. The contact sites are com-
posed of carrier proteins for the transport and regula-
Inner Mitochondrial Membrane tory proteins for the recognition of markers denoting
the transportability of the specific macromolecules.
The inner mitochondrial membrane is folded into cristae These same contact sites are also used for the transport
to provide a larger surface area for ATP synthase and of proteins into the intermembrane space, provided that
the respiratory chain. the proteins bear markers specific for entry into that
space.
The inner mitochondrial membrane, which encloses the Additional sites are also available for the transport of
matrix space, is folded to form cristae. This membrane macromolecules that are destined for the outer or inner
is richly endowed with cardiolipin, a phospholipid that mitochondrial membrane or for the matrix. At these
possesses four, rather than the usual two, fatty acyl sites, the two membranes do not contact one another,
chains. The presence of this phospholipid in high con- but both inner and outer membranes possess receptor
centration makes the inner membrane nearly imper- molecules that recognize not only the macromolecule
meable to ions, electrons, and protons. that is being transported but also cytosolic carrier
Ch002-X2945.qxd 12/8/06 3:19 PM Page 40
molecules (and chaperones) responsible for the deliv- Acetyl CoA, formed through the β-oxidation of fatty
ery of that particular macromolecule. acids and the degradation of glucose, is oxidized in the
Viewed in negatively stained preparations, the inner citric acid cycle to produce, in addition to carbon
membrane displays the presence of a large number of dioxide (CO2), large quantities of the reduced cofactors
lollipop-like inner membrane subunits, protein com- nicotinamide adenine dinucleotide (NADH) and flavin
plexes known as ATP synthase, which are responsible adenine dinucleotide (FADH2). Each of these cofactors
for the generation of ATP from ADP and inorganic phos- releases a hydride ion (H+) which is stripped of its two
phate. The globular head of the subunit, about 10 nm in high-energy electrons and becomes a proton (H+). The
diameter, is attached to a narrow, flattened, cylinder-like electrons are transferred to the electron transport chain
stalk, 4 nm wide and 5 nm long, projecting from the inner and during mitochondrial respiration reduce oxygen
membrane into the matrix space (see Fig. 2-28). (O2) to form water (H2O).
Additionally, a large number of protein complexes, According to the chemiosmotic theory, the energy
the respiratory chains, are present in the inner mem- released by the sequential transfer of the electrons is
brane. Each respiratory chain is composed of three used to transport H+ from the matrix into the inter-
respiratory enzyme complexes: (1) NADH dehydroge- membrane space, establishing a high proton concentra-
nase complex, (2) cytochrome b-c1 complex, and (3) tion in that space exerting a proton motive force (see
cytochrome oxidase complex. These complexes form Fig. 2-28). Only through ATP synthase may these
an electron transport chain that is responsible for the protons leave the intermembrane space and reenter the
passage of electrons along this chain and, more impor- matrix. As the protons pass down this electrochemical
tant, that function as proton pumps that transport H+ gradient, the energy differential in the proton motive
from the matrix into the intermembrane space, estab- force is transformed into the stable high-energy bond
lishing an electrochemical gradient that provides of ATP by the globular head of the inner membrane
energy for the ATP-generating action of ATP synthase. subunit, which catalyzes the formation of ATP from
ADP + Pi, where Pi is inorganic phosphate. The newly
Matrix formed ATP either is utilized by the mitochondrion or
is transported, through an ADP-ATP antiport system,
The matrix space is filled with a dense fluid composed
into the cytosol. During the entire process of glycolysis,
of at least 50% protein, which accounts for its viscosity.
tricarboxylic acid cycle, and electron transport, each
Much of the protein component of the matrix is
glucose molecule yields 36 molecules of ATP.
enzymes responsible for the stepwise degradation of
In some cells, such as the brown fat cells of hiber-
fatty acids and pyruvate to the metabolic intermediate
nating animals, oxidation is uncoupled from phosphor-
acetyl CoA and the subsequent oxidation of this
ylation, resulting in the formation of heat instead of
intermediate in the tricarboxylic acid (Krebs) cycle.
ATP. This uncoupling is dependent on the presence of
Mitochondrial ribosomes, tRNA, mRNA, and dense
proton shunts, known as thermogenins, that resemble
spherical matrix granules (30 to 50 nm in diameter)
ATP synthase but that cannot generate ATP. As the
are also present in the matrix.
protons pass through thermogenins to reenter the
The function of matrix granules is not understood.
matrix, the energy of the proton motive force is trans-
They are composed of phospholipoprotein, although in
formed into heat. It is this heat that awakens the animal
some cells, especially cells of bone and cartilage, they
from its state of hibernation.
may also bind magnesium and calcium. Moreover, in
injured cells whose cytosolic Ca2+ levels are dangerously
high, matrix granules may sequester calcium to protect Origin and Replication
the cell from calcium toxicity. of Mitochondria
The matrix also contains the double-stranded mito-
Because of the presence of the mitochondrial genetic
chondrial circular deoxyribonucleic acid (cDNA)
apparatus, it is believed that mitochondria were free-
and the enzymes necessary for the expression of the
living organisms that either invaded or were phago-
mitochondrial genome. cDNA contains information for
cytosed by anaerobic eukaryotic cells, developing
the formation of only 13 mitochondrial proteins, 16S and
a symbiotic relationship. The mitochondrion-like
12S rRNA, and genes for 22 tRNAs. Therefore, most of
organism received protection and nutrients from its
the codes necessary for the formation and functioning of
host and provided its host with the capability of reduc-
mitochondria are located in the genome of the nucleus.
ing its O2 content and simultaneously supplying it with
a stable form of chemical energy.
Oxidative Phosphorylation Mitochondria are self-replicating, in that they are
generated from preexisting mitochondria. These
Oxidative phosphorylation is the process responsible for
organelles enlarge in size, replicate their DNA, and
the formation of ATP.
undergo fission. The division usually occurs through the
Ch002-X2945.qxd 12/8/06 3:19 PM Page 41
intracristal space of one of the centrally located cristae. Glycogen is the most common storage form of glucose in
The outer mitochondrial membrane of the opposing animals and is especially abundant in cells of muscle and
halves extends through that intracristal space; the halves liver. It appears in electron micrographs as clusters, or
meet and fuse with each other, thus dividing the mito- rosettes, of β particles (and larger α particles in the liver)
chondrion into two nearly equal halves. The two new that resemble ribosomes, located in the vicinity of the
mitochondria move away from each other. The average SER. On demand, enzymes responsible for glycogenolysis
life span of a mitochondrion is about 10 days. degrade glycogen into individual molecules of glucose.
Annulate Lamella
Annulate lamellae are parallel aggregates of membranes CLINICAL CORRELATIONS
that enclose cistern-like spaces, thus resembling multi-
ple copies, usually six to ten, of nuclear envelopes. They Some individuals suffer from glycogen storage
possess nuclear pore complex-like regions (annuli) that disorders as a result of their inability to degrade
are in register with those of neighboring membranes. glycogen, resulting in excess accumulation of this
The cisternae of these organelles are relatively evenly substance in the cells. There are three classifica-
spaced, separated by about 80 to 100 nm, and are con- tions of this disease: (1) hepatic, (2) myopathic,
tinuous with the cisternae of the RER. and (3) miscellaneous. The lack or malfunction of
These organelles are normally present only in cells that one of the enzymes responsible for the degrada-
have high mitotic indices, such as oocytes, tumor cells, and tion is responsible for these disorders (Table 2-2).
embryonic cells. Because of their resemblance to the
nuclear envelope, some authors suggest that they act as
reserves for the nuclear envelope in these rapidly dividing
cells. However, immunocytochemical studies of annulate Lipids
lamellae do not lend support to that supposition, and
Lipids are storage forms of triglycerides.
neither their function nor their significance is understood.
Lipids, triglycerides in storage form, not only are stored
INCLUSIONS in specialized cells (adipocytes) but also are located as
individual droplets in various cell types, especially
Inclusions are considered to be nonliving components of hepatocytes. Most solvents used in histological prepa-
the cell that do not possess metabolic activity and are not rations extract triglycerides from cells, leaving empty
bounded by membranes. The most common inclusions spaces indicative of the locations of lipids. However,
are glycogen, lipid droplets, pigments, and crystals. with the use of osmium and glutaraldehyde, the lipids
(and cholesterol) may be fixed in position as gray-to-
Glycogen black intracellular droplets. Lipids are very efficient
forms of energy reserves; twice as many ATPs are
Glycogen is the storage form of glucose.
derived from 1 g of fat as from 1 g of glycogen.
TABLE 2–2 Major Subgroups of Glycogen Storage Disorders
Type (Specific Deficient

Disease) Enzyme Tissue Changes Clinical Signs
Hepatic Glucose-6- Intracellular accumulation of Enlarged liver and kidneys; hypoglycemia

Hepatorenal (von phosphatase glycogen in hepatocytes and with subsequent convulsions; gout;
Gierke’s disease) cortical tubules of kidneys bleeding; 50% mortality rate
Myopathic Muscle Glycogen accumulation in Cramps following vigorous exercise; adult

(McArdle’s phosphorylase skeletal muscle cells onset
syndrome)
Miscellaneous Lysosomal acid Glycogen accumulation Massively enlarged heart; cardiac and
(Pompe’s disease) maltase Enlarged lysosomes in respiratory failure within 2 years of
hepatocytes onset; adults have milder form involving
only skeletal muscle
Ch002-X2945.qxd 12/8/06 3:19 PM Page 42
Pigments The cytoplasm of animal cells contains a cytoskeleton,

an intricate three-dimensional meshwork of protein
The most common pigment in the body, besides hemo- filaments that are responsible for the maintenance of
globin of red blood cells, is melanin, manufactured by cellular morphology. Additionally, the cytoskeleton is
melanocytes of the skin and hair, pigment cells of the an active participant in cellular motion, whether of
retina, and specialized nerve cells in the substantia nigra organelles or vesicles within the cytoplasm, regions of
of the brain. These pigments have protective functions the cell, or the entire cell. The cytoskeleton has three
in skin and aid in the sense of sight in the retina, but components: thin filaments (microfilaments), interme-
their role in hair and neurons is not understood. Addi- diate filaments, and microtubules.
tionally, in long-lived cells, such as neurons of the
central nervous system and cardiac muscle cells, a Thin Filaments
yellow-to-brown pigment, lipofuscin, has been demon-
strated. Unlike other inclusions, lipofuscin pigments are Thin filaments are actin filaments that interact with
membrane-bound and are believed to represent the myosin to bring about intracellular or cellular
indigestible remnants of lysosomal activity. They are movement.
formed from fusion of several residual bodies.
Thin filaments (microfilaments) are composed of two
Crystals chains of globular subunits (G-actin) coiled around
each other to form a filamentous protein, F-actin (Figs.
Crystals are not commonly found in cells, with the 2-30 and 2-31). Actin constitutes about 15% of the total
exception of Sertoli cells (crystals of Charcot- protein content of non-muscle cells. Only about half of
Böttcher), interstitial cells (crystals of Reinke) of the their total actin is in the filamentous form, because the
testes, and occasionally in macrophages (Fig. 2-29). It monomeric G-actin form is bound by small proteins,
is believed that these structures are crystalline forms of such as profilin and thymosin, which prevent their
certain proteins. polymerization. Actin molecules, present in the cells of
many different vertebrate and invertebrate species, are
CYTOSKELETON very similar to each other in their amino acid sequence,
attesting to their highly conserved nature.
Thin filaments are 6-nm thick and possess a faster-
The cytoskeleton has three major components: thin
growing plus end and a slower-growing minus end.
filaments, intermediate filaments, and microtubules.
When the actin filament reaches its desired length,
Figure 2–29 Electron micrograph of crystalloid

inclusions in a macrophage (×5100). (From Yamazaki
K: Isolated cilia and crystalloid inclusions in murine
bone marrow stromal cells. Blood Cells 13:407-416,
1988.)
Ch002-X2945.qxd 12/8/06 3:19 PM Page 43
A Microtubule opposite effect: it removes the gelsolin cap, permitting

Tubulin dimers elongation of the actin filament.
α Tubulin (heterodimers) Depending on their isoelectric point, there are three
β Tubulin classes of actin: a-actin of muscle, and b-actin and g-
5 nm (+) End
actin of non-muscle cells. Although actin participates
in the formation of various cellular extensions as well as
25 nm in assembling structures responsible for motility, its
basic composition is unaltered. It is capable of fulfilling
its many roles via its association with different actin-
Cross section Longitudinal view binding proteins. The most commonly known of these
proteins is myosin, but numerous other proteins, such
B Thin filaments (actin) as α-actinin, spectrin, fimbrin, filamin, gelsolin, and
talin, also bind to actin to perform essential cellular
functions (Table 2-3).
6 nm
Actin filaments form bundles of varied lengths,
depending on the function that they perform in non-
Actin monomer
muscle cells. These bundles form three types of
associations:
C Intermediate filaments
䡲 Contractile bundles
䡲 Gel-like networks
8–10 nm 䡲 Parallel bundles
Contractile bundles, such as those responsible for the
formation of cleavage furrows (contractile rings) during
mitotic division, are usually associated with myosin.
Their actin filaments are arranged loosely, parallel to
each other, with the plus and minus ends alternating in
Fibrous subunit direction. These assemblies are responsible for move-
ment not only of organelles and vesicles within the cell
but also for cellular activities, such as exocytosis and
D Centriole endocytosis, as well as the extension of filopodia and cell
migration.
The myosin associated with these contractile bundles
may be one of several types: myosin-I through myosin-
IX. Myosin-II forms thick filaments (15 nm in diam-
eter) and moves actin filaments, especially in muscle
cells. Myosin-V can bind not only to actin filaments but
also to other cytoplasmic components, such as vesicles,
0.5 µm moving them along an actin filament from one position
in the cell to another, whereas myosin-I has been impli-
cated in the formation and retraction of actin-directed
protrusions of the cell cortex, such as in the formation
of pseudopods.
Gel-like networks provide the structural founda-
Figure 2–30 Elements of the cytoskeleton and centriole. tion of much of the cell cortex. Their stiffness is due to
A, Microtubule; B, thin filaments (actin); C, intermediate filaments; the protein filamin, which assists in the establishment
D, centriole.
of a loosely organized network of actin filaments result-
ing in localized high viscosity. During the formation of
filopodia, the gel is liquefied by proteins such as gel-
members of a family of small proteins, capping pro- solin, which, in the presence of ATP and high Ca2+,
teins, attach to the plus end, terminating the lengthen- cleaves the actin filaments and, by forming a cap over
ing of the filament. The process of shortening of actin their plus end, prevents them from lengthening.
filaments is regulated in the presence of ATP, ADP, and The proteins fimbrin and villin are responsible for
Ca2+ by capping proteins, such as gelsolin, which forming actin filaments into closely packed parallel
prevent polymerization of the filament. The cell mem- bundles that form the core of microspikes and micro-
brane phospholipid polyphosphoinositide has the villi, respectively. These bundles of actin filaments are
Ch002-X2945.qxd 12/8/06 3:19 PM Page 44

graph of clathrin-coated vesicles
contacting filaments (arrowheads) in
granulosa cells of the rat ovary
(×35,000). (From Batten BE, Ander-
son E: The distribution of actin in
cultured ovarian granulosa cells. Am
J Anat 167:395-404, 1983.)
TABLE 2–3 Actin-Binding Proteins
Molecular Mass of Number of

Protein Each Subunit (Da) Subunits Function
α-Actinin 100,000 2 Bundling actin filaments for contractile bundles
Fimbrin 68,000 1 Bundling actin filaments for parallel bundles
Filamin 270,000 2 Cross-link actin filaments into gel-like network
Myosin-II 260,000 2 Contraction by sliding actin filaments
Myosin-V 150,000 1 Movement of vesicles and organelles along actin filaments
Spectrin Forms supporting network for plasma membrane of red blood

α 265,000 2 cell
β 260,000 2
Gelsolin 90,000 1 Cleaves and caps actin filaments
Thymosin 5000 1 Binds to G-actin subunits, maintaining them in

monomeric form
anchored in the terminal web, a region of the cell ment. Vinculin binds to α-actinin, the actin-binding
cortex composed of a network of intermediate filaments protein that assembles actin into contractile bundles.
and the protein spectrin. Spectrin molecules are flexi- These contractile bundles, referred to as stress fibers
ble, rod-like tetramers that assist the cell in maintain- in fibroblasts maintained in tissue culture, resemble
ing the structural integrity of the cortex. myofibrils of striated muscle. Stress fibers may extend
Actin is also important in the establishment and between two focal points or a focal point and interme-
maintenance of focal contacts of the cell with extra- diate filaments and assist the cell in exerting a tensile
cellular matrix (Fig. 2-32). At focal contacts, the inte- force on the extracellular matrix (as in the wound con-
grin (a transmembrane protein) of the cell membrane traction function of fibroblasts).
binds to structural glycoproteins, such as fibronectin,
of the extracellular matrix, permitting the cell to main-
tain its attachment. Simultaneously, the intracellular Intermediate Filaments
region of the integrin contacts the cytoskeleton via
Intermediate filaments and their associated proteins
intermediary proteins that attach it to actin filaments.
assist in the establishment and maintenance of the
The mode of attachment involves integrin binding to
three-dimensional framework of the cell.
talin, which contacts both vinculin and the actin fila-
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Cytoplasm
the same morphological and structural characteristics.
F-actin These rope-like intermediate filaments are constructed
of tetramers of rod-like proteins that are tightly bundled
into long helical arrays. The individual subunit of each
tetramer differs considerably for each type of intermedi-
ate filament. The categories of intermediate filaments
Talin include keratins, desmin, vimentin, glial fibrillary acidic
α-actinin protein, neurofilaments, and nuclear lamins (Table 2-4).
Several intermediate filament-binding proteins have
Cell
been discovered. As they bind to intermediate fila-
membrane ments, they link them into a three-dimensional network
Vinculin that facilitates the formation of the cytoskeleton. Four
of the best known of these proteins have the following
characteristics:
1 Filaggrin binds keratin filaments into bundles.
2 Synamin and plectin bind desmin and vimentin,
respectively, into three-dimensional intracellular
Fibronectin, β subunit of α subunit of meshworks.
laminin integrin integrin 3 Plakins assist the maintenance of contact between
Extracellular space
the keratin intermediate filaments and hemidesmo-
Figure 2–32 The cytoskeleton. Fibronectin and laminin recep- somes of epithelial cells as well as actin filaments with
tor regions of integrin molecules bind to fibronectin and laminin, neurofilaments of sensory neurons.
respectively, in the extracellular space. Intracellular talin-binding or
α-actinin–binding regions of integrin molecules bind to talin or α-
actinin, respectively. Thus, integrin molecules bridge the cytoskele-
ton to an extracellular support framework. CLINICAL CORRELATIONS
Immunocytochemical methods, utilizing specific
Electron micrographs display a category of filaments in immunofluorescent antibodies, are employed to
the cytoskeleton whose diameter of 8 to 10 nm places distinguish intermediate filament types in tumors
them between thick and thin filaments and they are of unknown origin. Knowledge of the source of
consequently named intermediate filaments (see Fig. these tumors assists not only in their diagnosis
2-30). These filaments and their associated proteins but also in devising effective treatment plans.
accomplish the following:
䡲 Provide structural support for the cell
䡲 Form a deformable three-dimensional structural Microtubules
framework for the cell
䡲 Anchor the nucleus in place Microtubules are long, straight, rigid tubular-appearing
䡲 Provide an adaptable connection between the cell structures that act as intracellular pathways.
membrane and the cytoskeleton
The centrosome is the region of the cell in the vicin-
䡲 Furnish a structural framework for the maintenance
ity of the nucleus that houses the centrioles (see later),
of the nuclear envelope as well as its reorganization
as well as several hundred ring-shaped g-tubulin ring
subsequent to mitosis
complex molecules. These γ-tubulin molecules act as
When microbeads bound to integrin molecules of the nucleation sites for microtubules, which are long,
cell membrane are micromanipulated, as when one pulls straight, rigid, hollow-like cylindrical structures 25 nm
on them, the tensile forces produce distortion of the in outer diameter, with a luminal diameter of 15 nm
cytoskeleton, with resultant deformation of the nucleus (Fig. 2-33; also see Fig. 2-30). Therefore, the centro-
and rearrangement of the nucleoli. Thus, it appears that some is considered to be the MTOC of the cell.
the cytoskeleton, and specifically the intermediate fila- Microtubules are polarized, having a rapidly growing
ments, react to forces generated in the extracellular matrix, plus end as well as a minus end, which must be stabi-
and by forcing modulations in the shape and location of cel- lized or it will depolymerize, thus shortening the micro-
lular constituents, they protect the structural and func- tubule. The minus end is stabilized by being embedded
tional integrity of the cell from external stresses and strains. in a γ-tubulin molecule. Microtubules are dynamic
Biochemical investigations have determined that there structures that frequently change their length by under-
are several categories of intermediate filaments that share going growth spurts and then becoming shorter; both
Ch002-X2945.qxd 12/8/06 3:19 PM Page 46
TABLE 2–4 Predominant Types of Intermediate Filaments
Polypeptide
Filament Component Size (Da) Cell Type Function
Keratins (30 Support cell assemblies and provide

variations) tensile strength to cytoskeleton
Type I (acidic) 40,000-70,000 Epithelial cells
Type II 40,000-70,000 Cells of hair and nails
(neutral/basic)
Tonofilaments 40,000-70,000 Epithelial cells, especially Assist in formation of desmosomes

stratified squamous and hemidesmosomes
keratinized
Desmin 53,000 All types of muscle cells Links myofibrils in striated muscle
(around Z disks); attaches to
cytoplasmic densities in smooth
muscle
Vimentin 54,000 Cells of embryo as well as Surrounds nuclear envelope; is

cells of mesenchymal associated with cytoplasmic aspect
origin: fibroblasts, of nuclear pore complex
leukocytes, endothelial
cells
Glial fibrillary acidic 50,000 Astrocytes, Schwann cells, Supports glial cell structure
protein (GFAP) oligodendroglia
Neurofilaments Neurons Form cytoskeleton of axons and

L: low molecular 68,000 dendrites; assist in the formation
weight (NF-L) of the gel state of the cytoplasm;
cross-linking responsible for great
M: medium 160,000 tensile strength
molecular
weight (NF-M)
H: high molecular 210,000
weight (NF-H)
Nuclear lamins 65,000-75,000 Lining of nuclear Control and assembly of the nuclear
A, B, and C envelopes of all cells envelope; organization of
perinuclear chromatin
processes occur at the plus ends, so that the average ization of the heterodimers requires the presence of
half-life of a microtubule is only about 10 minutes. The magnesium (Mg2+) and GTP. During cell division, rapid
main functions of microtubules are to: polymerization of existing as well as new microtubules is
responsible for the formation of the spindle apparatus.
䡲 Provide rigidity and maintain cell shape
䡲 Regulate intracellular movement of organelles and
vesicles
䡲 Establish intracellular compartments CLINICAL CORRELATIONS
䡲 Provide the capability of ciliary (and flagellar) motion The polymerization process is disrupted by
Each microtubule consists of 13 parallel protofila- antimitotic drugs, such as colchicine, that block
ments composed of heterodimers of the globular the mitotic event by binding to the tubulin
polypeptide α- and β-tubulin subunits, each consisting molecules, preventing their assembly into the
of about 450 amino acids and each having a molecular protofilament.
mass of about 50,000 daltons (see Fig. 2-30). Polymer-
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Figure 2–33 Electron micrograph of micro-

tubules assembled with and without microtubule-
associated proteins (MAPs) (×65,790). Top,
Microtubules assembled from unfractionated MAPs.
Center, Microtubules assembled in the presence of
MAP2 subfraction only. Bottom, Microtubules assem-
bled without MAPs. (From Leeson TS, Leeson CR,
and Papparo AA: Text/Atlas of Histology. Philadel-
phia, WB Saunders, 1988.)
Microtubule-Associated Proteins tubules and to assist in the intracellular movement of

organelles and vesicles.
Microtubule-associated proteins are motor proteins that Movement along a microtubule occurs in both direc-
assist in the translocation of organelles and vesicles tions and is toward both the plus end and the minus
inside the cell. end. The two major families of microtubule motor pro-
teins, the MAPs dynein and kinesin, bind to the
In addition to tubulin heterodimers, microtubules also microtubule as well as to vesicles (and organelles). It is
possess microtubule-associated proteins (MAPs) bound believed that different members of each motor protein
to their periphery at 32-nm intervals. There are various family transport their cargo at disparate, meticulously
types of MAPs, ranging in molecular weight from about controlled rates and that different organelles have their
50,000 to more than 300,000 daltons. Their primary own particular motor protein. In the presence of ATP,
functions are to prevent depolymerization of micro- dynein moves the vesicle toward the minus end of the
Ch002-X2945.qxd 12/8/06 3:19 PM Page 48
microtubule. Kinesin effects vesicular (and organelle) tioned closest to the center of the cylinder; “C” is the
transport in the opposite direction, toward the plus end, farthest away. Adjacent triplets are connected to each
but the mechanism of ATP utilization by these MAPs is other by a fibrous substance of unknown composition,
not understood. Additionally, dynein and kinesin par- extending from microtubule A to microtubule C. Each
ticipate in the organization of the minus and plus ends, triplet is arranged so that it forms an oblique angle with
respectively. the adjacent triplet and a straight angle with the fifth
triplet.
Centrioles During the S phase of the cell cycle, each centriole
of the pair replicates, forming a procentriole in some
Centrioles are small, cylindrical structures composed of unknown manner, at 90 degrees to itself. This procen-
nine microtubule triplets; they constitute the core of the triole initially possesses no microtubules, but tubulin
microtubule organizing center, or the centrosome. molecules begin to polymerize closest to the parent cen-
triole, with the plus end growing away from the parent.
Centrioles are small, cylindrical structures, 0.2 µm in The actual replication of the centriole requires the pres-
diameter and 0.5 µm in length (see Fig. 2-30). Usually, ence of γ-tubulin rings, structures that do not become
they are paired structures, arranged perpendicular to part of but serve to direct the elongation of the forming
each other, and are located in the microtubule organiz- microtubules by occupying the forming plus and minus
ing center, the centrosome, in the vicinity of the Golgi ends. It is believed that the γ-tubulin rings and peri-
apparatus. The centrosome assists in the formation centrin serve as beams that support the developing cen-
and organization of microtubules as well as in its self- triole. Additionally, δ-tubulins, related to the α- and
duplication before cell division. β-tubulin superfamily, are also required to form the
Centrioles are composed of a specific arrangement triplet structure of the microtubule arrays.
of nine triplets of microtubules arranged around a Centrioles function in the formation of the centro-
central axis. Each microtubule triplet consists of one some, and during mitotic activity they are responsible
complete and two incomplete microtubules fused to for the formation of the spindle apparatus. Additionally,
each other, so that the incomplete ones share three centrioles are the basal bodies that guide the formation
protofilaments. The complete microtubule “A” is posi- of cilia and flagella.
Ch003-X2945.qxd 12/8/06 3:20 PM Page 49
3 䡲䡲䡲
Nucleus
The nucleus is the largest organelle of the cell (Fig. 3- and outer nuclear membranes are continuous with one
1). It contains nearly all of the deoxyribonucleic acid another. The nuclear envelope helps to control move-
(DNA) possessed by the cell as well as the mechanisms ment of macromolecules between the nucleus and the
for ribonucleic acid (RNA) synthesis, and its resident cytoplasm and assists in organizing the chromatin.
nucleolus is the location for the assembly of ribosomal
subunits. The nucleus, bounded by two lipid mem- Inner Nuclear Membrane
branes, houses three major components: The inner nuclear membrane is about 6-nm thick and
䡲 Chromatin, the genetic material of the cell faces the nuclear contents. It is in close contact with the
䡲 The nucleolus, the center for ribosomal RNA nuclear lamina, an interwoven meshwork of interme-
(rRNA) synthesis diate filaments, 80- to 100-nm thick, composed of
䡲 Nucleoplasm, containing macromolecules and nuclear lamins A, B, and C and located at the periphery of the
particles involved in the maintenance of the cell. nucleoplasm. The nuclear lamina help in organizing and
providing support to the lipid bilayer membrane and
The nucleus is usually spherical and is centrally the perinuclear chromatin, as well as play a role in the
located in the cell; however, in some cells it may be assembly of vesicles to re-form the nuclear envelope
spindle-shaped to oblong-shaped, twisted, lobulated, subsequent to cell division. Certain integral proteins of
or even disk-shaped. Although usually each cell has a the inner nuclear membrane act either directly or via
single nucleus, some cells (such as osteoclasts) possess other nuclear matrix proteins as contact sites for nuclear
several nuclei, whereas mature red blood cells have RNAs and chromosomes.
extruded nuclei. The size, shape, and form of the
nucleus are generally constant for a particular cell type, Outer Nuclear Membrane
a fact useful in clinical diagnoses of the degree of malig-
nancy of certain cancerous cells. The outer nuclear membrane is also about 6-nm thick,
faces the cytoplasm, and is continuous with the rough
endoplasmic reticulum (RER). It is considered by some
NUCLEAR ENVELOPE authors as a specialized region of the RER (see Figs. 3-
2 and 3-3). Its cytoplasmic surface is surrounded by a
The nuclear envelope is composed of two parallel unit thin, loose meshwork of the intermediate filaments,
membranes that fuse with each other at certain regions termed vimentin. Its cytoplasmic surface usually pos-
to form perforations known as nuclear pores. sesses ribosomes actively synthesizing transmembrane
proteins that are destined for the outer or inner nuclear
The nucleus is surrounded by the nuclear envelope, membranes.
composed of two parallel unit membranes: the inner
and outer nuclear membranes, separated from each Nuclear Pores
other by a 10- to 30-nm space called the perinuclear
Nuclear pores are interruptions in the nuclear envelope,
cisterna (Figs. 3-2 and 3-3). The nuclear envelope is
where the inner and outer nuclear membranes fuse with
perforated at various intervals by nuclear pores (dis-
each other, establishing sites where communication may
cussed later) that permit communication between the
occur between the nucleus and the cytoplasm.
cytoplasm and the nucleus. At these pores, the inner
49
Ch003-X2945.qxd 12/8/06 3:21 PM Page 50
50 䡲䡲䡲 Chapter 3 䡲 Nucleus
Figure 3–1 Cell nuclei. Light

micrograph (×1323). Typical cells,
ChG each containing a spherical nucleus
(N). Observe the chromatin granules
(ChG) and the nucleolus (n).
At certain locations on the surface of the nuclear enve- Associated Glycoproteins

lope, the outer and inner nuclear membranes are con-
tinuous with each other, creating openings known as The cytoplasmic ring, composed of eight subunits, is
nuclear pores, which permit communication between located on the rim of the cytoplasmic aspect of the
the nuclear compartment and the cytoplasm (Fig. 3-4). nuclear pore. Each subunit possesses a cytoplasmic fil-
The number of nuclear pores ranges from a few dozen ament, believed to be a Ran-binding protein (a family
to several thousand, correlated directly with the meta- of guanosine triphosphate [GTP]-binding proteins),
bolic activity of the cell. that extends into the cytoplasm. It has been suggested
High-resolution electron microscopy has revealed that these fibers may mediate import into the nucleus
that the nuclear pore is surrounded by nonmembra- through the nuclear pore complex by moving substrates
nous structures (glycoproteins) embedded in its rim. along their length toward the center of the pore.
These structures and the pore are called the nuclear The luminal spoke ring (middle ring) is com-
pore complex, which selectively guards passage posed of a set of eight transmembrane proteins that
through the pore (Fig. 3-5). Evidence suggests that each project into the lumen of the nuclear pore as well as
of the nuclear pore complexes is in communication with into the perinuclear cistern. These spoke-like proteins
the others via the nuclear lamina and certain pore- appear to anchor the glycoprotein components of the
connecting fibers. nuclear pore complex into the rim of the nuclear pore.
The center of the middle ring is occupied by an
oblong-shaped structure known as the transporter,
Nuclear Pore Complex which is coupled to the spoke-like proteins of the
luminal ring. Note that the presence of the transporter
The nuclear pore complex is composed of the nuclear (central plug) is not universally accepted because some
pore and its associated glycoproteins. investigators consider it to be the material being trans-
ported into or out of the nucleus; thus it is not presented
The nuclear pore complex is about 100 to 125 nm in within the model in Figure 3-6. The central lumen of
diameter and spans the two nuclear membranes. It is the middle ring is believed to be a gated channel that
composed of three ring-like arrays of proteins stacked restricts passive diffusion between the cytoplasm and
on top of the other, each ring displaying eight-fold sym- the nucleoplasm. It is associated with additional protein
metry and interconnected by a series of spokes arranged complexes that facilitate the regulated transport of
in a vertical fashion. In addition, the nuclear pore materials across the nuclear pore complex.
complex has cytoplasmic fibers, a transporter, and a A nuclear ring (nucleoplasmic ring), analogous to
nuclear basket (Fig. 3-6). the cytoplasmic ring, is located on the rim of the nucleo-
Ch003-X2945.qxd 12/8/06 3:21 PM Page 51
Chapter 3 䡲 Nucleus ■ ■ ■ 51
Figure 3–2 Cell nucleus. Electron

micrograph (×16,762). Observe the elec-
tron-dense nucleolus, the peripherally
located dense heterochromatin, and the
light euchromatin. The nuclear envelope
surrounding the nucleus is composed of an
inner nuclear membrane and an outer
nuclear membrane that is interrupted by
the nuclear pores (arrows). (From Fawcett
DW: The Cell. Philadelphia, WB Saunders,
1981.)
plasmic aspect of the nuclear pore and assists in the Although the nuclear pore is relatively large, it is nearly
export of several types of RNA. A filamentous, flexible, filled with the structures constituting the nuclear pore
basket-like structure, the nuclear basket, appears to be complex. Because of the structural conformation of
suspended from the nucleoplasmic ring and protruding those subunits, several 9- to 11-nm wide channels are
into the nucleoplasm. The nuclear basket becomes available for simple diffusion of ions and small mole-
deformed during the process of nuclear export. Attached cules. However, macromolecules and particles larger
to the distal aspect of the nuclear basket is the distal ring. than 11 nm cannot reach or leave the nuclear compart-
ment via simple diffusion; instead, they are selectively
Nuclear Pore Function transported via a receptor-mediated transport
process. Signal sequences of molecules to be trans-
The nuclear pore functions in bidirectional
ported through the nuclear pores must be recognized
nucleocytoplasmic transport.
by one of the many receptor sites of the nuclear pore
Ch003-X2945.qxd 12/8/06 3:21 PM Page 52
Recently it has been reported that certain other trans-

port mechanisms literally shuttle in both directions.
These transport signals are called nucleocytoplasmic
shuttling (NS) signals. Proteins that carry this signal
Euchromatin
interact with mRNA.
Nuclear
envelope CHROMATIN
Nuclear
Chromatin is a complex of DNA and proteins and
lamina
represents the relaxed, uncoiled chromosomes of the
interphase nucleus.
Heterochromatin
DNA, the cell’s genetic material, resides in the nucleus
in the form of chromosomes, which are clearly visible
Nucleolus during cell division. In the interval between cell divi-
sions, the chromosomes are unwound in the form of
chromatin (see Figs. 3-2 and 3-3). Depending on its
Nuclear pore transcriptional activity, chromatin may be condensed as
heterochromatin or extended as euchromatin.
Heterochromatin, a condensed inactive form of
chromatin, stains deeply with Feulgen stains, which make
Endoplasmic
reticulum it visible with the light microscope. It is located mostly
at the periphery of the nucleus. The remainder of the
chromatin, scattered throughout the nucleus and not
Ribosomes
visible with the light microscope, is euchromatin. This is
the active form of chromatin in which the genetic mate-
rial of the DNA molecules is being transcribed into RNA.
When euchromatin is examined with electron micros-
Figure 3–3 Nucleus. The outer nuclear membrane is studded
copy, it is seen to be composed of a thread-like mate-
with ribosomes on its cytoplasmic surface, and it is continuous with rial 30-nm thick. More careful evaluation indicates that
the rough endoplasmic reticulum. The space between the inner and these threads may be unwound, resulting in an 11-nm
outer nuclear membranes is the perinuclear cistern. Observe that the wide structure resembling “beads on a string.” The
two membranes are united at the nuclear pores. beads are termed nucleosomes, and the string, which
is the DNA molecule, appears as a thin filament 2 nm
in diameter (Fig. 3-8).
complex. Transport across the nuclear pore complex is Each nucleosome is composed of an octomer of pro-
frequently an energy-requiring process. teins, duplicates of each of four types of histones (H2
The bidirectional traffic between the nucleus and the A, H2 B, H3, and H4). The nucleosome is also wrapped
cytoplasm is mediated by a group of target proteins con- with two complete turns (~150 nucleotide pairs) of the
taining nuclear localization signals (NLSs), known as DNA molecule that continues as linker DNA extend-
importins, and nuclear export signals (NESs), known ing to the next “bead.” The spacing between each nu-
as exportins (also known as karyopherins, PTACs, cleosome is about 200 base pairs. This configuration of
transportins, and Ran-binding proteins). Exportins the nucleosome with its coils of DNA represents the
transport macromolecules (e.g., RNA) from the nucleus simplest arrangement of chromatin packaging in the
into the cytoplasm, whereas importins transport cargo nucleus. Because only a small amount of the chromatin
(e.g., protein subunits of ribosomes) from the cytoplasm in the cell is in this configuration, it is thought to rep-
into the nucleus. Exportin and importin transport is reg- resent regions where the DNA is being transcribed.
ulated by a family of GTP-binding proteins known as During the cell cycle, chromatin assembly factor
Ran (Fig. 3-7). These specialized proteins along with 1 (CAF-1) expedites the rapid assembly of the nucleo-
other nucleoporins located along receptor sites in the somes of the newly synthesized DNA into chromatin
nuclear pore complex facilitate the signal-mediated so that it cannot become a template. Therefore, the
import and export processes. nucleosome/histone assembly not only provides a struc-
Some protein trafficking is more like shuttling, tural framework for the chromatin but also imparts
because some proteins pass back and forth between the control mechanisms important in DNA repair, replica-
cytoplasm and the nucleus in a continuous fashion. tion, and transcription.
Ch003-X2945.qxd 12/8/06 3:21 PM Page 53
Figure 3–4 Nuclear pores. Electron

micrograph (×47,778). Many nuclear pores
may be observed in this freeze-fractured
preparation of a nucleus. (From Leeson TS,
Leeson CR, Paparo AA: Text/Atlas of His-
tology. Philadelphia, WB Saunders, 1988.)
Figure 3–5 Nuclear pore. Elec-

tron micrograph (×24,828). Note the
heterochromatin adjacent to the
inner nuclear membrane and that
the inner and outer nuclear mem-
branes are continuous at the nuclear
pore. (From Fawcett DW: The Cell.
Ch003-X2945.qxd 12/8/06 3:21 PM Page 54
NUCLEAR PORE COMPLEX

Cytoplasmic
filaments
Lumenal spoke
Cytoplasmic ring
ring
Outer nuclear
membrane
Figure 3–6 Nuclear pore complex. This illustration of the

current understanding of the structure of the nuclear pore
complex demonstrates that it is made up of several combinations
Scaffold Inner nuclear of eight units each. Note that the model does not include a trans-
membrane porter (see text). (Based on Alberts B, Bray D, Lewis J, et al: Mol-
ecular Biology of the Cell, 3rd ed. New York, Garland Publishing,
Nuclear ring Nuclear basket 1994; and on Beck M, Förster F, Ecke M, et al: Nuclear pore
complex structure and dynamics revealed by cryoelectron tomog-
Distal ring raphy. Science 306:1387-1390, 2004.)
Cytoplasm
Importin β
Protein GDP
NLSs Importin α
Importin β GDP
Ran GAP
GDP
GTP
Pi
Nuclear pore
complex
Ran
GTP GTP
GTP
GTP
GTP
GTP
Nucleus
Figure 3-7 Role of Ran in nuclear import. Ran/guanosine diphosphate (GDP) is present in high concentration in the cytoplasm whereas
Ran/guanosine triphosphate (GTP) is present in high concentration in the nucleus. Proteins to be imported into the nucleus form complexes
with nuclear localization signals (NLSs) importin α and importin β. Upon import through the nuclear pore complex, Ran/GTP binds to importin
β, thus releasing importin α and the imported protein. To complete the cycle, the Ran/GTP/importin β complex exits the nucleus to enter the
cytoplasm via the nuclear pore complex. Here the Ran/GTPase-activating protein (RanGAP) hydrolyzes GTP, forming Ran/GDP, thus releas-
ing importin β back into the cytoplasm.
Ch003-X2945.qxd 12/8/06 3:21 PM Page 55
Condensed section
of chromosome
30 nm
Chromatin fiber
of packed
nucleosomes “Beads-on-a-string”
form of chromatin
11 nm 2 nm
300 nm
700 nm
1400 nm
Metaphase Extended section DNA double helix

chromosome of chromosome
Figure 3–8 Chromatin packaging. Note the complex packaging of chromatin to form a chromosome.
Electron microscopic studies of the nuclear contents maximally condensed chromosomes observed in the
following more careful manipulation has revealed chro- metaphase stage of mitosis or meiosis (see Fig. 3-8).
matin fibers exhibiting 30-nm diameters. Packaging of The number of chromosomes in somatic cells is spe-
chromatin into 30-nm threads is believed to occur by cific for the species and is called the genome, the total
helical coiling of consecutive nucleosomes at six nucleo- genetic makeup. In humans, the genome consists of 46
somes per turn of the coil and cooperatively bound chromosomes, representing 23 homologous pairs of chro-
there with histone H1 (see Fig. 3-8). Nonhistone pro- mosomes. One member of each of the chromosome pairs
teins are also associated with the chromatin, but their is derived from the maternal parent; the other comes
function is not clear. from the paternal parent. Of the 23 pairs, 22 are called
autosomes; the remaining pair, which determines
Chromosomes gender, are the sex chromosomes. The sex chromo-
somes of the female are two X chromosomes (XX); those
Chromosomes are chromatin fibers that become so of the male are the X and Y chromosomes (XY) (Fig. 3-9).
condensed and tightly coiled during mitosis and meiosis
that they are visible with the light microscope. Sex Chromatin
As the cell leaves the interphase stage and prepares to Only one of the two X chromosomes in female somatic
undergo mitotic or meiotic activity, the chromatin fibers cells is transcriptionally active. The inactive X chromo-
are extensively condensed to form chromosomes, some, randomly determined early in development,
visible with light microscopy. Tighter condensing of the remains inactive throughout the life of that individual.
chromatin material is accomplished by looping the Microscopic study of interphase nuclei of cells from
coiled 30-nm fibers into 300-nm-diameter loops, held females displays a very tightly coiled clump of chro-
together by specific protein/DNA-bound complexes matin, the sex chromatin (Barr body), the inactive
located at their bases. Further coiling of the 300-nm counterpart of the two X chromosomes. Epithelial cells
loops into tightly woven 700-nm helical loops forms the obtained from the lining of the cheek and neutrophils
Ch003-X2945.qxd 12/8/06 3:21 PM Page 56
Figure 3–9 Human karyotype. A normal human karyotype illustrating banding. (From Bibbo M: Comprehensive Cytopathology. Philadel-
obtained from blood smears are especially useful for

studying sex chromatin. The sex chromatin is observed CLINICAL CORRELATIONS
at the edge of the nuclear envelope in smears of the oral
epithelial cells and as a small drumstick-like evagination One item that may be observed from the karyo-
of the nuclei of the neutrophils. A number of cells must type is aneuploidy, an abnormal chromosome
be examined to observe sex chromatin because the X number. People with Down syndrome, for
chromosome must be in the proper orientation to be example, have an extra chromosome 21 (trisomy
displayed for observation. 21); they exhibit mental retardation, stubby
hands, and many congenital malformations, espe-
cially of the heart, among other manifestations.
Ploidy Certain syndromes are associated with abnor-
Cells containing the full complement of chromosomes malities in the number of sex chromosomes.
(46) are said to be diploid (2n). Germ cells (mature ova Klinefelter syndrome results when an individ-
or spermatozoa) are said to be haploid (ln); that is, only ual possesses three sex chromosomes (XXY).
one member of each of the homologous pairs of chro- These persons exhibit the male phenotype, but
mosomes is present. Upon fertilization, the chromoso- they do not develop secondary sexual character-
mal number is restored to the diploid (2n) amount as istics and are usually sterile. Turner syndrome
the nuclei of the two germ cells unite. is another example of aneuploidy called mono-
Certain alkaloids, such as colchicine, a plant deriva- somy of the sex chromosomes. The karyotype
tive, arrest a dividing cell in the metaphase stage of exhibits only one sex chromosome (XO). These
mitosis when the chromosomes are maximally con- individuals are females whose ovaries never
densed, thus permitting the pairing and numbering of the develop and who have undeveloped breasts, a
chromosomes via a conventional system of karyotyping, small uterus, and mental retardation.
an analysis of chromosome number (see Fig. 3-9).
Ch003-X2945.qxd 12/8/06 3:21 PM Page 57
Giemsa reagent stains the adenine-thymine–rich Ribonucleic Acid

regions of chromosomes, producing a pattern of G
bands that is unique for each chromosome pair and is RNA is similar to DNA except that it is single-stranded,
characteristic for each species. Careful analysis of the G one of its bases is uracil instead of thymine, and its
bands can help reveal deletions of certain portions of sugar is ribose instead of deoxyribose.
the chromosome, nondisjunctions, translocations, and
so on, that may assist in the diagnosis of certain genetic Like DNA, RNA is composed of a linear sequence of
disorders or diseases resulting from chromosomal nucleotides, but RNA is single-stranded and the sugar
anomalies. in RNA is ribose, not deoxyribose. One of the bases,
thymine, is replaced by uracil (U), which, similar to
Deoxyribonucleic Acid thymine, is complementary to adenine.
The DNA in the nucleus serves as a template for syn-
DNA, the genetic material of the cell, is located in the thesis of a complementary strand of RNA, a process
nucleus, where it acts as a template for RNA called transcription (Fig. 3-10). Synthesis of the three
transcription. types of RNA is catalyzed by three different RNA
polymerases:
Nearly all of the DNA, a double-stranded polynu-
cleotide chain wound into a double helix, is housed in 䡲 Messenger RNA (mRNA) by RNA polymerase II
the nucleus of the cell. Each nucleotide is composed of 䡲 Transfer RNA (tRNA) by RNA polymerase III
a nitrogenous base, a deoxyribose sugar, and a phos- 䡲 Ribosomal RNA (rRNA) by RNA polymerase I
phate molecule. Further, the nucleotides are linked to The mechanism of transcription is generally the
one another by phosphodiester bonds formed between same for all three types of RNA.
the sugar molecules.
There are two types of bases: purines (adenine and
guanine) and pyrimidines (cytosine and thymine). A Messenger RNA
double helix is established by the formation of hydro-
gen bonds between complementary bases on each Messenger RNA carries the genetic code from the
strand of the DNA molecule. These bonds are formed nucleus to the cytoplasm to act as a template for protein
between adenine (A) and thymine (T) and between synthesis.
guanine (G) and cytosine (C).
mRNA serves as an intermediary for carrying the
Genes genetic information encoded in DNA that specifies the
primary sequence of proteins from the nucleus to
The biological information that is passed from one cell the protein-synthesizing machinery in the cytoplasm
generation to the next—the units of heredity—are (see Fig. 3-10). Each mRNA is a complementary copy
located at specific regions on the DNA molecule called of the region of the DNA molecule that constitutes one
genes. Each gene represents a specific segment of the gene. An mRNA molecule thus consists of a series of
DNA molecule that codes for the synthesis of a partic- codons corresponding to particular amino acids. It also
ular protein. The sequential arrangement of bases con- contains a start codon (AUG), which is necessary for
stituting the gene represents the sequence of amino initiating protein synthesis, and one or more stop
acids of the protein. The genetic code is designed in codons (UAA, UAG, or UGA), which act to terminate
such a manner that a triplet of consecutive bases, a protein synthesis. Once formed in the nucleus, mRNA
codon, denotes a particular amino acid. Each amino is transported to the cytoplasm, where it is translated
acid is represented by a different codon. into protein (see Chapter 2).
Prior to beginning the Human Genome Project, it
was believed that the 3 billion nucleotide bases in the
TRANSCRIPTION
human genome represented about 100,000 genes. Pre-
liminary analysis at the conclusion of the Project indi- Transcription of DNA into mRNA begins with attach-
cated that the number of genes was far less than ment of RNA polymerase II to a core promoter, a spe-
expected. Currently the data indicate that the human cific DNA sequence located adjacent to a gene. In the
genome contains about 25,000 genes, all of which have presence of a series of cofactors, RNA polymerase II
been sequenced and mapped. Findings from this and initiates transcription by unwinding the double helix of
other studies have already increased our understanding the DNA two turns, thus exposing the nucleotides and,
of some genetic disorders as well as indicated better therefore, the codons on the DNA strand. The enzyme
treatment modalities for several diseases, with the uses one of the exposed DNA strands as a template on
promise of many other discoveries and applications in which to assemble and polymerize complementary
the years to come. bases of the RNA molecule.
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TRANSCRIPTION
Nucleus
RNA processing
Nucleotides about
DNA strand to join growing
Pre-mRNA RNA strand
New RNA
strand
DNA transcription
DNA template strand
Nuclear
envelope
Nuclear pores
Transport of mRNA Ribosomes
mRNA
Translation of
mRNA
Protein
Figure 3–10 DNA transcription into messenger RNA (mRNA). (Modified from Alberts B, Bray D, Lewis J, et al: Molecular Biology of
the Cell, 3rd ed. New York, Garland Publishing, 1994.)
The process is repeated as a new region of the DNA spliced together. For that to occur, pre-mRNA and
double helix is unwound and more nucleotides are po- nuclear processing proteins form complexes of het-
lymerized into the growing mRNA chain. As the erogenous nuclear ribonucleoprotein particles
enzyme moves along the DNA molecule, the polymer- (hnRNPs) that begin RNA splicing, thus reducing the
ized mRNA chain is separated from the template DNA length of the pre-mRNA molecule. Additional process-
strand, permitting the two DNA strands to re-form into ing involves spliceosomes, complexes of five small
the double helix configuration (see Fig. 3-10). nuclear ribonucleoprotein particles (snRNPs) and
Transcription begins at a DNA triplet corresponding a large number of non-snRNP splicing factors that
to the start codon AUG and is concluded when the RNA assist in the splicing mechanism to produce messenger
polymerase II recognizes a chain-terminator site com- ribonucleoprotein (mRNP). Finally, the nuclear pro-
plementary to the stop codons UAA, UAG, or UGA. cessing proteins are removed from the complex, leaving
When the enzyme reaches the chain terminator, it is mRNA ready to be transported out of the nucleus via
released from the DNA molecule, permitting it to the nuclear pore complexes (see Fig. 3-10).
repeat the process of transcription. Simultaneously, the Because there is an abundance of DNA within the
newly formed RNA strand (primary transcript) is euykaryotic genome, much of it was believed to be evo-
released from the DNA molecule, leaving it free in the lutionary remnants without coding function. During
nucleoplasm. transcription, DNA unwinds and codes for strands of
The primary transcript is a long, single-stranded RNA comprising exons (coding segments) and introns
RNA molecule, called precursor messenger RNA (noncoding segments). Later in this process, the exons
(pre-mRNA). It contains both coding segments are spliced together to form continual sequences of
(exons) and noncoding segments (introns). The mRNA for translation to a protein in the cytoplasm. The
introns must be removed and the exons have to be introns removed from the primary RNA transcript were
Ch003-X2945.qxd 12/8/06 3:21 PM Page 59
thought to have no function, even though their RNA the mRNA; the other is the amino acid-bearing region,
represents about 95% more RNA than the protein- which resides at the 3’ end of the molecule. tRNA is
coding genes. aminoacylated not only in the cytoplasm but also in the
Recent evidence suggests that although these intronic nucleus. This is believed to be a “proofreading” step that
RNA segments do not encode protein, they perform facilitates functional readiness in the cytoplasm. tRNA
regulatory functions that are in parallel with regulatory then transfers activated amino acids to the ribosome-
proteins. Their role may relate to differentiation, devel- mRNA complex, where they are incorporated into the
opment, gene expression, and evolution. If proved polypeptide chain forming the protein (see Chapter 2).
correct, this could have a profound impact on under-
standing certain disease processes and their treatment. Ribosomal RNA
For example, it is known that noncoding RNAs are linked
to several cancers, autism, and schizophrenia. Ribosomal RNA forms associations with proteins and
This description of mRNA synthesis is only a brief enzymes in the nucleus to form ribosomes.
overview and omits many details. Readers desiring
more information should consult texts in molecular and rRNA is synthesized in the fibrillar (pars fibrosa) region
cellular biology. of the nucleolus by RNA polymerase I (Fig. 3-11). The
primary transcript is called 45S rRNA (pre-rRNA), a
Transfer RNA huge molecule of about 13,000 nucleotides. A 5S rRNA
molecule, synthesized in the nucleus, and ribosomal
Transfer RNA ferries activated amino acids to the proteins, synthesized in the cytoplasm, are transported
ribosome/mRNA complex, resulting in the formation of into the nucleolus. Here they associate with the 45S
the protein. rRNA molecule, forming a very large ribonucleopro-
tein particle (RNP). This RNP is processed by several
tRNA is a small RNA molecule produced from DNA resident molecules into precursors of the large and
by RNA polymerase III. It is about 80 nucleotides in small ribosomal subunits in the pars granulosa region of
length and is folded upon itself to resemble a cloverleaf the nucleolus. Thereafter, assembled small ribosomal
with base pairing between some of the nucleotides. subunits, made up of 18S rRNAs and other ribosomal
Two regions of the tRNA are of special significance. proteins, make their way from the nucleolus to the cyto-
One of these, the anticodon, recognizes the codon of plasm by transport via the nuclear pore complexes. The
RIBOSOME FORMATION
Transcription Nucleus
Nucleolus
rRNA
Ribosomal
proteins
synthesized
in cytoplasm
Large
Immature ribosomal subunit
subunits composed
of rRNA and ribosomal
proteins Small
subunit
Figure 3–11 Ribosome forma-

tion. mRNA, messenger RNA; rRNA,
ribosomal RNA. (Modified from Subunits combine
on mRNA to become
Alberts B, Bray D, Lewis J, et al: Mo-
functional ribosomes
lecular Biology of the Cell, 3rd ed.
mRNA
New York, Garland Publishing, 1994.)
Ch003-X2945.qxd 12/8/06 3:21 PM Page 60
remaining 28S, 5.8S, and 5S rRNAs are assembled into proteins, carcinogen binding, DNA viruses, and viral
large ribosomal subunits and are transported out of the proteins. This list is not inclusive and does not address
nucleus to the cytoplasm by way of the nuclear pore the functional natures of each of these associations
complexes. because they are still unclear. It has been suggested,
however, that the nucleus may contain many interactive
Nucleoplasm subcompartments that function spatially and temporally
in a tightly coordinated fashion to facilitate gene
The nucleoplasm consists of interchromatin and expression.
perichromatin granules, RNPs, and the nuclear matrix.
Nucleolus
Interchromatin granules (IGs), which are 20 to 25
nm in diameter, contain RNPs and several enzymes, The nucleolus is the deeply staining non–membrane-
including adenosine triphosphatase (ATPase), guano- bounded structure within the nucleus that is involved in
sine triphosphatase (GTPase), β-glycerophosphatase, rRNA synthesis and in the assembly of small and large
and nicotinamide adenine dinucleotide (NAD) pyrophos- ribosomal subunits
phatase. They are located in clusters scattered through-
out the nucleus among the chromatin material and The nucleolus, a dense nonmembranous structure
appear to be connected to each other by thin fibrils. located in the nucleus, is observed only during inter-
Their function is unclear. phase because it dissipates during cell division. It stains
Perichromatin granules are 30 to 50 nm in diam- basophilic with hematoxylin and eosin, being rich in
eter and are located at the margins of the heterochro- rRNA and protein. The nucleolus contains only small
matin. These electron-dense particles are surrounded amounts of DNA, which is also inactive and thus does
by a 25-nm wide halo of a less dense region. They are not stain with Feulgen stains. Usually, there are no more
composed of densely packed fibrils of 4.7S low molec- that two or three nucleoli per cell; however, their
ular weight RNA complexed to two peptides, resem- number, size, and shape generally are species-specific
bling hnRNPs. and relate to the synthetic activity of the cell. In cells
snRNPs participate in splicing, cleaving, and trans- that are actively synthesizing protein, the nucleolus may
porting hnRNPs. Although most snRNPs are located in occupy up to 25% of the nuclear volume. Densely stain-
the nucleus, some are limited to nucleoli. Several minor ing regions are the nucleolus-associated chromatin,
subgroups of these particles have been discovered which is being transcribed into rRNA (see Figs. 3-2 and
recently, but their function has yet to be elucidated. 3-3).
Four distinct areas of the nucleolus have been
described:
Nuclear Matrix
䡲 A pale-staining fibrillar center, containing inactive
The nuclear matrix is defined both in structural and bio- DNA (not being transcribed)
chemical terms. It appears that differences reported in 䡲 Pars fibrosa, containing nucleolar RNAs being
its components may be due to the extraction methods transcribed
employed in studying its contents. Biochemically, the 䡲 Pars granulosa, in which maturing ribosomal sub-
matrix contains about 10% of the total protein, 30% of units are assembled
the RNA, 1% to 3% of the total DNA, and 2% to 5% of 䡲 Nucleolar matrix, a network of fibers active in
the total nuclear phosphate. The structural components nucleolar organization
include the nuclear pore–nuclear lamina complex,
residual nucleoli, residual RNP networks, and fibrillar Also located in the pale-staining regions are the
elements. Recent studies have revealed that the nucleus tips of chromosomes 13, 14, 15, 21, and 22 (in humans),
possesses a nucleoplasmic reticulum that is continuous containing the nucleolar-organizing regions, where
with the endoplasmic reticulum of the cytoplasm and gene loci that encode rRNA are located.
the nuclear envelope. This reticulum houses nuclear The cell’s ribosomal subunits are organized and
calcium that functions within the nucleus. Further, this assembled within the nucleolus, except those located in
reticulum possesses receptors for inositol 1,4,5- the mitochondria. However, recent evidence shows that
trisphosphate that ultimately regulate calcium signals the nucleolus performs additional functions. These
within certain compartments of the nucleus—namely, include regulating some of the events in the cell
regions dedicated to protein transport, transcription of cycle such as cytokinesis; inactivating mitotic cyclin-
certain genes, and possibly others. dependent kinases by sequestering cell cycle regulatory
Functionally, the nuclear matrix is associated with proteins; modifying small RNAs that moderate and
DNA replication sites, rRNA and mRNA transcription modify pre-rRNA; assembling RNP; engaging in
and processing, steroid receptor binding, heat shock nuclear export; and playing a role in aging.
Ch003-X2945.qxd 12/8/06 3:21 PM Page 61
giving rise to two daughter cells. The cell cycle may be

CLINICAL CORRELATIONS thought of as beginning at the conclusion of the telophase
stage in mitosis, after which the cell enters interphase.
Some suggest that the rDNA in the nucleolus Cells that become highly differentiated after the last
may become unstable, thereby accelerating the mitotic event may cease to undergo mitosis either per-
aging process. In malignant cells, the nucleolus manently (e.g., neurons, muscle cells) or temporarily
may become hypertrophic. Furthermore, it is (e.g., peripheral lymphocytes) and return to the cell
known that in tumor cells the nucleolar-organiz- cycle at a later time. Cells that have left the cell cycle
ing regions become larger and more numerous, are said to be in a resting stage, the G0 (outside) phase,
thus indicating a poorer clinical prognosis. or the stable phase.
Interphase
Interphase is subdivided into three phases:
THE CELL CYCLE
䡲 G1 (gap) phase, when the synthesis of macromole-
The cell cycle is a series of events within the cell that
cules essential for DNA duplication begins
䡲 S (synthetic) phase, when the DNA is duplicated
prepare the cell for dividing into two daughter cells.
䡲 G2 phase, when the cell undergoes preparations for
The cell cycle is divided into two major events: inter- mitosis
phase, a long period of time during which the cell
increases its size and content and replicates its genetic Gap 1
material (Fig. 3-12), and mitosis, a shorter period of time
during which the cell divides its nucleus and cytoplasm, The G1 phase (gap 1 phase) is a period of cell growth,
RNA synthesis, and other events in preparation for the
next mitosis.
CELL CYCLE
Daughter cells formed during mitosis enter the G1
phase. During this phase, the cells synthesize RNA,
regulatory proteins essential to DNA replication, and
enzymes necessary to carry out these synthetic activities.
Thus, the cell volume, reduced by dividing the cell in
I II III IV V VI half during mitosis, is restored to normal. Additionally,
the nucleoli are reestablished during the G1 phase. It is
during this time that the centrioles begin to duplicate
themselves, a process that is completed by the G2 phase.
The triggers inducing the cell to enter the cell cycle
Mitosis G0 may be (1) a mechanical force (e.g., stretching of
smooth muscle), (2) injury to the tissue (e.g., ischemia),
and (3) cell death. All of these incidents cause the
Division
release of ligands by signaling cells in the involved
tissue. Frequently these ligands are growth factors that
G2
indirectly induce the expression of proto-oncogenes,
genes that are responsible for controlling the prolifera-
tive pathways of the cell.
Obviously the expression of proto-oncogenes must
G1 be very strictly regulated to prevent unwanted and
Interphase uncontrolled cell proliferation. Mutations in proto-
oncogenes that enable the cell to escape control and
divide in an unrestrained fashion are responsible for
S
many cancers. Such mutated proto-oncogenes are
known as oncogenes.
Ligands designed to induce proliferation bind to cell
surface receptor proteins of the target cell and activate
Figure 3–12 The cell cycle in actively dividing cells. Nondivid-
ing cells, such as neurons, leave the cycle to enter the G0 phase
one of the signal transduction pathways described
(resting stage). Other cells, such as lymphocytes, may return to the in Chapter 2. Hence, extracellular signals that are
cell cycle. perceived at the cell surface are transmuted into
Ch003-X2945.qxd 12/8/06 3:21 PM Page 62
intracellular events, most of which involve the sequen- division. In contrast, germ cells produced by meiosis
tial activation of a cascade of cytoplasmic protein possess the haploid (1n) number of chromosomes and
kinases. These kinases activate a series of intranuclear also the haploid (1n) amount of DNA.
transcription factors that regulate the expression of
proto-oncogenes, resulting in cell division. G2 Phase
The capability of the cell to begin and advance through
the cell cycle is governed by the presence and interactions The gap 2 phase (G2 phase) is the period between the
of a group of related proteins known as cyclins, with spe- end of DNA synthesis and the beginning of mitosis.
cific cyclin-dependent kinases (CDKs). Thus:
During the G2 phase, the RNA and proteins essential to
䡲 Cyclin D, synthesized during early G1 phase, binds to cell division are synthesized, the energy for mitosis is
CDK4 as well as to CDK6. Additionally, in the late G1 stored, tubulin is synthesized for assembly into micro-
phase cyclin E is synthesized and binds to CDK2. These tubules required for mitosis, DNA replication is analyzed
three complexes, through other intermediaries, permit for possible errors, and any of these errors is corrected.
the cell to enter and progress through the S phase.
䡲 Cyclin A binds to CDK2 and CDK1 and these com- Mitosis
plexes permit the cell to leave the S phase and enter
the G2 phase and induce the formation of cyclin B. Mitosis is the process of cell division that results in the
䡲 Cyclin B binds to CDK1, and this complex allows the formation of two identical daughter cells.
cell to leave the G2 phase and enter the M phase.
Mitosis (M) occurs at the conclusion of the G2 phase
Once the cyclins have performed their specific func- and thus completes the cell cycle. Mitosis is the process
tions, they enter the ubiquitin-proteasome pathway, whereby the cytoplasm and the nucleus of the cell are
where they are degraded into their component mole- divided equally into two identical daughter cells (Figs.
cules. The cell also employs quality control mecha- 3-13 to 3-15). First, the nuclear material is divided in a
nisms, known as checkpoints, to safeguard against process called karyokinesis, followed by division of the
early transition between the phases. These checkpoints cytoplasm, called cytokinesis. The process of mitosis is
ensure the meticulous completion of essential events, divided into five distinct stages: prophase, prometa-
such as adequate cell growth, correct DNA synthesis, phase, metaphase, anaphase, and telophase (Fig.
and proper chromosome segregation, before permitting 3-16).
the cell to leave its current phase of the cell cycle. The
cell accomplishes such delays in the progression
through the cell cycle by activating inhibitory pathways
and/or by suppressing activating pathways.
The actual control mechanisms are considerably
more involved and complicated than the steps just
described. For example, it appears that the nucleolus M
plays a regulatory role in the cell cycle by sequestering
certain proteins, thus inhibiting their function. The com-
plete sequence of steps is beyond the scope of this text-
book. (For more details, see relevant textbooks of cell
biology as well as current literature on the cell cycle.)
S Phase
DNA synthesis occurs during the S phase. A
During the S phase, the synthetic phase of the cell cycle,

the genome is duplicated. All of the requisite nucleo- P
proteins, including the histones, are imported and
incorporated into the DNA molecule, forming the chro-
matin material. The cell now contains twice the normal
complement of its DNA. The amount of DNA present
in autosomal and germ cells also varies. Autosomal cells
contain the diploid (2n) amount of DNA before the syn-
thetic (S) phase of the cell cycle when the diploid (2n) Figure 3–13 Stages of mitosis. Light micrograph (×270). Note
amount of DNA is doubled (4n) in preparation for cell the various stages: A, anaphase; M, metaphase; P, prophase.
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Figure 3–14 Anaphase stage of

mitosis. Light micrograph (×540).
Sister chromatids have separated
from the metaphase plate and are
now migrating away from each other
to opposite poles.
Figure 3–15 Immunoflorescent

image of a cell in the prometaphase
stage of mitosis. Note the spindle
microtubules (green) and the chro-
mosomes (blue). (Courtesy of Alexey
Khodjakov, PhD, Research Scientist
and Associate Professor, Wadsworth
Center, Albany, New York.)
Prophase Each chromosome consists of two parallel sister chro-

matids, joined together at one point along their length,
During prophase, the chromosomes condense and the the centromere. As chromosomes condense, the nucle-
nucleolus disappears. olus disappears. The centrosome also divides into two
regions, each half containing a pair of centrioles and a
At the beginning of prophase, the chromosomes are microtubule-organizing center (MTOC), which mig-
condensing, and thus becoming visible microscopically. rate away from each other to opposite poles of the cell.
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MITOSIS
Interphase Prophase Prometaphase Metaphase
Cytokinesis Telophase Anaphase
Figure 3–16 Stages of mitosis in a cell containing a diploid (2n) number of 6 chromosomes.
From each MTOC, astral rays and spindle fibers migration of the chromosomes so that they become ori-
develop, giving rise to the mitotic spindle apparatus. ented into an alignment with the mitotic spindle.
It is thought that the astral rays (microtubules that
radiate out from the pole of the spindle) may assist in Metaphase
orienting the MTOC at the pole of the cell. Those
microtubules that attach to the centromere region of Metaphase begins as the newly duplicated chromosomes
the chromosome are the spindle fibers, which assist in align themselves on the equator of the mitotic spindle.
directing the chromosome migration to the pole. In the
absence of centrioles, the microtubule-nucleating mate- During metaphase, the chromosomes become maximally
rial is dispersed within the cytoplasm with the result condensed and are lined up at the equator of the mitotic
that astral rays and spindle fibers do not form properly, spindle (metaphase plate configuration). Each chro-
and mitosis does not proceed in the appropriate manner. matid parallels the equator, and spindle microtubules are
At the centromere region of each chromatid, a new attached to its kinetochore, radiating to the spindle pole.
MTOC, the kinetochore, develops. Spindle fibers bind Sister chromatids must be maintained in close proximity
to the kinetochore in preparation for chromatid migra- as the chromosome condenses and aligns on the meta-
tion to effect karyokinesis. phase mitotic spindle. During anaphase, cohesion pro-
teins located between the chromatids disappear.
Prometaphase
Anaphase
Prometaphase begins when the nuclear envelope
disappears. During anaphase, the sister chromatids separate and
begin to migrate to opposite poles of the cell, and a
Prometaphase begins as the nuclear lamins are phospho- cleavage furrow begins to develop.
rylated, resulting in the breakdown and disappearance of
the nuclear envelope. During this phase, the chromo- Anaphase begins when sister chromatids, located at the
somes are arranged randomly throughout the cytoplasm. equator of the metaphase plate, pull apart and begin
Microtubules that become attached to the kinetochores their migration toward the opposite poles of the mitotic
are known as mitotic spindle microtubules, whereas spindle. The spindle/kinetochore attachment site leads
microtubules that do not become incorporated into the the way, with the arms of the chromatids simply trailing,
spindle apparatus are called polar microtubules. Some contributing nothing to the migration or its pathway.
believe that the polar microtubules are responsible for It has been postulated that the observed movement of
maintaining the spacing between the two poles during the the chromatids toward the pole in anaphase may be the
mitotic event. The mitotic spindle microtubules assist in result of shortening of the microtubules via depolymeri-
Ch003-X2945.qxd 12/8/06 3:21 PM Page 65
zation at the kinetochore end. This, coupled with the lated and the nuclear envelope is reconstituted. The
recent discovery of dynein associated with the kineto- chromosomes uncoil and become organized into het-
chore, may be analogous to vesicle transport along erochromatin and euchromatin of the interphase cell.
microtubules. In late anaphase, a cleavage furrow The nucleolus is developed from the nuclear-organizing
begins to form at the plasmalemma, indicating the region regions on each of five pairs of chromosomes.
where the cell will be divided during cytokinesis. Cytokinesis is the division of the cytoplasm into two
equal parts during mitosis. The cleavage furrow continues
Telophase to deepen until only the midbody, a small bridge of cyto-
plasm, and remaining polar microtubules connect the two
Telophase, the terminal phase of mitosis, is characterized daughter cells (Fig. 3-17). The polar microtubules are sur-
by cytokinesis, reconstitution of the nucleus and nuclear rounded by a contractile ring, which lies just inside the
envelope, disappearance of the mitotic spindle, and plasma membrane. The contractile ring is composed of
unwinding of the chromosomes into chromatin. actin and myosin filaments attached to the plasma mem-
brane. Constriction of the ring is followed by depolymer-
At telophase, each set of chromosomes has reached its ization of the remaining spindle microtubules separating
respective pole, the nuclear lamins are dephosphory- the two daughter cells. During separation of the daughter
Figure 3–17 Cytokinesis. Electron

micrograph (×8092). A spermatogonium
in late telophase demonstrating the
forming midbody (arrowhead). The
chromosomes in the daughter nuclei are
beginning to uncoil. (From Miething A:
Intercellular bridges between germ cells
in the immature golden hamster testis:
Evidence for clonal and nonclonal mode
of proliferation. Cell Tissue Res 262:
559-567, 1990.)
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cells and shortly thereafter, the elements of the contractile Meiosis

ring and the remaining microtubules of the mitotic appa-
ratus are disassembled, concluding cytokinesis. Whereas mitosis is cell division of somatic cells into two
Each daughter cell resulting from mitosis is identi- identical daughter cells, meiosis is a special type of cell
cal in every respect, including the entire genome, and division resulting in the formation of gametes (spermatozoa
each daughter cell possesses a diploid (2n) number of or ova) whose chromosome number has been reduced
chromosomes. from the diploid (2n) to the haploid (1n) number.
Meiosis begins at the conclusion of interphase in the

cell cycle. It produces the germ cells—the ova and the
CLINICAL CORRELATIONS spermatozoa. This process has two crucial results:
1 Reduction in the number of chromosomes from the
A more complete understanding of mitosis and
diploid (2n) to the haploid (1n) number, ensuring
the cell cycle has greatly aided cancer chemo-
that each gamete carries the haploid amount of DNA
therapy, making it possible to use drugs at the
and the haploid number of chromosomes.
time when the cells are in a particular stage of
2 Recombination of genes, ensuring genetic variability
the cell cycle. For example, vincristine and
and diversity of the gene pool.
similar drugs disrupt the mitotic spindle, arrest-
ing the cell in mitosis. Colchicine, another plant Meiosis is divided into two separate events:
alkaloid that produces the same effect, has been Meiosis I, or reductional division (first event).
used extensively in studies of individual chromo- Homologous pairs of chromosomes line up, mem-
somes and karyotyping. Methotrexate, which bers of each pair separate and go to opposite poles,
inhibits purine synthesis, and 5-fluorouracil, and the cell divides; thus, each daughter cell receives
which inhibits pyrimidine synthesis, both halt the half the number of chromosomes (haploid number).
cell cycle in the S phase, preventing cell division; Meiosis II, or equatorial division (second event).
both are common chemotherapy agents. The two chromatids of each chromosome are sep-
Oncogenes are mutated forms of normal arated, as in mitosis, followed by migration of the
genes called proto-oncogenes, which code for chromatids to opposite poles and the formation of
proteins that control cell division. Oncogenes two daughter cells. These two events produce four
may result from a viral infection or random cells (gametes), each with the haploid number of
genetic accidents. When present in a cell, chromosomes and haploid DNA content.
oncogenes dominate genes over the normal
proto-oncogene alleles, causing unregulated cell Meiosis I
division and proliferation. Examples of cancer
cells arising from oncogenes include bladder Meiosis I (reductional division) separates the
cancer and acute myelogenous leukemia. homologous pairs of chromosomes, thus reducing
the number from diploid (2n) to haploid (1n).
MEIOSIS I
Prophase I Metaphase I Anaphase I Telophase I

Chromosomes that have Tetrads are held together Homologous chromosomes The chromosomes have
been replicated condense by chiasmata. Chromosomes separate and migrate to formed two groups. The cell
and pair with homologues arrange themselves on the opposite poles of the cell. begins to constrict across
to form tetrads. equator of the spindle. the middle. Separates into
two daughter cells.
Figure 3–18 Stages of meiosis in an idealized cell containing a diploid (2n) number of 4 chromosomes.
Ch003-X2945.qxd 12/8/06 3:21 PM Page 67
In gametogenesis, when the germ cells are in the S Metaphase I

phase of the cell cycle preceding meiosis, the amount
of DNA is doubled to 4n but the chromosome number Metaphase I is characterized by homologous pairs of
remains at 2n (46 chromosomes). Meiosis I proceeds as chromosomes, each composed of two chromatids, lining
outlined in Figure 3-18. up on the equatorial plate of the meiotic spindle.
During metaphase I, homologous chromosomes align

as pairs on the equatorial plate of the spindle apparatus in
Prophase I random order, ensuring a subsequent reshuffling of
the maternal and paternal chromosomes. Spindle fibers
Prophase I, the commencement of meiosis, begins after
become attached to the kinetochores of the chromosomes.
the DNA has been doubled to 4n in the S phase.
Anaphase I
Prophase of meiosis I lasts a long time and is subdivided
into the following five phases: Anaphase I is evident when the homologous pairs of
chromosomes begin to pull apart, commencing their
1 Leptotene. Individual chromosomes, composed of migrations to opposite poles of the cell.
two chromatids joined at the centromere, begin to
condense, forming long strands in the nucleus. In anaphase I, homologous chromosomes migrate
2 Zygotene. Homologous pairs of chromosomes away from each other, going to opposite poles. Each
approximate each other, lining up in register (gene chromosome still consists of two chromatids.
locus to gene locus), and make synapses via the Telophase I
synaptonemal complex, forming a tetrad.
3 Pachytene. Chromosomes continue to condense, During Telophase I, the migrating chromosomes, each
becoming thicker and shorter; chiasmata (crossing consisting of two chromatids, reach opposite poles.
over sites) are formed as random exchange of
genetic material occurs between homologous Telophase I is similar to telophase of mitosis. The
chromosomes. chromosomes reach the opposing poles, nuclei are re-
4 Diplotene. Chromosomes continue to condense and formed and cytokinesis occurs, giving rise to two daugh-
then begin to separate, revealing chiasmata. ter cells. Each cell possesses 23 chromosomes, the
5 Diakinesis. Chromosomes condense maximally and haploid (1n) number, but because each chromosome is
the nucleolus disappears, as does the nuclear composed of two chromatids, the DNA content is still
envelope, freeing the chromosomes into the diploid. Each of the two newly formed daughter cells
cytoplasm. enters meiosis II.
MEIOSIS II
Prophase II Metaphase II Anaphase II Telophase II

The chromosomes of the The chromosomes then The newly separated The cells constrict across the
two daughter cells condense migrate to the equator. chromosomes of the two nuclear membrane. Four
again in preparation for a daughter cells move to haploid nuclei are formed,
second meiotic division. opposite poles of their spindle. each with one member of each
pair of chromosomes from the
original nucleus.
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Meiosis II APOPTOSIS
Meiosis II (equatorial division) occurs without DNA Cells die as a result of various factors, including (1)
synthesis and proceeds rapidly through four phases and acute injury, (2) accidents, (3) lack of a vascular supply,
cytokinesis to form four daughter cells each with the (4) destruction by pathogens or the immune system,
haploid chromosome number. and (5) genetic programming. During embryogenesis,
many cells, such as those that would give rise to a
The equatorial division is not preceded by an S phase. It tail in the human embryo, are driven into the geneti-
is very similar to mitosis and is subdivided into prophase cally determined process of dying. This process con-
II, metaphase II, anaphase II, telophase II, and tinues on throughout adult life to establish a balance
cytokinesis (see Fig. 3-18). The chromosomes line up between cell proliferation and cell death. For example,
on the equator, the kinetochores attach to spindle fibers, in the adult human billions of cells die each hour
followed by the chromatids migrating to opposite poles, within the bone marrow and digestive tract to balance
and cytokinesis divides each of the two cells, resulting in cell proliferation in these tissues. Cell death by
a total of four daughter cells from the original diploid this means is called programmed cell death (apop-
germ cell. Each of the four cells contains a haploid tosis). In contrast to apoptosis, during necrosis the
amount of DNA and a haploid chromosome number. cell dies because of attack or injury that causes the
Unlike the daughter cells resulting from mitosis, each cell to rupture, thereby exposing its contents to neigh-
of which contains the diploid number of chromosomes boring cells and thus initiating an inflammatory
and is an identical copy of the other, the four cells result- response. Because apoptosis has formidable conse-
ing from meiosis contain the haploid number of chromo- quences for the cell involved as well as for the organ-
somes and are genetically distinct because of reshuffling ism, it must be carefully regulated, controlled, and
of the chromosomes and crossing over. Thus, every monitored.
gamete contains its own unique genetic complement. The process of apoptosis is regulated by a number
of highly conserved genes that code for a family of
enzymes known as caspases, which degrade regulatory
CLINICAL CORRELATIONS and structural proteins in the nucleus and in the cyto-
Abnormalities in chromosome numbers may plasm. Activation of caspases is induced when certain
occur during meiosis. During meiosis I, when cytokines, such as tumor necrosis factor (TNF),
homologous pairs normally separate, nondis- released by signaling cells, binds to the TNF receptor
junction may occur; thus, one daughter cell will of the target cell. These TNF receptors are trans-
have both rather than one chromosome of the membrane proteins whose cytoplasmic aspect binds
homologous pair, resulting in 24 chromosomes, to adapter molecules to which caspases are bound.
whereas the other daughter cell will have only Once TNF binds to the extracellular moiety of its
22 chromosomes. At fertilization with a normal receptor, the signal is transduced and caspase becomes
gamete (containing 23 chromosomes), the result- activated. The activated caspase is released and, in
ant zygote will have either 47 chromosomes turn, triggers a cascade of caspases that results in the
(trisomy) or 45 chromosomes (monosomy). degradation of chromosomes, nuclear lamins, and
Nondisjunction occurs more frequently with cytoskeletal proteins. Finally, the entire cell becomes
certain chromosomes (i.e., trisomy of chromo- fragmented. The cell fragments are then phagocytosed
somes 8, 9, 13, 18, 21) that produce unique char- by macrophages. However, these macrophages do not
acteristics (e.g., the characteristics of Down release cytokines that would initiate an inflammatory
syndrome [trisomy 21]). response.
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4 䡲䡲䡲
Extracellular Matrix
Cells of multicellular organisms congregate to form

structural and functional associations, known as tissues. GROUND SUBSTANCE
Each of the four basic tissues of the body—epithelium,
connective tissue, muscle, and nervous tissue—pos- Ground substance is an amorphous gel-like material
sesses specific, defined characteristics, which are composed of glycosaminoglycans, proteoglycans, and
detailed in subsequent chapters. However, all tissues glycoproteins.
are composed of cells and an extracellular matrix
(ECM), a complex of nonliving macromolecules manu- The three families of macromolecules that compose
factured by the cells and exported by them into the ground substance form various interactions with each
extracellular space. other, with fibers, and with the cells of connective tissue
Some tissues, such as epithelium, form sheets of cells and epithelium (Fig. 4-2).
with only a scant amount of ECM. At the opposite
extreme is connective tissue, composed mostly of ECM Glycosaminoglycans
with a limited number of cells scattered throughout the
matrix. Cells maintain their associations with the ECM Glycosaminoglycans (GAGs) are negatively charged, long,
by forming specialized junctions that hold them to the rod-like chains of repeating disaccharides that have the
surrounding macromolecules. This chapter explores the capability of binding large quantities of water.
nature of the ECM not only as it relates to the tissues
that house it but also as it relates to the cells contained GAGs are long, inflexible, unbranched polysaccharides
within it. Although it was initially believed that the composed of chains of repeating disaccharide units.
ECM merely forms the skeletal elements of the tissue One of the two repeating disaccharides is always an
in which it resides, it is now known that it may also: amino sugar (N-acetylglucosamine or N-acetylgalac-
䡲 Modify the morphology and functions of cells tosamine); the other typically is a uronic acid (iduronic
䡲 Modulate the survival of cells or glucuronic) (Table 4-1). Because the amino sugar is
䡲 Influence the development of cells usually sulfated and because these sugars also have car-
䡲 Regulate the migration of cells boxyl groups projecting from them, they are negatively
䡲 Direct mitotic activity of cells charged and thus attract cations such as sodium (Na+).
䡲 Form junctional associations with cells A high sodium concentration in the ground substance
attracts extracellular fluid, which (by hydrating the
The ECM of the connective tissue proper, the most intercellular matrix) assists in the resistance to forces of
common connective tissue of the body, is composed of compression. As these molecules come into close prox-
a hydrated gel-like ground substance with fibers imity to each other, their negative charges repel one
embedded in it. Ground substance resists forces of another, which causes them to have a slippery texture,
compression, and fibers withstand tensile forces. The as evidenced by the slickness of mucus, vitreous humor
water of hydration permits the rapid exchange of nutri- of the eye, and synovial fluid.
ents and waste products carried by the extracellular All but one of the major GAGs of the ECM matrix
fluid as it percolates through the ground substance (Fig. are sulfated, each consisting of fewer than 300 repeat-
4-1). ing disaccharide units (see Table 4-1). The sulfated
69
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70 䡲䡲䡲 Chapter 4 䡲 Extracellular Matrix
Arteriole
Co
Capillary
GS
EF
Figure 4–2 Light micrograph (×132) of areolar connective tissue,

displaying cells, collagen fibers (Co), elastic fibers (EF), and ground
Lymphatic Venule substance (GS). Observe that in this very loose type of connective
capillary tissue the fibers, although interwoven, present a relatively haphazard
arrangement, thus permitting stretching of the tissue in any direction.
The cells of areolar connective tissue are principally of three types:
fibroblast, macrophages, and mast cells. The extensive extracellular
Figure 4–1 Tissue fluid flow. Fluid from the higher pressure
spaces are occupied by ground substance composed mainly of gly-
arterial ends of the capillary bed enters the connective tissue spaces
cosaminoglycans and proteoglycans, a large component of which is
and becomes known as extracellular fluid, which percolates through
aggrecan aggregate, a highly hydrated macromolecule.
the ground substance. Some, but not all, of the extracellular fluid then
reenters the blood circulatory system at the lower-pressure venous
end of the capillary bed and the venules. The extracellular fluid that
did not reenter the blood vascular system will enter the even lower-
pressure lymphatic system which will eventually deliver it to the blood molecule into the ECM. It has been suggested that this
vascular system. macromolecule also has intracellular functions. Some of
the newly released hyaluronic acid is endocytosed by
some cells, especially during the cell cycle, where it has
a role in maintaining space and modulating microtubu-
GAGs include keratan sulfate, heparan sulfate, heparin, lar activities during the metaphase and anaphase stages
chondroitin 4-sulfate, chondroitin 6-sulfate, and der- of mitosis, thus facilitating chromosomal movements.
matan sulfate. These GAGs are usually linked covalently Additional intracellular roles may involve modulation of
to protein molecules to form proteoglycans. The only intracellular trafficking and influencing intracytoplas-
nonsulfated GAG is hyaluronic acid (hyaluronan), mic-specific and intranuclear-specific kinases.
which may have as many as 10,000 repeating disaccha-
ride units. It is a very large macromolecule that does not Proteoglycans
form covalent links to protein molecules (although pro-
teoglycans do become attached to it via link proteins). Proteoglycans constitute a family of macromolecules;
Note that all GAGs are synthesized within the Golgi each is composed of a protein core to which
apparatus by resident enzymes—except hyaluronic glycosaminoglycans are covalently bonded.
acid, which is synthesized as a free linear polymer at the
cytoplasmic face of the plasma membrane by hyaluro- When sulfated GAGs form covalent bonds with a
nan synthases. These enzymes are integral membrane protein core, they form a family of macromolecules
proteins that not only catalyze the polymerization but known as proteoglycans, many of which occupy huge
also facilitate the transfer of the newly formed macro- domains. These large structures look like a bottle brush,
Ch004-X2945.qxd 12/8/06 3:22 PM Page 71
Chapter 4 䡲 Extracellular Matrix ■ ■ ■ 71
TABLE 4–1 Types of Glycosaminoglycans (GAGs)
Covalent
Molecular Repeating Linkage To
Type Mass (Da) Disaccharides Protein Location In Body
Hyaluronic acid 107-108 D-Glucuronic acid-beta-1,3-N- No Most connective tissue,

acetyl-D-glucosamine synovial fluid, cartilage,
dermis
Keratan sulfate 10,000-30,000 Galactose-beta-1,4-N-acetyl-D- Yes Cornea (keratan sulfate I),

I and II glucosamine-6-SO4 Cartilage (keratan sulfate II)
Heparan sulfate 15,000-20,000 D-Glucuronic acid-beta-1,3-N- Yes Blood vessels, lung, basal
acetyl galactosamine lamina
L-Iduronic acid-2 or -SO4-beta-
1,3-N-acetyl-D-galactosamine
Heparin (90%) 15,000-20,000 L-Iduronic acid-beta-1,4-sulfo- No Mast cell granule, liver,

D-glucosamine-6-SO4 lung, skin
(10%) D-Glucuronic acid-beta-1,4-N-
acetylglucosamine-6-SO4
Chondroitin 4- 10,000-30,000 D-Glucuronic acid-beta-1,3-N- Yes Cartilage, bone, cornea,

sulfate acetylgalactosamine-6-SO4 blood vessels
Chondroitin 6- 10,000-30,000 D-Glucuronic acid-beta-1,3-N- Yes Cartilage, Wharton’s jelly,

sulfate acetylgalactosamine-6-SO4 blood vessels
Dermatan 10,000-30,000 L-Iduronic acid-alpha-1,3-N- Yes Heart valves, skin, blood

sulfate acetylglucosamine-4-SO4 vessels
with the protein core resembling the wire stem and the form bonds with both the core protein of aggrecan as
various sulfated GAGs projecting from its surface in well as with the sugar groups of hyaluronic acid.
three-dimensional space, as do the bristles of the brush Because hyaluronic acid may be as much as 20 µm in
(Fig. 4-3). length, the result of this association is an aggrecan com-
Proteoglycans are of various sizes, ranging from posite that occupies a very large volume and may have
about 50,000 Da (decorin and betaglycan) to as many a molecular mass as large as several hundred million Da.
as 3 million Da (aggrecan). The protein cores of pro- This immense molecule is responsible for the gel state
teoglycans are manufactured on the rough endoplasmic of the ECM and acts as a barrier to fast diffusion of
reticulum (RER); they are then transported to the Golgi aqueous deposits, as when one observes the slow dis-
apparatus, where resident enzymes covalently bind appearance of an aqueous bubble after its subdermal
tetrasaccharides to its serine side chains; the GAG is injection.
then assembled by the addition of sugars one at a time.
Sulfation, catalyzed by sulfotransferases, and epimer-
ization (rearrangement of various groups around the CLINICAL CORRELATIONS
carbon atoms of the sugar units) also occur in the Golgi
apparatus. Many pathogenic bacteria, such as Staphylococ-
Many proteoglycans, especially aggrecan, a macro- cus aureus, secrete hyaluronidase, an enzyme
molecule found in cartilage and connective tissue that cleaves hyaluronic acid into numerous small
proper, attach to hyaluronic acid (see Fig. 4-3). The fragments, thus converting the gel state of the
mode of attachment involves a noncovalent ionic inter- ECM to a sol state. The consequence of this
action between the sugar groups of the hyaluronic acid reaction is to permit the rapid spread of the bac-
and the core protein of the proteoglycan molecule. The teria through the connective tissue spaces.
connection is reinforced by small link proteins that
Ch004-X2945.qxd 12/8/06 3:22 PM Page 72
Collagen fibrils Hyaluronic acid β. By binding these signaling molecules, proteoglycans

molecule
can either impede their function by preventing the mol-
ecules from reaching their destinations, or enhance their
function by concentrating them in a specific location.
Some proteoglycans, such as decorins, are required for
the formation of collagen fibers; mutated mice that
cannot produce decorins or that produce defective
decorins, possess skin with reduced tensile strength.
Some proteoglycans, such as syndecans, instead of
being released into the ECM, remain attached to the
cell membrane. The core proteins of syndecans act as
transmembrane proteins and are attached to the actin
filaments of the cytoskeleton. Their extracellular moi-
eties bind to components of the ECM, thus permitting
the cell to become attached to macromolecular compo-
nents of the matrix. In addition, syndecans of fibroblasts
function as co-receptors because they bind fibroblast
growth factor and present it to cell membrane fibroblast
growth factor receptors in their vicinity.
Glycoproteins
Hyaluronic acid
Cell adhesive glycoproteins have binding sites for several
Link protein
components of the ECM as well as for integrin molecules
of the cell membrane that facilitate the attachment of
Core protein cells to the ECM.
Chondroitin sulfate The ability of cells to adhere to components of the

ECM is mediated to a great extent by cell adhesive
Proteoglycan
glycoproteins. These large macromolecules have several
domains, at least one of which usually binds to cell
Collagen (type II)
surface proteins called integrins, one to collagen fibers,
and one to proteoglycans. In this manner, adhesive gly-
coproteins fasten the various components of tissues to
each other. The major types of adhesive glycoproteins
Figure 4–3 The association of aggrecan molecules with collagen are fibronectin, laminin, entactin, tenascin, chon-
fibers. Inset displays a higher magnification of the aggrecan molecule,
indicating the core protein of the proteoglycan molecule to which the
dronectin, and osteonectin.
glycosaminoglycans are attached. The core protein is attached to the Fibronectin is a large dimer composed of two
hyaluronic acid by link proteins. (Adapted from Fawcett DW: Bloom similar polypeptide subunits, each about 220,000 Da,
and Fawcett’s A Textbook of Histology, 11th ed. Philadelphia, WB attached to one another at their carboxyl ends by disul-
Saunders, 1986.) fide bonds. Each arm of this V-shaped macromolecule
has binding sites for various extracellular components
Functions of Proteoglycans (e.g., collagen, heparin, heparan sulfate, and hyaluronic
acid) and for integrins of the cell membrane. The region
Proteoglycans have numerous functions. By occupying of the fibronectin that is specific for adhering to the cell
a large volume, they resist compression and retard the membrane has the three-residue sequence arginine,
rapid movement of microorganisms and metastatic glycine, and aspartate, referred to as the RGD
cells; however, in the same fashion, they facilitate sequence. This sequence of amino acids is character-
normal cellular locomotion by permitting migrating istic of the integrin binding site in many adhesive
cells to move into the space that these hydrated macro- glycoproteins. Fibronectin is produced mainly by con-
molecules occupied. In addition, in association with the nective tissue cells known as fibroblasts. The actin
basal lamina, they form molecular filters of varying pore components of the cytoskeleton of these cells and their
sizes and charge distributions that selectively screen and associated myosin counterparts interact, placing tension
retard macromolecules as they pass through them. on their plasmalemma. The integrin molecules relay the
Proteoglycans also possess binding sites for certain tensile forces to the newly exocytosed fibronectin mol-
signaling molecules, such as transforming growth factor- ecules, stretching them just enough to expose hidden
Ch004-X2945.qxd 12/8/06 3:22 PM Page 73
binding sites that permit fibronectins to bind to each venience when describing organs that possess large
other, thus forming the fibronectin matrix. quantities of this particular collagen type.
Fibronectin is also present in blood as plasma
fibronectin, where it facilitates wound healing, phago- Collagen Fibers:
cytosis, and coagulation. Fibronectin may be temporar- Structure and Function
ily attached to the plasma membrane as cell-surface
fibronectin. Fibronectin marks migratory pathways for Collagen fibers are composed of tropocollagen subunits
embryonic cells so that the migrating cells of the devel- whose a-chain amino acid sequences permit the
oping organism can reach their destination. classification of collagen into at least 20 different fiber
Laminin is a very large glycoprotein (950,000 Da), types. There are three categories of collagen: fibril-forming,
composed of three large polypeptide chains, A, B1, and fibril-associated, and network-forming; there are also
B2. The B chains wrap around the A chain, forming a collagen-like proteins that form an additional category.
cross-like pattern of one long and three short chains.
The three chains are held in position by disulfide bonds. The capability of the ECM to withstand compressive
The location of laminin is almost strictly limited to the forces is due to the presence of the hydrated matrix
basal lamina; therefore, this glycoprotein has binding formed by GAGs and proteoglycans. Tensile forces are
sites for heparan sulfate, type IV collagen, entactin, and resisted by fibers of the tough, firm, inelastic protein colla-
the cell membrane. gen. This family of proteins is very abundant, constituting
The sulfated glycoprotein entactin (also known as about 20% to 25% of all the proteins in the body. Collagens
nidogen) binds to the laminin molecule where the are classified into three categories, fibril-forming, fibril-
three short arms of that molecule meet each other. associated, and network-forming collagens. An additional
Entactin also binds to type IV collagen, thus facilitating category, collagen-like proteins, is also recognized.
the binding of laminin to the collagen meshwork. Fibril-forming collagen, as its classification
Tenascin is a large glycoprotein composed of six implies, forms flexible fibers (Fig. 4-4) whose tensile
polypeptide chains held together by disulfide bonds. strength is greater than that of stainless steel of compa-
This macromolecule, which resembles a bug whose six rable diameter. Large collections of collagen fibers
legs project radially from a central body, has binding appear glistening white in live tissue; therefore, colla-
sites for the transmembrane proteoglycan syndecans gen fiber bundles are also referred to as white fibers.
and for fibronectin. Tenascin’s distribution is usually Collagen fibers of connective tissue are usually less than
limited to embryonic tissue, where it marks migratory 10 µm in diameter and are colorless when unstained.
pathways for specific cells. Stained with hematoxylin and eosin, they appear as
Chondronectin and osteonectin are similar to long, wavy, pink fiber bundles.
fibronectin. The former has binding sites for type II col- Electron micrographs of collagen fibers stained with
lagen, chondroitin sulfates, hyaluronic acid, and inte- heavy metals display cross-banding at regular intervals
grins of chondroblasts and chondrocytes. Osteonectin of 67 nm, a characteristic property of these fibers. These
possesses domains for type I collagen, proteoglycans, fibers are formed from parallel aggregates of thinner
and integrins of osteoblasts and osteocytes. In addition, fibrils 10 to 300 nm in diameter and many micrometers
it may facilitate the binding of calcium hydroxyapatite in length (Fig. 4-5). The fibrils themselves are fashioned
crystals to type I collagen in bone. from a highly regular assembly of even smaller subunits,
tropocollagen (collagen) molecules, each about
280 nm long and 1.5 nm in diameter. Individual
FIBERS tropocollagen molecules are composed of three poly-
peptide chains, called a-chains, wrapped around each
Collagen and elastic fibers, the two major fibrous other in a triple helical configuration.
proteins of connective tissue, have distinctive Each α-chain possesses about 1000 amino acid
biochemical and mechanical properties as a consequence residues. Every third amino acid is glycine, and most of
of their structural characteristics. the remaining amino acids are composed of proline,
hydroxyproline, and hydroxylysine. It is believed that
The fibers of the ECM provide tensile strength and glycine, because of its small size, permits the close asso-
elasticity to this substance. Classical histologists have ciation of the three α-chains; the hydrogen bonds of
described three types of fibers on the basis of their mor- hydroxyproline hold the three α-chains together; and
phology and reactivity with histological stains: colla- hydroxylysine permits the formation of fibrils by binding
gen, reticular, and elastic (see Fig. 4-2). Although it the tropocollagen molecules to each other.
is now known that reticular fibers are in fact a type of Although at least 20 different types of collagen
collagen fiber, many histologists retain the term reticu- are known, depending on the amino acid sequence of
lar fibers not only for historical reasons but also for con- their α-chains, only 10 of them are of interest in this
Ch004-X2945.qxd 12/8/06 3:22 PM Page 74
Figure 4–4 Scanning electron

micrograph of collagen fiber bundles
from the epineurium of the rat
sciatic nerve (×2034). Note that the
thick fiber bundles are interwoven
and that they are arranged in an
almost haphazard manner. Also, fiber
bundles split (arrow) into thinner
bundles (or thinner bundles coalesce
to form larger bundles). Moreover,
each of the thick fiber bundles is
composed of numerous fine fibrils
that run a parallel course in each
bundle. (From Ushiki T, Ide C:
Three-dimensional organization of
the collagen fibrils in the rat sciatic
nerve as revealed by transmission
and scanning electron microscopy.
Cell Tissue Res 260:175-184, 1990.)
Tendon
Bundle
Muscle
Fiber
Fibril Tropocollagen
triple helix
Figure 4–5 Components of a col-
lagen fiber. The ordered arrangement
of the tropocollagen molecules gives
rise to gap and overlap regions, respon-
sible for the 67-nm cross-banding of
Overlapping type I collagen. The gap region is the
region Gap area between the head of one tropocol-
region lagen molecule and the tail of the next.
The overlapping region is the area
where the tail of one tropocollagen
molecule overlaps the tail of another in
the row above or below. In three
dimensions, the overlap region coin-
cides with numerous other overlap
regions, and the gap regions coincide
with numerous other gap regions. The
heavy metals that are used in electron
microscopy precipitate into the gap
regions and make them visible as the
67-nm cross-banding. Type I collagen
is composed of two identical a1(I)
chains (blue) and one a2(I) chain
Packing of tropocollagen molecules (pink).
Ch004-X2945.qxd 12/8/06 3:22 PM Page 75
textbook. Each α-chain is coded by a separate messen- known as propeptides, at both the amino and carboxyl
ger ribonucleic acid (mRNA). These different collagen ends. As a preprocollagen molecule is being synthe-
types are located in specific regions of the body, where sized, it enters the cisterna of the RER, where it is mod-
they serve various functions (Table 4-2; Fig. 4-6). ified. First, the signal sequence directing the molecule
to the RER is removed; then some of the proline and
lysine residues are hydroxylated (by the enzymes
CLINICAL CORRELATIONS peptidyl proline hydroxylase and peptidyl lysine hy-
droxylase) in a process known as post-translational
At the end of surgery, the cut surfaces of skin are modification to form hydroxyproline and hydroxylysine,
carefully sutured; usually, a week later the respectively. Subsequently, selected hydroxylysines are
sutures are removed. The tensile strength of the glycosylated by the addition of glucose and galactose.
dermis at that point is only about 10% that of Three preprocollagen molecules align with each other
normal skin. Within the next 4 weeks, the tensile and assemble to form a tight helical configuration known
strength increases to about 80% of normal, but as a procollagen molecule. It is believed that the preci-
in many cases it never reaches 100%. The initial sion of their alignment is accomplished by the propep-
weakness is attributed to the formation of type tides. Because these propeptides do not wrap around
III collagen during early wound healing, whereas each other, the procollagen molecule resembles a tightly
the later improvement in tensile strength is due wound rope with frayed ends. The propeptides apparen-
to scar maturation, when type III collagen is tly have the additional function of keeping the procolla-
replaced by type I collagen. gen molecules soluble, thus preventing their spontaneous
Some individuals, especially blacks, are pre- aggregation into collagen fibers within the cell.
disposed to an excessive accumulation of colla- The procollagen molecules leave the RER via trans-
gen during wound healing. In these patients, the fer vesicles that transport them to the Golgi apparatus,
scar forms an elevated growth known as a keloid. where they are further modified by the addition of
oligosaccharides. The modified procollagen molecules
are packaged in the trans Golgi network and are imme-
Collagen Synthesis diately ferried out of the cell.
As procollagen enters the extracellular environment,
The synthesis of collagen occurs on the rough proteolytic enzymes, called procollagen peptidases,
endoplasmic reticulum as individual preprocollagen cleave the propeptides (removing a portion of the frayed
chains (α-chains). ends) from both the amino and carboxyl ends (see Fig.
4-7). The newly formed molecule is shorter (280 nm in
The synthesis of collagen occurs on the RER as indi- length) and is known as a tropocollagen (collagen)
vidual preprocollagen chains (Fig. 4-7), which are α- molecule. Tropocollagen molecules spontaneously
chains possessing additional amino acid sequences, self-assemble (see Fig. 4-7), in a specific head-to-tail

graph (×22,463) of collagen fibers
from the perineurium of the rat
sciatic nerve. Ep, epineurium; En,
endoneurium; P, perineurium.
(From Ushiki T, Ide C: Three-
dimensional organization of the col-
lagen fibrils in the rat sciatic nerve,
as revealed by transmission and
scanning electron microscopy. Cell
Tissue Res 260:175-184, 1990.)
Ch004-X2945.qxd 12/8/06 3:22 PM Page 76
TABLE 4–2 Major Types and Characteristics of Collagen
Molecular Synthesizing
Molecular Type Formula Cells Function Location in Body
I (fibril-forming); most [α(I)]2α2(I) Fibroblasts, Resists tension Dermis, tendon,

common of all collagens osteoblasts, ligaments, capsules
odontoblasts, of organs, bone,
cementoblasts dentin, cementum
II (fibril-forming) [α1(II)]3 Chondroblasts Resists pressure Hyaline cartilage,

elastic cartilage
III (fibril-forming); also [α1(III)]3 Fibroblasts, Forms structural Lymphatic system,

known as reticular fibers. reticular framework of spleen, spleen, liver,
Highly glycosylated cells, smooth liver, lymph nodes, cardiovascular
muscle cells, smooth muscle, system, lung, skin
hepatocytes adipose tissue
IV (network-forming); do [α1(IV)]2α2(IV) Epithelial cells, Forms meshwork of Basal lamina

not display 67-nm muscle cells, the lamina densa of
periodicity and α-chains Schwann cells the basal lamina to
retain propeptides provide support and
filtration
V (fibril-forming) [α1(V)]2α2(V) Fibroblasts, Associated with type I Dermis, tendon,

mesenchymal collagen, also with ligaments, capsules
cells placental ground of organs, bone,
substance cementum, placenta
VII (network-forming); [α1(VII)]3 Epidermal cells Forms anchoring fibrils Junction of epidermis
form dimers that that fasten lamina and dermis
assemble into densa to underlying
anchoring fibrils lamina reticularis
IX (fibril-associated); [α1(IX)α2(IX)α3 Epithelial cells Associates with type II Cartilage

decorate the surface of (IX)] collagen fibers
type II collagen fibers
XII (fibril-associated); [α1(XII)]3 Fibroblasts Associates with type I Tendons, ligaments,

decorate the surface of collagen fibers and aponeuroses
type I collagen fibers
XVII (collagen-like protein); [α1(XVII)]3 Epithelial cells ? Hemidesmosomes

a transmembrane protein,
formerly known as bullous
pemphigoid antigen
XVIII (collagen-like [α1(XVIII)]3 Endothelial cells ? Basal lamina of

protein); cleavage of endothelial cells
its C-terminal forms
endostatin and
angiogenesis inhibitor
direction, into a regularly staggered array, fashioning fibrils As the tropocollagen molecules self-assemble in a
that display a 67-nm wide banding representative of col- three-dimensional array, the spaces between the heads
lagen types I, II, III, and V (see Fig. 4-5). The formation and tails of successive molecules in a single row line up
and maintenance of the fibrillar structure are augmented as repeating gap regions (every 67 nm), not in adjoin-
by covalent bonds formed between lysine and hydroxyly- ing but in neighboring rows (see Figs. 4-5 and 4-7). Sim-
sine residues of neighboring tropocollagen molecules. ilarly, the overlaps of heads and tails in neighboring rows
Ch004-X2945.qxd 12/8/06 3:22 PM Page 77
Nucleus
DNA
1 Transcription in nucleus
mRNA
mRNA
2 Translation of
preprocollagen in RER
3 Hydroxylation ( )
in RER
4 Glycosylation ( )
in RER
5 Formation of procollagen
triple helix in RER
6 Secretion of procollagen
via trans Golgi network
Figure 4–7 Sequence of events in the synthesis of type I collagen.

Messenger RNA (mRNA) leaves the nucleus and attracts small and large
subunits of ribosomes. As translation begins, the polysome complex
translocates to the rough endoplasmic reticulum (RER), and the nascent 7 Cleavage of propeptides
alpha chains enter the lumen of the RER. Within the lumen, some to form tropocollagen
proline and lysine residues of the α-chains are hydroxylated, and the pre- molecule
procollagen molecule is glycosylated. Three α-chains form a helical con-
figuration—the procollagen triple helix. The procollagen is transferred to
the Golgi complex where further modification occurs. At the trans Golgi 8 Spontaneous self-
network the procollagen is packaged in clathrin-coated vesicles, and the assembly of
procollagen is exocytosed. As the procollagen leaves the cell, a mem- tropocollagen to form
brane-bound enzyme called procollagen peptidase cleaves the propep- collagen fibril
tides from both the carboxyl- and the amino-end of procollagen,
transforming it into tropocollagen. These newly formed macromolecules
self-assemble into collagen fibrils.
are in register with one another as the overlap regions. The alignment of the collagen fibrils and fiber
Heavy metal stains used in electron microscopy prefer- bundles is determined by the cells that synthesize
entially deposit in the gap regions. Consequently, them. The procollagen is released into folds and furrows
viewed in the electron microscope, collagen displays of the plasmalemma, which act as molds that arrange
alternating dark and light bands; the dark bands repre- the forming fibrils in the proper direction. The fibril
sent the gap regions filled with heavy metal, and the orientation is further enhanced as the cells tug on the
light bands represent overlap regions, where the heavy fibrils and physically drag them to fit the required
metal cannot be deposited (see Fig. 4-6). pattern.
Ch004-X2945.qxd 12/8/06 3:22 PM Page 78
Fibrillar structure is absent in type IV and type VII Elastic Fibers

collagen because the propeptides are not removed
from the procollagen molecule. Its procollagen mole- Elastic fibers, unlike collagen, are highly accommodating
cules assemble into dimers, which then form a felt-like and may be stretched one and a half times their resting
meshwork. length without breaking. When the force is released,
elastic fibers return to their resting length.
CLINICAL CORRELATIONS The elasticity of connective tissue is due, in great part,

to the presence of elastic fibers in the ECM (Figs. 4-9
Hydroxylation of proline residues requires the and 4-10; also see Fig. 4-2). These fibers are usually
presence of vitamin C. In individuals who suffer slender, long, and branching in loose connective tissue,
from a deficiency of this vitamin, the α-chains of but they may form coarser bundles in ligaments and
the tropocollagen molecules are unable to form fenestrated sheets. Such bundles are found in the liga-
stable helices, and the tropocollagen molecules mentum flava of the vertebral column, and concentric
are incapable of aggregating into fibrils. This con- sheets occur in the walls of larger blood vessels. In fact,
dition, known as scurvy, first affects connective elastic fibers constitute about 50% of the aorta by dry
tissues with a high turnover of collagen, such as weight.
the periodontal ligament and gingiva (Fig. 4-8). Elastic fibers are manufactured by fibroblasts of con-
Because these two structures are responsible for nective tissue as well as by smooth muscle cells of blood
maintaining teeth in their sockets, the symptoms vessels. They are composed of elastin, a protein that is
of scurvy include bleeding gums and loose teeth. rich in glycine, lysine, alanine, valine, and proline but
If the vitamin C deficiency is prolonged, other that has no hydroxylysine. Elastin chains are held
sites are also affected. These symptoms may be together in such a fashion that four lysine molecules,
alleviated by eating foods rich in vitamin C. each belonging to a different elastin chain, form cova-
Deficiency of the enzyme lysyl hydroxylase, lent bonds with each other to form desmosine cross-
a genetic disorder known as Ehlers-Danlos links. These desmosine residues are highly deformable
syndrome, results in abnormal cross-links and they impart a high degree of elasticity to elastic
among tropocollagen molecules. Individuals fibers to such an extent that these fibers may be
afflicted with this anomalous condition possess stretched to about 150% of their resting lengths before
abnormal collagen fibers that result in hypermo- breaking. After being stretched, elastic fibers return to
bile joints and hyperextensive skin. In many their resting length.
instances, the skin of affected patients is readily The core of elastic fibers is composed of elastin
traumatized and the patient is subject to disloca- and is surrounded by a sheath of microfibrils; each
tion of the affected joints. microfibril is about 10 nm in diameter and is composed
of the glycoprotein fibrillin (Fig. 4-11). During the for-
Figure 4–8 Degradation of type I collagen by fibroblasts. Collagen turnover is relatively slow in some regions of the body (e.g., in bone,
where it may be stable for as long as 10 years), whereas in other regions, such as the gingiva and the periodontal ligament, the half-life of col-
lagen may be weeks or months. Fibroblasts of the gingiva and periodontal ligament are responsible not only for the synthesis but also for the
resorption of collagen. (From Ten Cate AR: Oral Histology: Development, Structure, and Function, 4th ed. St. Louis, Mosby–Year Book, 1994.)
Ch004-X2945.qxd 12/8/06 3:22 PM Page 79
BASEMENT MEMBRANE
P
The basement membrane seen with light microscopy is
shown by electron microscopy to be composed of the
basal lamina and lamina reticularis.
The interface between epithelium and connective tissue

is occupied by a narrow, acellular region—the basement
membrane—which is well stained by the PAS reaction
and by other histological stains that detect GAGs. A
structure similar to the basement membrane, the exter-
nal lamina, surrounds smooth and skeletal muscle
cells, adipocytes, and Schwann cells. Electron micros-
copy shows that the basement membrane has two
constituents: the basal lamina, elaborated by epithe-
lial cells, and the lamina reticularis, manufactured by
cells of the connective tissue (Fig. 4-13). The epithelial
C sheath is bound to the underlying connective tissue by
these resilient acellular interfaces, the basal lamina and
lamina reticularis.
Basal Lamina
The basal lamina manufactured by the epithelium is
composed of the lamina lucida and the lamina densa.
Electron micrographs of the basal lamina display its

two regions: the lamina lucida, a 50-nm-thick electron-
lucent region just beneath the epithelium, and the
lamina densa, a 50-nm-thick electron-dense region
Figure 4–9 Light micrograph of elastic cartilage (×270). Note
the presence of elastic fibers (arrows) in the matrix. The large chon- (Figs. 4-13 to 4-15). The lamina lucida consists mainly
drocytes of elastic cartilage occupy spaces known as lacunae in the of the extracellular glycoproteins laminin and entactin,
proteoglycan-rich matrix. The large bundles of elastic fibers are as well as of integrins and dystroglycans, transmem-
clearly evident, and they appear to be arranged in a haphazard brane laminin receptors (both discussed later), that
fashion. Observe that the thicker elastic fibers are composed of fine
fibrils. C, chondrocyte; P, perichondrium.
project from the epithelial cell membrane into the basal
lamina. In rapidly frozen tissues, the lamina lucida is
frequently absent, suggesting that it may be an artifact
of fixation and that the lamina densa may be closer to
the integrins and dystroglycans of the basal cell mem-
mation of elastic fibers, the microfibrils are elaborated brane than previously believed.
first, and the elastin is then deposited in the space sur- The lamina densa comprises a meshwork of type IV
rounded by the microfibrils (Fig. 4-12). collagen, which is coated on both the lamina lucida and
lamina reticularis sides by the proteoglycan perlacan.
The heparan sulfate side chains projecting from the
CLINICAL CORRELATIONS protein core of perlacan form a polyanion. The lamina
reticularis aspect of the lamina densa also possesses
The integrity of elastic fibers depends on the fibronectin.
presence of microfibrils. Patients with Marfan Laminin has domains that bind to type IV collagen,
syndrome have a defect in the gene on chro- heparan sulfate, and the integrins and dystroglycans of
mosome 15 that codes for fibrillin; therefore, the epithelial basal cell membrane, thus anchoring the
their elastic fibers do not develop normally. epithelial cell to the basal lamina. The basal lamina
People who are severely affected with this con- appears to be well anchored to the reticular lamina by
dition are predisposed to fatal rupture of the several substances, including fibronectin, anchoring
aorta. fibrils (type VII collagen), and microfibrils (fibrillin), all
elaborated by fibroblasts of connective tissue (Fig. 4-16).
Ch004-X2945.qxd 12/8/06 3:22 PM Page 80

of dense, regular elastic connective
tissue (x270). Note that the elastic
fibers are short and are arranged
almost parallel with each other and
that their ends are somewhat curled.
Unlike collagen fibers of dense
regular connective tissue, where the
collagen fibrils and fibers closely par-
allel each other, these elastic fibers
appear to be somewhat misaligned.
Elastin localized in the basal cell membrane, and acting as a

core path for cellular migration, as in re-epithelialization
during wound repair or in the reestablishment of
myoneural junctions during regeneration of motor
nerves.
Lamina Reticularis
The lamina reticularis is derived from the connective
tissue component and is responsible for affixing the
lamina densa to the underlying connective tissue.
Microfibrils The lamina reticularis (see Figs. 4-13, 4-14, and

4-16), a region of varying thickness, is manufactured by
Figure 4–11 An elastic fiber, showing microfibrils surrounding fibroblasts and is composed of type I and type III col-
the amorphous elastin.
lagen. It is the interface between the basal lamina and
the underlying connective tissue, and its thickness
varies with the amount of frictional force on the over-
The basal lamina functions both as a molecular filter lying epithelium. Thus, it is quite thick in skin and very
and as a flexible, firm support for the overlying epithe- thin beneath the epithelial lining of the alveolus of the
lium. The filtering aspect is due not only to the type IV lung.
collagen, whose interwoven meshwork forms a physical Type I and type III collagen fibers of the connective
filter of specific pore size, but also to the negative tissue loop into the lamina reticularis, where they inter-
charges of its heparan sulfate constituent, which pref- act with and are bound to the microfibrils and anchor-
erentially restricts the passage of negatively charged ing fibrils of the lamina reticularis. Moreover, the basic
molecules. Additional functions of the basal lamina groups of the collagen fibers form bonds with the acidic
include facilitating mitotic activity and cell differentia- groups of the GAGs of the lamina densa. In addition,
tion, modulating cellular metabolism, assisting in the collagen-binding domains and GAG domains of
establishment of cell polarity, playing a role in the mod- fibronectin further assist in anchoring the basal lamina
ification of the arrangement of the integral proteins to the lamina reticularis.
Ch004-X2945.qxd 12/8/06 3:22 PM Page 81
Figure 4-13 Electron micrograph of the basal lamina of the

human cornea (×50,000). Note the hemidesmosomes (large arrows)
and the anchoring plaques among the anchoring fibrils (small arrows).
Observe that the basal cell membrane is clearly visible and that the
plaques of the hemidesmosomes are attached to the cytoplasmic
surface of the basal plasmalemma. The dense, amorphous-appearing
line that follows the contour of the basal plasma membrane is the
lamina densa, and the clear area between it and the basal cell mem-
brane is the lamina lucida. (From Albert D, Jakobiec FA: Principles
and Practice of Ophthalmology: Basic Sciences. Philadelphia, WB
Saunders, 1994.)
Figure 4–12 Electron micrograph of elastic fiber development.

Note the presence of microfibrils surrounding the amorphous matrix
of elastin as if a small space were to be delineated by slats of a picket receptor and its ligand. Integrins are much more
fence (arrowheads). These fibrillin-containing microfibrils are elabo-
rated and released first, and then the manufacturing cell—a fibroblast numerous than receptors, thus compensating for the
of connective tissue proper or a smooth muscle cell of a blood vessel— bond weakness and also permitting the migration of
releases elastin into the space enclosed by the microfibrils. (From cells along a surface of the ECM.
Fukuda Y, Ferrans VJ, Crystal RG: Development of elastic fibers of Integrins are heterodimers (~250,000 Da) com-
nuchal ligament, aorta, and lung of fetal and postnatal sheep: An ultra-
structural and electron microscopic immunohistochemical study. Am
posed of α and β glycoprotein chains whose carboxyl
J Anat 170:597-629, 1984.) ends are linked to talin and α-actinin of the cytoskele-
ton. Their amino ends possess binding sites for macro-
molecules of the ECM (see Chapter 2, Fig. 2-32).
Because integrins link the cytoskeleton to the ECM,
they are also called transmembrane linkers. The
INTEGRINS AND α-chain of the integrin molecule binds Ca2+ or Mg2+,
DYSTROGLYCANS divalent cations necessary for the maintenance of
proper binding with the ligand.
Integrins and dystroglycans are transmembrane Many integrins differ in their ligand specificity, cel-
glycoproteins that act as laminin receptors as well as lular distribution, and function. Some are commonly
organizers of basal lamina assembly. referred to as receptors for their ligands (e.g., laminin
receptor, fibronectin receptor). Cells can modulate the
Integrins are transmembrane proteins that are similar affinity of their receptor for its ligand by regulating the
to cell membrane receptors in that they form bonds availability of divalent cations, modifying the conforma-
with ligands. However, unlike those of receptors, their tion of the integrin, or otherwise altering the integrin’s
cytoplasmic regions are linked to the cytoskeleton, and affinity for the ligand. In this manner, cells are not
their ligands are not signaling molecules but structural locked into a particular position once their integrins
members of the ECM such as collagen, laminin, and bind to the macromolecules of the ECM but can release
fibronectin. Moreover, the association between an inte- their integrin-ligand bonds and move away from that
grin and its ligand is much weaker than that between a particular location.
Ch004-X2945.qxd 12/8/06 3:22 PM Page 82
Epithelial cell
Lamina
lucida
Basal
Lamina lamina
densa
Reticular fibers
(type III collagen)
Figure 4–14 Basal lamina and lamina

reticularis. (Adapted from Fawcett DW:
Anchoring fibrils Bloom and Fawcett’s A Textbook of His-
(type VII collagen) Lamina
Anchoring plaque reticularis tology, 12th ed. New York, Chapman and
(type IV collagen) Hall, 1994.)
Figure 4–15 This scanning

electron micrograph is of a 6-day
chick embryo cornea from which a
portion of the epithelium has been
removed, exposing epithelial cells on
the underlying basement mem-
brane. The membrane itself has
been partially removed, revealing
the underlying primary corneal
stroma composed of orthogonally
arrayed collagen fibrils. The white
bar at the lower left is the 10-µm
mark. (© Robert L. Trelstad.)
Ch004-X2945.qxd 12/8/06 3:22 PM Page 83
diverse signaling pathways, including mitogen-activated

protein kinase, protein kinase C, and phosphoinositide
pathways that lead to activation of the cell cycle, cell
differentiation, cytoskeletal reorganization, regulation
of gene expression, and even programmed cell death via
apoptosis. Frequently, integrins have to be activated by
focal adhesion kinase, a protein tyrosine kinase; other-
wise, they cannot initiate their signaling functions.
Dystroglycans are glycoproteins that are also com-
posed of two subunits, a transmembrane β-dystroglycan
and an extracellular α-dystroglycan. The α-dystroglycan
binds to the laminin of the basal lamina but at different
sites than does the integrin molecule. The intracellular
moiety of the β-dystroglycan binds to the actin-binding
protein dystrophin, which, in turn, binds to α-actinin
of the cytoskeleton.
Dystroglycans and integrins have significant roles in
the assembly of basal laminae because embryos lacking
either or both of these glycoproteins are unable to form
normal basal laminae.
Figure 4–16 Electron micrograph of the basal lamina of CLINICAL CORRELATIONS

the corneal epithelium (×165,000). H. Sulf., Heparan sulfate-rich. Individuals with the autosomal recessive disor-
(From Albert D, Jakobiec FA: Principles and Practice of Ophthal-
mology: Basic Sciences. Philadelphia, WB Saunders, 1994.) der leukocyte adhesion deficiency are inca-
pable of synthesizing the β-chain of the white
blood cell integrins. Their leukocytes are inca-
In addition to their roles in adhesion, integrins func- pable of adhering to the endothelial cells of
tion in transducing biochemical signals into intracellu- blood vessels and thus cannot migrate to sites of
lar events by activating second messenger system inflammation. Patients with this disease have dif-
cascades. The versatility of integrins in biochemical ficulty in fighting bacterial infections.
transduction is evidenced by their ability to stimulate
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5 䡲䡲䡲
Epithelium and Glands
The approximately 200 distinctly different types of cells 䡲 Control of movement of materials between body
composing the human body are arranged and coopera- compartments via selective permeability of inter-
tively organized into four basic tissues. Groups of these cellular junctions between epithelial cells
tissues are assembled in various organizational and 䡲 Detection of sensations via taste buds, retina of the
functional arrangements into organs, which carry out eye, and specialized hair cells in the ear.
functions of the body. The four basic tissue types are
epithelium, connective tissue, muscle, and nervous Epithelium
tissue. This and the next four chapters discuss each of
these tissues and the cells that constitute them. Tightly bound contiguous cells forming sheets covering
or lining the body are known as an epithelium.
EPITHELIAL TISSUE The sheets of contiguous cells in the epithelium are

tightly bound together by junctional complexes. Epithe-
Epithelial tissue is present in two forms: (1) as sheets of
lia display little intercellular space and little extracellu-
contiguous cells (epithelia) that cover the body on its
lar matrix. They are separated from the underlying
external surface and line the body on its internal
connective tissue by an extracellular matrix, the basal
surface, and (2) as glands, which originate from invagi-
lamina (discussed in Chapter 4), synthesized by the
nated epithelial cells.
epithelial cells. Because epithelium is avascular, the
Epithelia are derived from all three embryonic germ
adjacent supporting connective tissue through its capil-
layers, although most of the epithelia are derived from
lary beds supplies nourishment and oxygen via diffusion
ectoderm and endoderm. The ectoderm gives rise to
through the basal lamina.
the oral and nasal mucosae, cornea, epidermis of the
skin, and glands of the skin and the mammary glands.
The liver, the pancreas, and the lining of the respiratory Classification of Epithelial
and gastrointestinal tract are derived from the endo- Membranes
derm. The uriniferous tubules of the kidney, the lining
of the male and female reproductive systems, the endo- Cell arrangement and morphology are the bases of
classification of epithelium.
thelial lining of the circulatory system, and the mesothe-
lium of the body cavities develop from the mesodermal
Epithelial membranes are classified according to the
germ layer.
number of cell layers between the basal lamina and the
Epithelial tissues have numerous functions:
free surface and by the morphology of the epithelial
䡲 Protection of underlying tissues of the body from cells (Table 5-1). If the membrane is composed of a
abrasion and injury single layer of cells, it is called simple epithelium; if
䡲 Transcellular transport of molecules across epithe- it is composed of more than one cell layer, it is called
lial layers stratified epithelium (Fig. 5-1). The morphology of
䡲 Secretion of mucus, hormones, enzymes, and so the cells may be squamous (flat), cuboidal, or columnar
forth, from various glands when viewed in sections taken perpendicular to the
䡲 Absorption of material from a lumen (e.g., intestinal basement membrane. Stratified epithelia are classified
tract or certain kidney tubules) by the morphology of the cells in their superficial layer
85
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86 䡲䡲䡲 Chapter 5 䡲 Epithelium and Glands
TABLE 5–1 Classification of Epithelia
Shape of
Type Surface Cells Sample Locations Functions
Simple
Squamous Flattened Lining: pulmonary alveoli, loop of Henle, Limiting membrane, fluid
parietal layer of Bowman capsule, inner transport, gaseous exchange,
and middle ears, blood and lymphatic lubrication, reducing friction
vessels, pleural and peritoneal cavities (thus aiding movement of
viscera), lining membrane
Cuboidal Cuboidal Ducts of many glands, covering of ovary, Secretion, absorption,

form kidney tubules protection
Columnar Columnar Lining: oviducts, ductuli efferentes of Transportation, absorption,

testis, uterus, small bronchi, much of secretion, protection
digestive tract, gallbladder, large
ducts of some glands
Pseudostratified All cells rest on Lining: most of trachea, primary bronchi, Secretion, absorption
basal lamina but epididymis and ductus deferens, lubrication, protection,
not all reach auditory tube, part of tympanic cavity, transportation
epithelial surface; nasal cavity, lacrimal sac, male urethra,
surface cells are large excretory ducts
columnar
Stratified
Squamous, Flattened (with Lining: mouth, epiglottis, esophagus, Protection, secretion
nonkeratinized nuclei) vocal folds, vagina
Squamous, Flattened (without Epidermis of skin Protection

keratinized nuclei)
Cuboidal Cuboidal Lining: ducts of sweat glands Absorption, secretion
Columnar Columnar Conjunctiva of eye, some large excretory Secretion, absorption,

ducts, portions of male urethra protection
Transitional Dome-shaped Lining: urinary tract from renal calyces Protection, distensible
(relaxed), to urethra
flattened
(distended)
only. In addition to these two major classes of epithelia, section, however, only some cells display nuclei, because
which are further identified by cellular morphology, the plane of section frequently does not encounter the
there are two other distinct types: pseudostratified and nucleus. Simple squamous epithelia line pulmonary
transitional (see Fig. 5-1). alveoli, compose the loop of Henle and the parietal layer
of Bowman’s capsule in the kidney, and form the
Simple Squamous Epithelium endothelial lining of blood and lymph vessels as well as
the mesothelium of the pleural and peritoneal cavities.
Simple squamous epithelium is formed of a single layer
of flat cells. Simple Cuboidal Epithelium
Simple squamous epithelium is composed of a single Simple cuboidal epithelium is composed of a single layer
layer of tightly packed, thin, or low-profile polygonal of cells shaped like truncated hexagonal solids.
cells. When viewed from the surface, the epithelial sheet
looks much like a tile floor with a centrally placed, A single layer of polygon-shaped cells constitutes simple
bulging nucleus in each cell (Fig. 5-2A). Viewed in cuboidal epithelium (see Fig. 5-2A). When viewed in a
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Chapter 5 䡲 Epithelium and Glands ■ ■ ■ 87
Simple Pseudostratified
Squamous Cuboidal Columnar Pseudostratified

columnar
Stratified Transitional
Squamous nonkeratinized Cuboidal Transitional (relaxed) Transitional (distended)
Keratinized Columnar
Figure 5–1 Types of epithelia.
section cut perpendicular to the surface, the cells apical surface of the cells. The simple columnar epithe-
present a square profile with a centrally placed round lium that lines the uterus, oviducts, ductuli efferentes,
nucleus. Simple cuboidal epithelia make up the ducts and small bronchi is ciliated. In these organs, cilia (hair-
of many glands of the body, form the covering of the like structures) project from the apical surface of the
ovary, and compose some kidney tubules. columnar cells into the lumen.
Simple Columnar Epithelium Stratified Squamous Epithelium

Simple columnar epithelium is composed of a single Stratified squamous (nonkeratinized) epithelium
layer of tall cells shaped like hexagonal solids. comprises several layers of cells; the surface-most layer
possesses nuclei. Stratified squamous (keratinized)
The cells of simple columnar epithelium appear much epithelium is distinct in that the layers of cells
like those of simple cuboidal epithelium in a surface composing the free surface are dead, non-nucleated,
view; when viewed in longitudinal section, however, and filled with keratin.
they are tall, rectangular cells whose ovoid nuclei are
usually located at the same level in the basal half of the NONKERATINIZED
cell (Fig. 5-2B). Simple columnar epithelium is found
in the lining of much of the digestive tract, gallbladder, Stratified squamous (nonkeratinized) epithelium is
and large ducts of glands. Simple columnar epithelium thick; because it is composed of several layers of cells,
may exhibit a striated border, or microvilli (narrow, only the deepest layer is in contact with the basal lamina
finger-like cytoplasmic processes), projecting from the (Fig. 5-3A). The most basal (deepest) cells of this
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Figure 5–2 Light micrographs of simple epithelia. A, Simple squamous epithelium (arrows) (×270). Note the morphology of the cells and
their nuclei. Also present is simple cuboidal epithelium (arrowheads). Note the round, centrally placed nuclei. B, Simple columnar epithelium
(×540). Observe the oblong nuclei (N) and the striated border (arrows).
epithelium are cuboidal in shape; those located in the Stratified columnar epithelium is composed of a low
middle of the epithelium are polymorphous; and the polyhedral to cuboidal deeper layer in contact with the
cells composing the free surface of the epithelium are basal lamina and a superficial layer of columnar cells.
flattened (squamous)—hence the name stratified squa- This epithelium is found only in a few places in the
mous. Because the surface cells are nucleated, this body—namely, the conjunctiva of the eye, certain large
epithelium is called nonkeratinized. It is usually wet and excretory ducts, and regions of the male urethra.
is found lining the mouth, oral pharynx, esophagus, true
vocal folds, and vagina.
Transitional Epithelium
KERATINIZED
Transitional epithelium consists of several layers of cells.
Stratified squamous keratinized epithelium is similar to The surface layer is large and dome-shaped.
stratified squamous nonkeratinized epithelium, except
that the superficial layers of the epithelium are com- Transitional epithelium received its name because it
posed of dead cells whose nuclei and cytoplasm have was erroneously believed to be in transition between
been replaced with keratin (Fig. 5-3B). This epithelium stratified columnar and stratified squamous epithelia.
constitutes the epidermis of skin, a tough layer that This epithelium is now known to be a distinct type
resists friction and is impermeable to water. located exclusively in the urinary system, where it
lines the urinary tract from the renal calyces to the
Stratified Cuboidal Epithelium urethra.
Transitional epithelium is composed of many layers
Stratified cuboidal epithelium, which contains only two of cells; those located basally are either low columnar
layers of cuboidal cells, lines the ducts of the sweat or cuboidal cells. Polyhedral cells compose several
glands (Fig. 5-3C). layers above the basal cells. The most superficial cells
of the empty bladder are large, are occasionally binu-
Stratified Columnar Epithelium cleated, and exhibit rounded dome-shaped tops that
bulge into the lumen (Fig. 5-3D). These dome-shaped
Stratified columnar epithelium comprises more than one
cells become flattened and the epithelium becomes
layer of cells. The superficial layer is columnar in shape.
thinner when the bladder is distended.
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CC
Figure 5–3 Light micrographs of stratified epithelia. A, Stratified squamous nonkeratinized epithelium (×509). Observe the many layers of
cells and flattened (squamous) nucleated cells in the top layer (arrow). B, Stratified squamous keratinized epithelium (×125). C, Stratified
cuboidal epithelium of the duct of a sweat gland (CC) (×509). D, Transitional epithelium (×125). Observe that the surface cells facing the lumen
of the bladder are dome-shaped (arrows), which characterizes transitional epithelium.
Pseudostratified Columnar Epithelium of a single layer of cells. All of the cells in pseudostrat-
ified columnar epithelium are in contact with the basal
Pseudostratified columnar epithelium only appears lamina, but only some cells reach the surface of the
stratified; all cells are in contact with the basal lamina. epithelium (Fig. 5-4). Cells not extending to the surface
usually have a broad base and become narrow at their
As the name implies, pseudostratified columnar epithe- apical end. Taller cells reach the surface and possess a
lium appears to be stratified but it is actually composed narrow base in contact with the basal lamina and a
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with the basal lamina. Because these regions are distinct

functionally, each may have surface modifications and
specializations related to that function. For example,
the apical surfaces of many epithelial cells possess
microvilli or cilia, whereas their basolateral regions may
exhibit many types of junctional specializations and
intercellular interdigitations. The apical and basolateral
domains are separated from each other by tight junc-
tions that encircle the apical aspect of the cell.
BL
Apical Domain
The apical domain represents the free surface of the
epithelial cells.
The apical domain, the region of the epithelial cell

facing the lumen, is rich in ion channels, carrier pro-
teins, H+-ATPase (adenosine triphosphatase), glycopro-
teins, and hydrolytic enzymes, as well as aquaporins,
channel-forming proteins that function in regulation of
water balance. It also is the site where regulated secre-
tory products are delivered for release. Several surface
modifications are necessary for the apical domain of an
epithelium to carry out its many functions. These
Figure 5–4 Light micrograph of pseudostratified columnar include microvilli with associated glycocalyx and, in
epithelia (×540). This type of epithelium appears to be stratified;
however, all of the epithelial cells in this figure stand on the basal some cases, stereocilia, cilia, and flagella. Note that the
lamina (BL). only cells in the human body that possess flagella are the
spermatozoa. The structure of flagella is discussed in
Chapter 21, which covers the male reproductive system.
broadened apical surface. Because the cells of this
epithelium are of different heights, their nuclei are MICROVILLI
located at different levels, giving the impression of a
stratified epithelium even though it is composed of a Microvilli are small finger-like cytoplasmic projections
single layer of cells. Pseudostratified columnar epithe- emanating from the free surface of the cell into the
lium is found in the male urethra, epididymis, and lumen.
larger excretory ducts of glands.
The most widespread type of pseudostratified When observed by electron microscopy, absorptive
columnar epithelium is ciliated, having cilia on the columnar (and cuboidal) epithelial cells exhibit closely
apical surface of the cells that reach the epithelial packed microvilli, which are cylindrical, membrane-
surface. Pseudostratified ciliated columnar epithelium bound projections of the cytoplasm emanating from the
is found lining most of the trachea and primary bronchi, apical (luminal) surface of these cells (Fig. 5-5).
the auditory tube, part of the tympanic cavity, the nasal Microvilli represent the striated border of the intes-
cavity, and the lacrimal sac. tinal absorptive cells and the brush border of the kidney
proximal tubule cells observed by light microscopy.
Polarity and Cell-Surface In less active cells, microvilli may be sparse and
Specializations short; in intestinal epithelia, whose major function is
transport and absorption, they are crowded and 1 to
Epithelial cell polarity and cell-surface specializations are 2 µm in length, thus greatly increasing the surface area
related to cellular morphology and function. of the cells. Each microvillus contains a core of 25 to 30
actin filaments, cross-linked by villin, attached to an
Most epithelial cells have distinct morphological, bio- amorphous region at its tip and extending into the cyto-
chemical, and functional domains and thus commonly plasm, where the actin filaments are embedded in the
display a polarity that may be related to one or all of terminal web. The terminal web is a complex of actin
these differences. Such polarized cells, for instance, and spectrin molecules as well as intermediate filaments
possess an apical domain that faces a lumen and a baso- located at the cortex of the epithelial cells (Figs. 5-6
lateral domain whose basal component is in contact to 5-8). At regular intervals, myosin-I and calmodulin
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graph of microvilli of epithelial cells
from the small intestine (×2800).
(From Hopkins CR: Structure and
Function of Cells. Philadelphia, WB
Saunders, 1978.)
connect the actin filaments to the plasma membrane of cells, such as the hair cells of the vestibular apparatus
the microvillus, giving it support. Epithelia not func- in the inner ear, possess only a single cilium, which func-
tioning in absorption or transport may exhibit microvilli tions in a sensory mechanism.
without cores of actin filaments. Cilia are specialized to function in propelling mucus
Light microscopy of epithelia stained for carbohy- and other substances over the surface of the epithelium
drates reveals the glycocalyx, evident in electron micro- via rapid rhythmic oscillations. Cilia of the respiratory
graphs as an amorphous, fuzzy coating over the luminal tree, for example, move mucus and debris toward the
surface of the microvilli. The glycocalyx represents car- oropharynx, where it may be swallowed or expectorated.
bohydrate residues attached to the transmembrane pro- Cilia of the oviduct move the fertilized ovum toward the
teins of the plasmalemma. These glycoproteins function uterus.
in protection and cell recognition (see Chapter 2). Electron microscopy reveals that cilia possess a spe-
Stereocilia (not be confused with cilia) are long cific internal structure that is consistently conserved
microvilli found only in the epididymis and on the throughout the plant and animal kingdoms (Figs. 5-9
sensory hair cells of the cochlea (inner ear). It is and 5-10). The core of the cilium contains a complex of
believed that these nonmotile structures are unusually uniformly arranged microtubules called the axoneme.
rigid because of their core of actin filaments. In the epi- The axoneme is composed of a constant number of lon-
didymis, they probably function in increasing the gitudinal microtubules arranged in a consistent 9 + 2
surface area; in the hair cells of the ear, they function organization (Fig. 5-10B). Two centrally placed micro-
in signal generation. tubules (singlets) are evenly surrounded by nine dou-
blets of microtubules. The two microtubules located in
CILIA the center of the core are separated from each other,
each displaying a circular profile in cross section, com-
Cilia are long, motile, hair-like structures emanating posed of 13 protofilaments. Each of the nine doublets is
from the apical cell surface. Their core is composed of a composed of two subunits. In cross section, subunit A
complex arrangement of microtubules known as the is a microtubule composed of 13 protofilaments, exhibit-
axoneme. ing a circular profile. Subunit B possesses 10 protofila-
ments, exhibits an incomplete circular profile in cross
Cilia are motile, hair-like projections (diameter, 0.2 µm; section, and shares three protofilaments of subunit A.
length, 7 to 10 µm) that emanate from the surface of Several elastic protein complexes are associated with
certain epithelial cells. In the ciliated epithelia of the the axoneme. Radial spokes project from subunit A of
respiratory system (e.g., trachea and bronchi) and in the each doublet inward toward the central sheath sur-
oviduct, there may be hundreds of cilia in orderly arrays rounding the two singlets. Neighboring doublets are
on the luminal surface of the cells. Other epithelial connected by nexin, another elastic protein, extending
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sliding movement into a bending motion. As the cilium

bends, an energy-requiring process, the elastic protein
complex is stretched. When the dynein arms release
their hold on the B subunit, the elastic protein complex
returns to its original length, snapping the cilium back
to its straight position (which does not require energy),
effecting movement of material at the tip of the cilium.
CLINICAL CORRELATIONS
Kartagener’s syndrome results from hereditary
defects in the ciliary dynein that would normally
provide the energy for ciliary bending. Thus, cili-
ated cells without functional dynein are prohibited
from functioning. Persons having this syndrome
are susceptible to lung infections since their cili-
ated respiratory cells fail to clear the tract of debris
and bacteria. Additionally, males with this syn-
drome are sterile since their sperm are immotile.
The 9 + 2 microtubule arrangement within the

axoneme continues throughout most of the length of the
cilium except at its base, where it is attached to the basal
body (see Fig. 5-9). The morphology of the basal body
is similar to that of a centriole, in that it is composed of
nine triplets and no singlets.
Basal bodies develop from procentriole organiz-
ers. As tubulin dimers are added, the procentriole
lengthens to form the nine triplet microtubules charac-
teristic of the basal body. After formation, the basal
body migrates to the apical plasmalemma and gives rise
to a cilium. Nine doublet microtubules develop from
the nine triplets of the basal body, and a single pair of
microtubules form to give the cilium its characteristic 9
+ 2 microtubule arrangement.
Figure 5–6 High-magnification electron micrograph of
microvilli (×60,800). (From Hopkins CR: Structure and Function of Basolateral Domain
Cells. Philadelphia, WB Saunders, 1978.)
The basolateral domain includes the basal and lateral
aspects of the cell membrane.
from subunit A of one doublet to subunit B of the adja-
cent doublet (see Fig. 5-9). The basolateral domain may be subdivided into two
The microtubule-associated protein dynein, also regions: the lateral plasma membrane and the basal
active in flagella, which has ATPase activity, radiates plasma membrane. Each region possesses its own junc-
from subunit A of one doublet toward subunit B of the tional specializations and receptors for hormones and
neighboring doublet. These dynein arms are arranged neurotransmitters. In addition, these regions are rich in
at 24-nm intervals along the length of subunit A. Dynein Na+,K+-ATPase and ion channels and are sites for con-
ATPase, by hydrolyzing ATP, provides the energy for the stitutive secretion.
ciliary bending. Movement of the cilia is initiated by the
dynein arms transiently attaching to specific sites on LATERAL MEMBRANE
the protofilaments of the adjacent doublets, sliding SPECIALIZATIONS
them toward the tip of the cilium. However, nexin, an
Lateral membrane specializations reveal the presence of
elastic protein extending between adjacent doublets,
junctional complexes.
restrains this action to some degree, thus translating the
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Figure 5–7 Electron micrograph of the terminal web and microvillus. Observe that the actin filaments of the microvilli are attached to the
terminal web. A, ×83,060; B (inset), ×66,400. (From Hirokana N, Tilney LG, Fujiwara K, Heuser JE: Organization of actin, myosin, and inter-
mediate filaments in the brush border of intestinal epithelial cells. J Cell Biol 94:425-443, 1982.)
Ch005-X2945.qxd 12/8/06 3:24 PM Page 94
cells, thus coupling adjacent cells both electrically

Villin
and metabolically.
The three components of the junctional complex are
the zonulae occludentes, zonulae adherents, and
desmosomes (maculae adherentes).
Actin Zonulae Occludentes
filaments
Plasmalemma Zonulae occludentes prevent movement of membrane
proteins and function to prevent intercellular movement
Fimbrin of water-soluble molecules.
Also known as tight junctions, zonulae occludentes are

located between adjacent plasma membranes and are the
Linkage
most apically located junction between the cells of the
Lateral
to cell extension
epithelia (see Fig. 5-11). They form a “belt-like” junction
membrane that encircles the entire circumference of the cell. In
electron micrographs, the adjoining cell membranes
approximate each other; their outer leaflets fuse, then
diverge, and then fuse again several times within a dis-
tance of 0.1 to 0.3 µm (Fig. 5-12). At the fusion sites,
transmembrane junctional proteins called claudins and
occludins bind to each other, thus forming a seal occlud-
ing the intercellular space. Freeze-fracture analysis of
cell membranes at the zonulae occludentes displays a
“quilted” appearance of anastomosing strands, known as
tight junction strands, on the P-face and a correspon-
Intermediate Actin cortex ding network of grooves on the E-face (Fig. 5-13).
filaments linked by spectrin
Although both occludin and claudins participate
in the formation of the tight junction, it appears that
Figure 5–8 The structure of a microvillus. claudins have a more active role because these are the
proteins that are probably responsible for the oblitera-
tion of the intercellular space by forming the tight
junction strands described earlier. Not only are claudins
Light microscopy reveals zones, called terminal bars, calcium-independent, they do not form strong cell
where epithelial cells are in contact and, presumably, adhesions. As a result, their contact must be reinforced
attached to each other. Especially notable in the apical by cadherins as well as by cytoplasmic zonula occlu-
region of the simple columnar epithelium lining the gut, dens proteins such as ZO1, ZO2, and ZO3.
terminal bars were once thought to be composed of an Tight junctions function in two ways: (1) they prevent
amorphous intercellular cement substance. Horizontal the movement of membrane proteins from the apical
sections through the terminal bars showed that they domain to the basolateral domain; (2) they fuse plasma
were continuous around the entire circumference of membranes of adjacent cells to prohibit water-soluble
each cell, indicating that these cells were attached to molecules from passing between cells. Depending on
every adjacent cell. Electron microscopy has revealed the numbers and patterns of the strands in the zonula,
that terminal bars are in fact composed of intricate some tight junctions are said to be “tight,” whereas
junctional complexes. These complexes, which hold others are “leaky.” These terms reflect the efficiency of
contiguous epithelial cells together, may be classified the cells in maintaining the integrity of the epithelial
into three types (Fig. 5-11): barrier between two adjacent body compartments.
䡲 Occluding junctions function in joining cells to
Zonulae Adherentes
form an impermeable barrier, preventing material
from taking an intercellular route in passing across Zonulae adherentes are belt-like junctions that assist
the epithelial sheath. adjoining cells to adhere to one another.
䡲 Anchoring junctions function in maintaining cell-
to-cell or cell-to-basal lamina adherence. Zonulae adherentes of the junctional complex are
䡲 Communicating junctions function in permitting located just basal to the zonulae occludentes and also
movement of ions or signaling molecules between Text continued on p. 99
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Plasma
membrane
Shared
heterodimers
B A
Dynein
Peripheral
microtubule
doublet
Plasmalemma
Radial
spokes
Nexin
Central
Central
sheath
microtubule
pair
Microtubule
triplet
Plasma Basal body

membrane
Figure 5–9 The microtubular arrangement of the axoneme in the cilium.

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Figure 5–10 Electron micrographs of cilia. A, Longitudinal section of cilia (×36,000). B, Cross sectional view demonstrating microtubular
arrangement in cilia (×88,000). (From Leeson TS, Leeson CR, Paparo AA: Text/Atlas of Histology. Philadelphia, WB Saunders, 1988.)
Ch005-X2945.qxd 12/8/06 3:24 PM Page 97
Strands of Zonulae occludentes

transmembrane Extend along entire
proteins circumference of the cell.
Prevent material from taking
Extracellular
paracellular route in passing
space
from the lumen into the
connective tissues.
Adjacent plasma membranes
Extracellular
space Zonulae adherentes
Basal to zonulae occludentes.
E-cadherins bind to each
other in the intercellular space
and to actin filaments,
Actin filaments intracellularly.
Intermediate
filaments
Plaque
Maculae adherentes
E-cadherins are associated
with the plaque; intermediate
filaments form hairpin loops.
Desmogleins
Adjacent plasma membranes
Extracellular
space Gap junctions
Communicating junctions for
small molecules and ions to
pass between cells. Couple
Connexons
adjacent cells metabolically
and electrically.
Hemidesmosomes
Integrins Attach epithelial cells to
(transmembrane underlying basal lamina.
receptor proteins)
Figure 5–11 Junctional complexes, gap junctions, and hemidesmosomes.

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Figure 5–12 Electron micrograph of the junctional complex. (From Fawcett DW: The Cell, 2nd ed. Philadelphia, WB Saunders, 1981.)
Ch005-X2945.qxd 12/8/06 3:24 PM Page 99
mic aspect binds to a specialized region of the cell web,

specifically a bundle of actin filaments that run parallel
to and along the cytoplasmic aspect of the cell mem-
brane. The actin filaments are attached to each other and
to the cell membrane by the anchor proteins catenin,
vinculin, and a-actinin (see Chapter 2). The extracel-
lular region of the cadherins of one cell forms bonds with
those of the adjoining cell participating in the formation
of the zonula adherens. Thus, this junction not only joins
the cell membranes to each other but also links the
cytoskeleton of the two cells via the transmembrane
linker proteins.
Fascia adherens is similar to zonula adherens but
does not go around the entire circumference of the cell.
Instead of being belt-like, it is “ribbon-like.” Cardiac
muscle cells, for example, are attached to each other at
their longitudinal terminals via the fascia adherens.
Desmosomes (Maculae Adherentes)

Desmosomes are weld-like junctions along the lateral
cell membranes that help to resist shearing forces.
Desmosomes are the last of the three components of

the junctional complex. These “spot weld”-like junc-
tions also appear to be randomly distributed along the
lateral cell membranes of simple epithelia and through-
out the cell membranes of stratified squamous epithe-
lia, especially in the epidermis.
Disk-shaped attachment plaques (∼400 × 250 ×
10 nm) are located opposite each other on the cyto-
plasmic aspects of the plasma membranes of adjacent
epithelial cells (Fig. 5-14; also see Fig. 5-11). Each
plaque is composed of a series of attachment proteins,
the best characterized of which are desmoplakins and
pakoglobins.
Intermediate filaments (see Chapter 2) of cyto-
keratin are observed to insert into the plaque, where
they make a hairpin turn, then extend back out into the
cytoplasm. These filaments are thought to be responsi-
Figure 5–13 Freeze-fracture replica displaying the tight junc- ble for dispersing the shearing forces on the cell.
tion (zonula occludens) in guinea pig small intestine (×60,000). The In the region of the opposing attachment plaques, the
P-face of the microvillar membrane (M) possesses fewer intramem- intercellular space is up to 30 nm in width and contains
brane particles than the P-face of the lateral cell membrane (L). Note filamentous materials with a thin, dense, vertical line
the free terminal ridge-shaped protrusions (arrows) and desmosome
(D). (From Trier JS, Allan CH, Marcial MA, Madara JL: Structural
located in the middle of the intercellular space. High-
features of the apical and tubulovesicular membranes of rodent small resolution electron microscopy reveals that the fil-
intestinal tuft cells. Anat Rec 219:69-77, 1987.) amentous material is desmoglein and desmocollin,
extracellular components of the Ca2+-dependent trans-
membrane linker proteins of the cadherin family. In the
presence of Ca2+, they bond with transmembrane linker
encircle the cell (see Fig. 5-11). The intercellular space proteins from the adjoining cell. In the presence of a
of 15 to 20 nm between the outer leaflets of the two adja- calcium-chelating agent, the desmosomes break into two
cent cell membranes is occupied by the extracellular halves and the cells separate. Thus, two cells are required
moieties of cadherins (see Fig. 5-12). These Ca2+- for the formation of a desmosome. The cytoplasmic
dependent integral proteins of the cell membrane are aspects of the transmembrane linker proteins bind to the
transmembrane linker proteins. Their intracytoplas- desmoplakins and pakoglobins constituting the plaque.
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B
Figure 5–14 Electron micrographs of a desmosome. Observe the dense accumulation of intracellular intermediate filaments inserting into
the plaque of each cell (asterisk). (From Fawcett DW: The Cell, 2nd ed. Philadelphia, WB Saunders, 1981.)
Ch005-X2945.qxd 12/8/06 3:24 PM Page 101
communication by permitting the passage of various

CLINICAL CORRELATIONS small molecules between adjacent cells. The intercellu-
lar cleft at the gap junction is narrow and constant,
Some people produce autoantibodies against about 2 to 4 nm.
desmosomal proteins, especially those in the Gap junctions are built by six closely packed trans-
skin, resulting in a skin disease called pemphi- membrane channel-forming proteins (connexins) that
gus vulgaris. Binding of the autoantibodies to assemble to form channel-structures called connexons,
desmosomal proteins disrupts cell adhesion, aqueous pores through the plasma membrane that juts
leading to widespread blistering and consequent out about 1.5 nm into the intercellular space (see Fig.
loss of extracellular fluids; if untreated, this con- 5-11). Presently it is believed that there may be more
dition leads to death. Treatment with systemic than 20 different connexins which can assemble into
steroids and immunosuppressive agents usually many different arrays of connexons that may be related
controls the condition. to their specific function. Each gap junction may be
formed by clusters of a few to many thousands of con-
nexons. When a connexon of one plasma membrane is in
register with its counterpart of the adjacent plasma
Gap Junctions membrane, the two connexons fuse, forming a func-
tional intercellular hydrophilic communication channel
Gap junctions, also called nexus or communicating (Fig. 5-15). With a diameter of 1.5 to 2.0 nm, the
junctions, are regions of intercellular communication. hydrophilic channel permits the passage of ions, amino
acids, vitamins, cyclic adenosine monophosphate
Gap junctions are widespread in epithelial tissues (cAMP), certain hormones, and molecules smaller than
throughout the body as well as in cardiac muscle cells, 1 kDa in size.
smooth muscle cells, and neurons, but not in skeletal Gap junctions are regulated, and may be opened
muscle cells. They differ from the occluding and or closed rapidly. Although the opening and closing
anchoring junctions in that they mediate intercellular mechanism is not fully understood, it has been shown

graphs of freeze-fracture replica
showing the intramembrane particles
of the astrocyte (scale bar = 0.1 µm).
A, Protoplasmic fracture face.
Orthogonal arrays of particles (OAP;
arrows) are observed near the gap
junction (GJ). Note the respective
differences in OAP and GJ particles
in shape (square and circle), size
(average, 30 nm2 and 45 nm2), and
arrangement (orthogonal and hexag-
onal). B, Ectoplasmic fracture face.
Corresponding pits of OAP are ori-
ented into columns (arrows) near the
GJ pits. Three OAP are gathered
together (outlined rectangle). (From
Yakushigawa H, Tokunaga Y, Inanobe
A, et al: A novel junction-like mem-
brane complex in the optic nerve
astrocyte of the Japanese macaque
with a possible relation to a potassium
channel. Anat Rec 250:465-474,
1998.)
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experimentally that a decrease in cytosolic pH or an The basal surface of some epithelia, especially those
increase in cytosolic Ca2+ concentrations closes gap involved in ion transport, possesses multiple finger-like
junctions. Conversely, high pH or low Ca2+ concentra- enfoldings of the basal plasma membranes that increase
tions opens the channels. In addition, gap junctions the surface area of the plasmalemma and partition the
exhibit different properties with diverse channel per- mitochondria-rich basal cytoplasm. The mitochondria
meabilities in different cells. provide the energy required for active transport of ions
Gap junctions exhibit many diverse functions within in establishing osmotic gradients to ensure the move-
the body, including cellular sharing of molecules for ment of water across the epithelium, such as those of
coordinating physiological continuity within a particular the kidney tubules. The compactness of the enfolded
tissue. For example, when glucose is needed in the plasma membranes coupled with the arrangement of
bloodstream, the nervous system stimulates liver cells the mitochondria within the enfoldings gives a striated
(hepatocytes) to initiate glycogen breakdown. Because appearance when viewed with the light microscope; this
not all hepatocytes are individually stimulated, the is the origin of the term striated ducts describing
signal is dispersed to other hepatocytes via gap junc- certain ducts of the pancreas and salivary glands.
tions, thus coupling the hepatocytes. Gap junctions also
function in electrical coupling of cells (i.e., in heart Hemidesmosomes
muscle and in smooth muscle cells of the gut during
peristalsis), thus coordinating the activities of these Hemidesmosomes attach the basal cell membrane to the
cells. Gap junctions also are important during embryo- underlying basal lamina.
genesis in coupling the cells of the developing embryo
electrically and in distributing informational molecules Hemidesmosomes resemble half desmosomes and serve
throughout the migrating cell masses, thus keeping to attach the basal cell membrane to the basal lamina
them coordinated in the proper development pathway. (Fig. 5-16; also see Fig. 5-11). Attachment plaques,
composed of desmoplakins, plectin, and other associ-
ated proteins, are present on the cytoplasmic aspect of
the plasma membrane. Keratin tonofilaments insert
into these plaques, unlike those in the desmosome,
Mutations in connexin genes have been linked to where the filaments enter the plaque and then make a
a genetically based nonsyndromic deafness sharp turn to exit it. The cytoplasmic aspects of trans-
and to erythrokeratodermia variabilis, a skin membrane linker proteins are attached to the plaque,
disorder. In addition, dysfunctional migration of whereas their extracellular moieties bind to laminin
neural crest cells during development have been and type IV collagen of the basal lamina. The trans-
linked to mutations in the connexin genes, result- membrane linker proteins of hemidesmosomes are
ing in defects in the formation of the pulmonary integrins, a family of extracellular matrix receptors,
vessels of the heart. whereas those of desmosomes belong to the cadherin
family of cell-to-cell adhesion proteins.
BASAL SURFACE SPECIALIZATIONS Renewal of Epithelial Cells

Cells making up the epithelial tissues generally exhibit
Basal surface specializations include the basal lamina, a high turnover rate, which is related to their location
plasma membrane enfoldings, and hemidesmosomes. and function. The time frame for cell renewal remains
constant for a particular epithelium.
Three important features mark the basal surface of Cells of the epidermis, for example, are constantly
epithelia: the basal lamina, plasma membrane enfold- being renewed at the basal layer by cell division. From
ings, and hemidesmosomes, which anchor the basal here the cells begin their migration from the germinal
plasma membrane to the basal lamina. The basal lamina layer to the surface, being keratinized on their route
is an extracellular supporting structure secreted by an until they reach the surface, die, and are sloughed—the
epithelium and is located at the boundary between the total event taking approximately 28 days. Other epithe-
epithelium and the underlying connective tissue. The lial cells are renewed in less time.
structure and appearance of the basal lamina are dis- Cells lining the small intestine are replaced every 4
cussed in Chapter 4.
to 6 days by regenerative cells in the base of the crypts.
The new cells then migrate to the tips of the villi, die,
Plasma Membrane Enfoldings and are sloughed. Still other epithelia, for example, are
Enfoldings of the basal plasma membrane increase the renewed periodically until adulthood is reached; subse-
surface area available for transport. quently, the cell population remains for life. Even then,
however, when a large number of cells are lost because
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A B
Figure 5–16 Electron micrographs of hemidesmosomes illustrating the relationship of striated anchoring fibers (SAFs), composed of type
VII collagen, with the lamina densa and type III collagen of the lamina reticularis. c, Collagen fibers; ER, endoplasmic reticulum; F, cell exten-
sions. Wide arrows indicate the cytoplasmic aspect of hemidesmosomes; asterisk indicates SAF plaque. (From Clermont Y, Xia L, Turner JD,
Hermo L: Striated anchoring fibrils-anchoring plaque complexes and their relation to hemidesmosomes of myoepithelial and secretory cells in
mammary glands of lactating rats. Anat Rec 237:318-325, 1993.)
of injury or acute toxic destruction, cell proliferation is

triggered and the cell population is restored. GLANDS
Glands originate from epithelial cells that leave the
surface where they developed and penetrate into the
underlying connective tissue, manufacturing a basal
CLINICAL CORRELATIONS lamina around themselves. The secretory units, along
Each epithelium within the body has its own with their ducts, are the parenchyma of the gland,
unique characteristics, location, cell morphology, whereas the stroma of the gland represents the ele-
and so on, all of which are related to function. In ments of the connective tissue that invade and support
certain pathological conditions, the cell popula- the parenchyma.
tion of an epithelium may undergo metaplasia, Glandular epithelia manufacture their product intra-
transforming it into another epithelial type. cellularly by synthesis of macromolecules that are
Pseudostratified ciliated columnar epithelium usually packaged and stored in vesicles called secretory
of the bronchi of heavy smokers may undergo granules. The secretory product may be a polypeptide
squamous metaplasia, transforming it into hormone (e.g., from the pituitary gland); a waxy sub-
stratified squamous epithelium. This change stance (e.g., from the ceruminous glands of the ear
impairs function, but the process may be canal); a mucinogen (e.g., from the goblet cells); or milk,
reversed when the pathological insult is removed. a combination of protein, lipid, and carbohydrates (e.g.,
Tumors that arise from epithelial cells may be from the mammary glands). Other glands (such as sweat
benign (nonmalignant) or malignant. Malignant glands) secrete little besides the exudate they receive
tumors arising from epithelia are called carcino- from the bloodstream. In addition, striated ducts (e.g.,
mas; those arising from glandular epithelial cells those of the major salivary glands) act as ion pumps that
are called adenocarcinomas. It is interesting to modify the substances produced by their secretory units.
note that cancers in adults are most often adeno- Glands are classified into two major groups on the
carcinomas and after age 45 about 90% are of basis of the method of distribution of their secretory
epithelial cell origin. However, in children under products:
10 years of age, epithelium-derived cancers are 䡲 Exocrine glands secrete their products via ducts
the least prevalent type of cancer. onto the external or internal epithelial surface from
which they originated.
Ch005-X2945.qxd 12/8/06 3:24 PM Page 104
䡲 Endocrine glands are ductless, having lost their a serous fluid. The sublingual and submandibular glands
connections to the originating epithelium, and thus are examples of mixed glands (Fig. 5-18).
secrete their products into the blood or lymphatic Cells of exocrine glands exhibit three different
vessels for distribution. mechanisms for releasing their secretory products: (1)
holocrine, (2) merocrine, and (3) apocrine (Fig. 5-19).
Many cell types secrete signaling molecules called
The release of the secretory product of merocrine
cytokines, which perform the function of cell-to-cell
glands (e.g., parotid gland) occurs via exocytosis; as a
communication. Cytokines are released by signaling
cells and act on target cells, which possess receptors
for the specific signaling molecule. (Hormone signaling
is discussed in detail in Chapter 2.)
Depending on the distance the cytokine must travel
to reach its target cell, its effect may be one of the
following:
䡲 Autocrine: The signaling cell is its own target; thus
the cell stimulates itself.
䡲 Paracrine: The target cell is located in the vicinity
of the signaling cell; thus, the cytokine does not have
to enter the vascular system for distribution to its
target.
䡲 Endocrine: The target cell and signaling cell are far
from each other; thus, the cytokine has to be trans-
ported either by the blood or by the lymph vascular
system.
Glands that secrete their products via a constitutive
secretory pathway do so continuously, releasing their
secretory products immediately without storage and Figure 5–17 Serous gland. Light micrograph of a plastic-embed-
without requiring a prompt by signaling molecules. ded monkey pancreas (×540).
Glands that exhibit a regulated secretory pathway
concentrate and store their secretory products until the
proper signaling molecule for its release is received (see
Chapter 2; Figs. 2-20 and 2-22).
Exocrine Glands
Exocrine glands secrete their products via a duct to the
surface of their epithelial origin.
Exocrine glands are classified according to the nature

of their secretion, their mode of secretion, and the
number of cells (unicellular or multicellular). Many
exocrine glands in the digestive, respiratory, and uro-
genital systems secrete substances that are described as S
mucous, serous, or mixed (both) types.
Mucous glands secrete mucinogens, large glyco-
sylated proteins that, upon hydration, swell to become
a thick, viscous, gel-like protective lubricant known as
mucin, a major component of mucus. Examples of
mucous glands include goblet cells and the minor sali- M
vary glands of the tongue and palate.
Serous glands (Fig. 5-17), such as the pancreas,
secrete an enzyme-rich watery fluid.
Mixed glands contain acini (secretory units) that
produce mucous secretions as well as acini that produce
serous secretions; in addition, some of the mucous acini Figure 5–18 Light micrograph of the monkey submandibular
possess serous demilunes, a group of cells that secrete gland (×540). M, mucous acini; S, serous demilunes.
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A B C
Secretion
Disintegrating
cell and its
contents Intact cell
(secretion)
New cell
Pinched off
Figure 5–19 Modes of secretion: portion of cell
A, holocrine; B, merocrine; C, apocrine. (secretion)
Microvilli
GC
Theca
Mucinogen
droplets
Nucleus
Stem
Figure 5–20 Light micrograph of goblet cells (GC) in the
epithelial lining of monkey ileum (×540).
result, neither cell membrane nor cytoplasm becomes Figure 5–21 Ultrastructure of a goblet cell illustrating the tightly
a part of the secretion. Although many investigators packed secretory granules of the theca. (From Lentz TL: Cell Fine
question the existence of the apocrine mode of secre- Structure: An Atlas of Drawings of Whole-Cell Structure. Philadel-
tion, historically it was believed that in apocrine phia, WB Saunders, 1971.)
glands (e.g., lactating mammary gland), a small portion
of the apical cytoplasm is released along with the secre- Unicellular exocrine glands, represented by isolated
tory product. In holocrine glands (e.g., sebaceous secretory cells in an epithelium, are the simplest form
gland), as a secretory cell matures, it dies and becomes of exocrine gland. A primary example is the goblet cell,
the secretory product. which is dispersed individually in the epithelia lining the
digestive tract and portions of the respiratory tract
Unicellular Exocrine Glands (Figs. 5-20 and 5-21). The secretions released by these
mucous glands protect the linings of these tracts.
Unicellular exocrine glands are the simplest form of
Goblet cells derive their name from their shape, that
exocrine gland.
of a goblet (Fig. 5-22). Their thin basal region sits on
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Figure 5–22 Electron micrograph of goblet cells from the colon of a rabbit (×9114). Note the presence of several Golgi complexes (arrow-
heads) and the numerous, compactly packed mucinogen granules (MG) that occupy much of the apical portion of the cells. (From Radwan KA,
Oliver MG, Specian RD: Cytoarchitectural reorganization of rabbit colonic goblet cells during baseline secretion. Am J Anat 198:365-376, 1990.)
the basal lamina, whereas their expanded apical portion, Multicellular exocrine glands consist of clusters of
the theca, faces the lumen of the digestive tube or res- secretory cells arranged in varying degrees of organiza-
piratory tract. The theca is filled with membrane-bound tion. These secretory cells do not act alone and inde-
secretory droplets, which displace the cytoplasm to the pendently but instead function as secretory organs.
cell’s periphery and the nucleus toward its base. The Multicellular glands may have a simple structure, exem-
process of mucinogen release is regulated and stimu- plified by the glandular epithelium of the uterus and
lated by chemical irritation and parasympathetic inner- gastric mucosa, or a complex structure, composed of
vation, resulting in exocytosis of the entire secretory various types of secretory units and organized in a com-
contents of the cell, thus lubricating and protecting the pound branching fashion.
epithelial sheet. Because of their structural arrangement, multicellu-
lar glands are subclassified according to the organiza-
tion of their secretory and duct components as well
Multicellular Exocrine Glands as according to the shape of their secretory units
(Fig. 5-23).
Multicellular exocrine glands exist as organized clusters
Multicellular glands are classified as simple if their
of secretory units.
ducts do not branch and compound if their ducts
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Secretory
portion
Simple tubular Simple branched Simple coiled Simple acinar Simple branched acinar
tubular tubular
Duct
Compound tubular Compound acinar Compound tubuloacinar
Figure 5–23 Classification of multicellular exocrine glands. Green represents the secretory portion of the gland; lavender represents the
duct portion.
branch. They are further categorized according to the Endocrine Glands

morphology of their secretory units as tubular, acinar
(also referred to as alveolar, resembling a grape), or Endocrine glands are ductless, and thus their secretory
tubuloalveolar. products are released directly into the bloodstream or
Larger multicellular glands are surrounded by a the lymphatic system.
collagenous connective tissue capsule, which sends
septae (strands of connective tissue) into the gland, Endocrine glands release their secretions (hormones)
subdividing it into smaller compartments known into blood or lymphatic vessels for distribution to
as lobes and lobules (Fig. 5-24). Vascular elements, target organs. The major endocrine glands of the body
nerves, and ducts utilize the connective tissue septa to include the suprarenal (adrenal), pituitary, thyroid,
enter and exit the gland. In addition, the connective parathyroid, and pineal glands and the ovaries, placenta,
tissue elements provide structural support for the and testes.
gland. The islets of Langerhans and the interstitial cells of
Acini of many multicellular exocrine glands such as Leydig are unusual because they are composed of clus-
sweat glands and major salivary glands possess ters of cells ensconced within the connective tissue
myoepithelial cells that share the basal lamina of stroma of other organs (the pancreas and the testes,
the acinar cells. Although myoepithelial cells are respectively). Hormones secreted by endocrine glands
of epithelial origin, they have some characteristics of include peptides, proteins, modified amino acids,
smooth muscle cells, particularly contractility. These steroids, and glycoproteins. Because of their complex-
cells exhibit small nuclei and sparse fibrillar cytoplasm ity and important role in regulating bodily processes,
radiating out from the cell body, wrapping around the endocrine glands are discusses in detail in
the acini and some of the small ducts (Fig. 5-25; Chapter 13.
also see Fig. 5-24). Their contractions assist in express- The secretory cells of endocrine glands are organized
ing secretions from the acini and from some small either in cords of cells or in a follicular arrangement. In
ducts. the cord type, the most common arrangement, cells
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Intercalated Striated
duct cell duct cell
Mixed salivary gland
Myoepithelial
Intercalated duct cell
Striated duct
Serous cell
Serous acinus
Mucous acinus
Main duct
Serous demilunes
Lobar duct Mucous cell
Intralobular
duct
Intralobular
duct
Intercalated
duct
Acinus
Lobule Multicellular gland
Figure 5–24 Salivary gland: its organization, secretory units, and system of ducts.
Ch005-X2945.qxd 12/8/06 3:24 PM Page 109
Figure 5–25 Light micrograph of myoep-

ithelial cells immunostained for actin (×640).
Myoepithelial cells surround the acini. (From
Satoh Y, Habara Y, Kanno T, Ono K: Car-
bamylcholine-induced morphological changes
and spatial dynamics of [Ca2+]c in harderian
glands of guinea pigs: Calcium-dependent lipid
secretion and contraction of myoepithelial cells.
Cell Tiss Res 274:1-14, 1993.)
form anastomosing cords around capillaries or blood

sinusoids. The hormone to be secreted is stored intra-
cellularly and is released upon the arrival of the proper
signaling molecule or neural impulse. Examples of the
cord type of endocrine gland are the suprarenal gland,
anterior lobe of the pituitary gland, and parathyroid
gland.
In the follicle type of endocrine gland, secretory
cells (follicular cells) form follicles that surround a
cavity that receives and stores the secreted hormone.
When a release signal is received, the stored hormone
is resorbed by the follicular cells and released into the
connective tissue to enter the blood capillaries. An
example of a follicle type of endocrine gland is the
thyroid gland.
Some glands of the body are mixed; for example, the
parenchyma contains both exocrine and endocrine
secretory units. In these mixed glands (e.g., pancreas,
ovary, and testes), the exocrine portion of the gland Figure 5–26 Light micrograph of diffuse neuroendocrine
system (DNES) cell (×540). Note the pale-staining DNES cells
secretes its product into a duct, whereas the endocrine (APD) located in the mucosa of the ileum (arrow).
portion of the gland secretes its product into the blood-
stream.
Diffuse Neuroendocrine System facture various paracrine and endocrine hormones

(Fig. 5-26). Because these cells are capable of taking up
The diffuse neuroendocrine system produces paracrine precursors of amines and decarboxylating amino acids,
and endocrine hormones. they were also called APUD (amine precursor uptake
and decarboxylation) cells. At one time some of these
Widespread throughout the digestive tract and in the cells were called argentaffin and argyophil cells
respiratory system are endocrine cells interspersed because of the way they stained with silver salts. This
among other secretory cells. These cells, members of entire cell group is now called the DNES, which is
the diffuse neuroendocrine system (DNES), manu- described in greater detail in Chapter 17.
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6 䡲䡲䡲
Connective Tissue
Connective tissue, as the name implies, forms a contin- 䡲 Providing structural support
uum with epithelial tissue, muscle, and nervous tissue 䡲 Serving as a medium for exchange
as well as with other components of connective tissues 䡲 Aiding in the defense and protection of the body
to maintain a functionally integrated body. Most con- 䡲 Forming a site for storage of fat
nective tissues originate from mesoderm, the middle
germ layer of the embryonic tissue. From this layer, the Bones, cartilage, and the ligaments holding the
multipotential cells of the embryo, the mesenchyme, bones together, as well as the tendons attaching muscles
develop, although in certain areas of the head and neck, to bone, act as support. Similarly, the connective tissue
mesenchyme also develops from neural crest cells of that forms the capsules encasing organs and the stroma
the developing embryo. Mesenchymal cells migrate forming the structural framework within organs has
throughout the body, giving rise to the connective support functions. Connective tissue also functions as a
tissues and their cells, including those of bone, cartilage, medium for exchange of metabolic waste, nutrients,
tendons, capsules, blood and hemopoietic cells, and and oxygen between the blood and many of the cells of
lymphoid cells (Fig. 6-1). the body.
Mature connective tissue is classified as connective The functions of defense and protection are carried
tissue proper, the major subject of this chapter, or spe- out by (1) the body’s phagocytic cells, which engulf and
cialized connective tissue (i.e., cartilage, bone, and destroy cellular debris, foreign particles, and microor-
blood), detailed in Chapters 7 and 10. ganisms; (2) the body’s immunocompetent cells, which
Connective tissue is composed of cells and extracel- produce antibodies against antigens; and (3) certain cells
lular matrix consisting of ground substance and fibers that produce pharmacological substances that help in
(Figs. 6-2 and 6-3). The cells are the most important controlling inflammation. Connective tissues also help
components in some connective tissues, whereas fibers protect the body by forming a physical barrier to inva-
are the most important component in other connective sion by and dissemination of microorganisms.
tissue types. For example, fibroblasts are the most
important cell component of loose connective tissue EXTRACELLULAR MATRIX
because these cells manufacture and maintain the fibers
and ground substance composing the extracellular The extracellular matrix, composed of ground sub-
matrix. In contrast, fibers are the most important com- stance and fibers, resists compressive and stretching
ponent of tendons and ligaments. In still other connec- forces. The components of the extracellular matrix are
tive tissues, the ground substance is most important described in Chapter 4, and their salient features are
component because it is the site where certain special- reviewed briefly here.
ized connective tissue cells carry out their functions.
Thus, all three components are critical to the role of Ground Substance
connective tissue function in the body. Ground substance is a hydrated, amorphous material
that is composed of glycosaminoglycans, long
FUNCTIONS OF unbranched polymers of repeating disaccharides; pro-
CONNECTIVE TISSUE teoglycans, protein cores to which various gly-
cosaminoglycans are covalently linked; and adhesive
Although many functions are attributed to connective glycoproteins, large macromolecules responsible for
tissue, its primary functions include: fastening the various components of the extracellular
111
Ch006-X2945.qxd 15/8/06 2:35 PM Page 112
Undifferentiated
mesenchymal cell
Endothelial
Chondroblast Adipocyte cell
Osteoblast
Fibroblast Mesothelial
cell
Chondrocytes Osteocyte
Hematopoietic
stem cell
Red blood
Lymphocyte cell
precursor
T lymphocyte
Monocyte Neutrophil
B lymphocyte
Mast cell
Plasma cell
Eosinophil
Macrophage
Basophil
Osteoclast Megakaryocyte
Figure 6–1 Origins of connective tissue cells (not drawn to scale).

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Chapter 6 䡲 Connective Tissue ■ ■ ■ 113
Collagen
Endothelial
cell Fat cells
C
Pericyte
E
Fibroblast
Macrophages
Plasma
cells
Elastic
fiber
Figure 6–2 Light micrograph of loose (areolar) connective tissue
displaying collagen (C) and elastic (E) fibers and some of the cell types
common to loose connective tissue (×132). Mast
cell
matrix to one another and to integrins and dystroglycans

of the cell membrane (see Chapter 4 and Fig. 4-3).
Glycosaminoglycans are of two major types: sulfated,
including keratan sulfate, heparan sulfate, heparin, Figure 6–3 Cell types and fiber types in loose connective tissue
(not drawn to scale).
chondroitin sulfates, and dermatan sulfate; and nonsul-
fated, including hyaluronic acid.
Proteoglycans are covalently linked to hyaluronic
acid, forming huge macromolecules called aggrecan hydroxyproline, and hydroxylysine. The six major
aggregates, which are responsible for the gel state of collagen types (see Table 4-2) are:
the extracellular matrix. 䡲 Type I: in connective tissue proper, bone, dentin, and
Adhesive glycoproteins are of various types. Some cementum
are localized preferentially to the basal lamina, such as 䡲 Type II: in hyaline and elastic cartilages
laminin, or to cartilage and bone, such as chon- 䡲 Type III: reticular fibers
dronectin and osteonectin, respectively. Still others 䡲 Type IV: lamina densa of the basal lamina
are generally dispersed throughout the extracellular 䡲 Type V: in the placenta; associated with type I
matrix, such as fibronectin. collagen
䡲 Type VII: attaching the basal lamina to the lamina
Fibers reticularis
Fibers of the extracellular matrix are collagen (and Most of the fiber types display a 67-nm periodicity
reticular) and elastic fibers. Collagen fibers are inelas- in electron micrographs, which is due to the deposition
tic and possess great tensile strength. Each fiber is com- of heavy metals in the gap regions of the fiber (see
posed of fine subunits, the tropocollagen molecule, Fig. 4-5). Type IV collagen is not assembled into fibers
composed of three α-chains wrapped around one and thus does not possess a periodicity.
another in a helical configuration. About 20 different Elastic fibers are composed of elastin and micro-
types of collagen fibers are known, which vary in the fibrils. These fibers are highly elastic and may be
amino acid sequences of their α-chains. The most stretched to 150% of their resting length without break-
common amino acids of collagen are glycine, proline, ing. Their elasticity is due to the protein elastin, and
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114 䡲䡲䡲 Chapter 6 䡲 Connective Tissue
their stability is due to the presence of microfibrils. undifferentiated mesenchymal cells and synthesize the
Elastin is an amorphous material whose main amino acid extracellular matrix of connective tissue (see Fig. 6-1).
components are glycine and proline. Additionally, elastin Fibroblasts are the least specialized of the cells making
is rich in lysine, the amino acid responsible for the for- up connective tissue and may even be represented by
mation of the highly deformable desmosine residues several different functioning populations within certain
that impart a high degree of elasticity to these fibers. areas of the body. Because mature and immature fibro-
blasts may exist side by side, the immature cells, difficult
to distinguish from mysenchymal cells, may—depend-
CELLULAR COMPONENTS ing upon the signal proteins present—differentiate into
The cells in connective tissues are grouped into two cat- other cell members of connective tissue (i.e., fat cells,
egories: fixed cells and transient cells (see Fig. 6-1). osteoblasts, chondroblasts and myofibroblasts).
Fixed cells are a resident population of cells that Fibroblasts may occur in either an active state or a
have developed and remain in place within the con- quiescent state. Some histologists differentiate between
nective tissue, where they perform their functions. The them, calling the quiescent cells fibrocytes; however,
fixed cells are a stable and long-lived population that because the two states are transitory, the term fibroblast
includes: is used in this text.
Active fibroblasts often reside in close association
䡲 Fibroblasts with collagen bundles, where they lie parallel to the
䡲 Adipose cells long axis of the fiber (Fig. 6-4). Such fibroblasts are
䡲 Pericytes elongated, fusiform cells possessing pale-staining cyto-
䡲 Mast cells plasm, which is often difficult to distinguish from colla-
䡲 Macrophages gen when stained with hematoxylin and eosin (H&E)
Additionally, some authors consider certain cells of (see Fig. 6-18). The most obvious portion of the cell is
the macrophages (e.g., Kupffer cells of the liver) to be the darker-stained, large, granular, ovoid nucleus con-
fixed connective tissue cells. taining a well-defined nucleolus. Electron microscopy
Transient cells (free or wandering cells) originate reveals a prominent Golgi apparatus and abundant
mainly in the bone marrow and circulate in the blood- rough endoplasmic reticulum (RER) in the fibroblast,
stream. Upon receiving the proper stimulus or signal, especially when the cell is actively manufacturing
these cells leave the bloodstream and migrate into the matrix, as in wound healing. Actin and α-actinin are
connective tissue to perform their specific functions. localized at the periphery of the cell, whereas myosin is
Because most of these motile cells are usually short- present throughout the cytoplasm.
lived, they must be replaced continually from a large In contrast to active fibroblasts, Inactive fibroblasts
population of stem cells. Transient cells include: are smaller, more ovoid, and possess an acidophilic
cytoplasm. Their nucleus is smaller, elongated, and
䡲 Plasma cells more deeply stained. Electron microscopy reveals sparse
䡲 Lymphocytes amounts of RER but an abundance of free ribosomes.
䡲 Neutrophils
䡲 Eosinophils
䡲 Basophils
䡲 Monocytes CLINICAL CORRELATIONS
䡲 Macrophages Although considered to be fixed cells in the con-
nective tissues, fibroblasts are capable of some
Fixed Connective Tissue Cells movement. Fibroblasts seldom unergo cell divi-
The four connective tissue cell types that are clearly sion but may do so during wound healing. These
fixed are described here. Macrophages, which exhibit cells, however, may differentiate into adipose cells,
some fixed and some transient properties, are discussed chondrocytes (during formation of fibrocartilage),
later under “Macrophages.” and osteoblasts (under pathological conditions).
Fibroblasts
Fibroblasts, the most abundant cell type in the
connective tissue, are responsible for the synthesis of
Myofibroblasts
almost all of the extracellular matrix.
Myofibroblasts are modified fibroblasts that
demonstrate characteristics similar to those of both
Fibroblasts, the most abundant and most widely distrib-
fibroblasts and smooth muscle cells.
uted resident cells of connective tissue, are derived from
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graph displaying a portion of a
fibroblast and the packed collagen
fibers in rat tendon. Observe the
heterochromatin in the nucleus and
the rough endoplasmic reticulum
(RER) in the cytoplasm. Banding
in the collagen fibers also may
be observed. (From Ralphs JR,
Benjamin M, Thornett A: Cell and
matrix biology of the suprapatella in
the rat: A structural and immunocy-
tochemical study of fibrocartilage in
a tendon subject to compression.
Anat Rec 231:167-177, 1991.)
Histologically, fibroblasts and myofibroblasts are not contain actin, myosin, and tropomyosin, suggesting that
easily distinguished by routine light microscopy. Elec- they may function in contraction. Under certain condi-
tron microscopy, however, reveals that myofibroblasts tions, they may differentiate into other cells. Pericytes
have bundles of actin filaments and myosin and dense are discussed more fully in Chapter 11.
bodies similar to those of smooth muscle cells. Addi-
tionally, the surface profile of the nucleus resembles Adipose Cells
that of a smooth muscle cell. Myofibroblasts differ from
smooth muscle cells in that an external lamina (basal Adipose cells are fully differentiated cells that function
lamina) is absent. Myofibroblasts represent transitional in the synthesis, storage, and release of fat.
modifications of fibroblasts as a result of being con-
tacted by signaling molecules within a regional inter- Fat cells, or adipocytes, are derived from undifferen-
cellular matrix. Myofibroblasts are abundant in areas tiated fibroblast-like mesenchymal cells (Fig. 6-5; see
undergoing wound healing, where they function in also Figs. 6-1 and 6-3), although under certain condi-
wound contraction; they also are found in the peri- tions histologists believe that fibroblasts may give rise to
odontal ligament, where they probably assist in tooth adipose cells. Adipose cells are fully differentiated and
eruption. do not undergo cell division. They function in the syn-
thesis and storage of triglycerides. There are two types
Pericytes of fat cells, which constitute two types of adipose tissue.
Cells with a single, large lipid droplet, called unilocu-
Pericytes surround endothelial cells of capillaries and lar fat cells, form white adipose tissue, and cells with
small venules and technically reside outside the multiple, small lipid droplets, called multilocular fat
connective tissue compartment, because they possess cells, form brown adipose tissue. White fat is much
their own basal lamina. more abundant than brown fat. As discussed later, the
distribution and histophysiology of the two types of fat
Pericytes, derived from undifferentiated mesenchymal tissue differ. Here we describe the histologic character-
cells, partly surround the endothelial cells of capillaries istics of the adipocytes themselves.
and small venules (see Fig. 6-3). These multipotential Adipocytes of white fat are large spherical cells, up
perivascular cells are outside the connective tissue com- to 120 µm in diameter, that become polyhedral when
partment because they are surrounded by their own crowded into adipose tissue (Fig. 6-6). Unilocular fat
basal lamina, which may be fused with that of the cells continuously store fat in the form of a single
endothelial cells. Pericytes possess characteristics of droplet, which enlarges so much that the cytoplasm and
endothelial cells and smooth muscle cells in that they nucleus are displaced peripherally against the plasma
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Figure 6–5 Electron micrograph of adipocytes

in various stages of maturation in rat hypodermis.
Observe the adipocyte at the top of the micrograph
with its nucleus and cytoplasm crowded to the
periphery by the fat droplet. (From Hausman GJ,
Campion DR, Richardson RL, Martin RJ: Adipocyte
development in the rat hypodermis. Am J Anat
161:85-100, 1981.)
membrane, thus giving these cells a “signet ring” profile Storage and Release of Fat by
when viewed by light microscopy. Electron micrographs Adipose Cells
reveal a small Golgi complex situated adjacent to the
nucleus, only a few mitochondria, and sparse RER, but During digestion, fats are broken down in the duode-
an abundance of free ribosomes. That the fat droplet is num by pancreatic lipase into fatty acids and glyc-
not bounded by a membrane is clear in electron micro- erol. The intestinal epithelium absorbs these
graphs but unclear in light micrographs. The external substances and reesterifies them in the smooth endo-
surfaces of the plasma membranes are enveloped by a plasmic reticulum to triglycerides, which then are
basal lamina-like substance. Minute pinocytotic vesi- surrounded by proteins to form chylomicrons.
cles, whose function is unclear, have been noted on the Chylomicrons are released into the extracellular space
surface of the plasma membrane. During fasting, the at the basolateral membranes of the surface absorptive
cell surface becomes irregular, having pseudopod-like cells, enter the lacteals of the villus, and are carried by
projections. the lymph to the bloodstream. Additionally, very-low-
Multilocular adipocytes contrast with unilocular density lipoprotein (VLDL), which is synthesized by the
adipocytes in several ways. First, brown fat cells are liver, and albumin-bound fatty acids are present in the
smaller and more polygonal than white fat cells. More- bloodstream.
over, because the brown fat cell stores fat in several Once in the capillaries of adipose tissue, VLDL, fatty
small droplets rather than a single droplet, the spheri- acids, and chylomicrons are exposed to lipoprotein
cal nucleus is not squeezed up against the plasma mem- lipase (manufactured by fat cells), which breaks them
brane. Multilocular fat cells contain many more down into free fatty acids and glycerol (Fig. 6-8). The
mitochondria but fewer free ribosomes than unilocular fatty acids enter the connective tissue and diffuse
fat cells (Fig. 6-7). Although brown fat cells lack RER, through the cell membranes of adipocytes. These cells
they do have smooth endoplasmic reticulum (SER). then combine their own glycerol phosphate with the
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ovoid and possess a centrally placed, spherical nucleus

(Fig. 6-9). Unlike the three types of fixed cells discussed
earlier, mast cells probably derive from precursors in
the bone marrow (see Fig. 6-1).
The presence of numerous granules in the cytoplasm
is the identifying characteristic of mast cells (Fig. 6-10).
These membrane-bound granules range in size from 0.3
to 0.8 µm. Because they contain heparin (or chon-
droitin sulfate), a sulfated glycosaminoglycan, these
granules stain metachromatically with toluidine blue
(i.e., toluidine blue stains the granules purple).
S Electron microscopic studies of the granules reveal
differences in size and form and display variations in
ultrastructure even within the same cell. Otherwise, the
cytoplasm is unremarkable; it contains several mito-
chondria, a sparse number of RER profiles, and a rela-
tively small Golgi complex.
S In addition to heparin, mast cell granules also
contain histamine (or chondroitin sulfates), neutral
proteases (tryptase, chymase, and carboxypeptidases),
aryl sulfatase (as well as other enzymes, such as γ-
glucuronidase, kininogenase, peroxidase, and superox-
ide dismutase), eosinophil chemotactic factor
Figure 6–6 Light micrograph of white adipose tissue from
(ECF), and neutrophil chemotactic factor (NCF).
monkey hypodermis (×132). The lipid was extracted during tissue pro- These pharmacological agents present in the granules
cessing. Note how the cytoplasm and nuclei (arrows) are crowded to are referred to as the primary mediators (also known
the periphery. Septa (S) divide the fat into lobules. as preformed mediators). Besides the substances
found in the granules, mast cells synthesize a number
imported fatty acids to form triglycerides, which are of mediators from membrane arachidonic acid precur-
added to the forming lipid droplets within the adipocytes sors. These newly synthesized mediators include leuko-
until needed. Adipose cells can convert glucose and trienes (C4, D4, and E4), thromboxanes (TXA2 and
amino acids into fatty acids when stimulated by insulin. TXB2), and prostaglandins (PGD2). A number of
Norepinephrine is released from nerve endings of other cytokines are also released that are not arachi-
postganglionic sympathetic neurons in the vicinity of donic acid precursors, such as platelet-activating
fat cells. Also, during strenuous exercise, epinephrine factor (PAF), bradykinins, interleukins (IL-4, IL-5,
and norepinephrine are released from the suprarenal IL-6), and tumor necrosis factor-alpha (TNF-a). All
medulla. These two hormones bind to their respective of these newly synthesized mediators are formed at the
receptors of the adipocyte plasmalemma, activating time of their release and are collectively referred to as
adenylate cyclase to form cyclic adenosine mono- secondary (or newly synthesized) mediators.
phosphate (cAMP), a second messenger, resulting in
activation of hormone-sensitive lipase. This enzyme Mast Cell Development and Distribution
cleaves triglycerides into fatty acids and glycerol, which
are released into the bloodstream. Because basophils and mast cells share some charac-
Fat cells are found throughout the body in loose teristics, it was once believed that mast cells were
connective tissue and are concentrated along blood basophils that had left the bloodstream to perform their
vessels. They may also accumulate into masses, forming tasks in the connective tissues. It is now known that
adipose tissue. basophils and mast cells are different cells and have dif-
ferent precursors (see Fig. 6-1). Mast cell precursors
Mast Cells probably originate in the bone marrow, circulate in the
blood for a short time, and then enter the connective
Mast cells arise from bone marrow stem cells and tissues, where they differentiate into mast cells and
function in mediating the inflammatory process and acquire their characteristic cytoplasmic granules. These
immediate hypersensitivity reactions. cells have a life span of less than a few months and occa-
sionally undergo cell division.
Mast cells, among the largest of the fixed cells of the Mast cells are located throughout the body in the
connective tissue, are 20 to 30 µm in diameter. They are connective tissue proper, where they are concentrated
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Figure 6–7 Multilocular tissues (brown fat) in

the bat (×11,000). Note the numerous mitochondria
dispersed throughout the cell. (From Fawcett, DW:
An Atlas of Fine Structure. The Cell. Philadelphia,
WB Saunders, 1966.)
along small blood vessels. They also are present in the Mast Cell Activation and Degranulation
subepithelial connective tissue of the respiratory and
digestive systems. Mast cells in connective tissue Mast cells possess high-affinity cell-surface Fc receptors
contain mostly heparin in their granules, whereas those (FceRI) for immunoglobulin E (IgE). They function in
located in the alimentary tract mucosa contain chon- the immune system by initiating an inflammatory response
droitin sulfate instead of heparin. These latter cells are known as the immediate hypersensitivity reaction
called mucosal mast cells. (whose systemic form, known as an anaphylactic reac-
The reason for the existence of the two diverse pop- tion, may have lethal consequences). This response com-
ulations of mast cells is not understood. Furthermore, monly is induced by foreign proteins (antigens) such as
it has been determined that mast cells vary in pheno- bee venom, pollen, and certain drugs, as follows:
type, morphology, histochemistry, mediator content, 1 The first exposure to any of these antigens elicits for-
and response. Thus, phenotypically different mast cell mation of IgE antibodies, which bind to the FceRI
populations are thought to function differently in health receptors of the plasmalemma of mast cells, thereby
and disease. For example, mucosal mast cells release sensitizing these cells.
histamine to facilitate the activation of parietal cells of 2 On subsequent exposure to the same antigen, the
the stomach to produce hydrochloric acid. antigen binds to the IgE on the mast cell surface,
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FAT CELL CAPILLARY
Figure 6–8 Transport of lipid

between a capillary and an adipocyte.
Lipids are transported in the blood-
stream in the form of chylomicrons Cleavage of Glycerol
and very-low-density lipoproteins triglycerides to
(VLDLs). The enzyme lipoprotein glycerol and fatty
Triglyceride acids by hormone- Fatty acids
lipase, manufactured by the fat cell
and transported to the capillary lumen, stored in droplet sensitive lipase
Albumin
hydrolyzes the lipids to fatty acids and
glycerol. Fatty acids diffuse into the
connective tissue of the adipose tissue Transport
and into the lipocytes, where they in blood
are reesterified into triglycerides for
storage. When required, triglycerides Glucose
stored within the adipocyte are hydro-
lyzed by hormone-sensitive lipase into
fatty acids and glycerol. These then Glycerol Chylomicrons
enter the connective tissue spaces of phosphate
adipose tissue and from there into a VLDL
capillary, where they are bound to particles
Free
albumin and transported in the blood. fatty acids
Glucose from the capillary can be Breakdown by
transported to adipocytes, which can lipoprotein lipase
manufacture lipids from carbohydrate to free fatty acids
sources. within the capillary
Figure 6–9 Light micrograph of mast cells (arrows) in monkey Figure 6–10 Electron micrograph of a mast cell in the rat
connective tissue (×540). The granules within the mast cells contain (×5500). Observe the dense granules filling the cytoplasm. (From
histamine and other preformed pharmacological agents. Leeson TS, Leeson CR, Paparo AA: Text/Atlas of Histology. Philadel-
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causing cross-linking of the bound IgE antibodies tory granules to fuse with one another, as well as with
and clustering of the receptors (Fig. 6-11). the cell membrane. These processes lead to degran-
3 Cross-linking and clustering activate membrane- ulation, the release of the granule contents, namely
bound receptor coupling factors, which in turn histamine, heparin, neutral proteases, aryl sulfatase
initiates at least two independent processes—the and other enzymes, eosinophil chemotactic factor,
release of primary mediators from the granules and and neutrophil chemotactic factor.
synthesis and the release of the secondary media- 6 Cross-linking of the membrane-bound IgE also acti-
tors from arachidonic acid precursors as well as from vates phospholipase A2, which acts on membrane
other cytoplasmic or membrane lipid sources. phospholipids to form arachidonic acid.
4 The release of preformed mediators is accomplished 7 Arachidonic acid is converted into the secondary
by activation of adenylate cyclase, the enzyme mediators leukotrienes C4, D4, and E4, pro-
responsible for the conversion of adenosine diphos- staglandin D2, and thromboxane A2. Additionally,
phate (ADP) to cAMP. the mast cell releases other newly formed pharma-
5 This increase in cAMP levels activates the release of cological agents and cytokines. It is important to note
calcium ion (Ca2+) from intracellular storage sites and that these secondary mediators are not stored in the
facilitates an influx from extracellular sources. The mast cell granules but are manufactured and imme-
resulting increase in cytosolic Ca2+ causes the secre- diately released.
1 Binding of antigen to IgE-receptor

complex causes cross-linking of IgE
and consequent clustering of receptors
Antigen IgE
Fc
receptor
Receptor
coupling factor
2 Activation of
adenylate cyclase
3 Activation of
protein kinase
4 Phosphorylation
of protein
+
5 Release of Ca2
5a Activation of 6 Fusion of granules

phospholipases
7 Release of Chondroitin sulfate
granules' contents Histamine
6a Conversion of Heparin
arachidonic acid ECF
in membrane NCF
Aryl sulfatase
7a Secretion of:
Leukotrienes
Thromboxanes
Prostaglandins
Figure 6–11 Binding of antigens and cross-linking of immunoglobulin E (IgE)-receptor complexes on the mast cell plasma membrane.
This event triggers a cascade that ultimately results in the synthesis and release of leukotrienes and prostaglandins as well as in degranulation,
thus releasing histamine, heparin, eosinophil chemotactic factor (ECF), and neutrophil chemotactic factor (NCF).
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Table 6-1 lists the sources and activities of the prin- antigen-antibody complexes, destroy any parasites
cipal primary and secondary mediators released from present, and limit the inflammatory response.
mast cells during immediate hypersensitivity reactions. 4 Neutrophil chemotactic factor attracts neu-
These mediators initiate the inflammatory response, trophils to the site of inflammation. These cells
activate the body’s defense system by attracting leuko- phagocytose and kill microorganisms, if present.
cytes to the site of inflammation, and modulate the 5 Leukotrienes C4, D4, and E4 increase vascular
degree of inflammation. permeability and cause bronchiospasms. They are
several thousand times more potent than histamine
in their vasoactive effects.
SEQUENCE OF EVENTS IN THE
6 Prostaglandin D2 causes bronchiospasm and
INFLAMMATORY RESPONSE
increases secretion of mucus by the bronchial
1 Histamine causes vasodilation and increases the vas- mucosa.
cular permeability of blood vessels in the vicinity. It 7 PAF causes greater vascular permeability.
also causes bronchiospasm and increases mucus pro- 8 Thromboxane A2 is a vigorous platelet-aggregating
duction in the respiratory tract. mediator and also causes vasoconstriction. It is
2 Complement components leak out of blood vessels quickly transformed into thromboxane B2, its inactive
and are cleaved by neutral proteases to form addi- form.
tional agents of inflammation. 9 Bradykinin is a powerful vascular dilator that causes
3 Eosinophil chemotactic factor attracts eosinophils vascular permeability. It is also responsible for
to the site of inflammation. These cells phagocytose pain.
TABLE 6–1 Principal Primary and Secondary Mediators Released by Mast Cells
Type of
Substance Mediator Source Action
Histamine Primary Granule Increases vascular permeability, vasodilation, smooth

muscle contraction of bronchi, mucus production
Heparin Primary Granule Anticoagulant binds and inactivates histamine
Chondroitin sulfate Primary Granule Binds to and inactivates histamine
Aryl sulfatase Primary Granule Inactivates leukotriene C4, thus limiting the inflammatory
response
Neutral proteases Primary Granule Protein cleavage to activate complement (especially

C3a); increases inflammatory response
Eosinophil Primary Granule Attracts eosinophils to site of inflammation

chemotactic factor
Neutrophil Primary Granule Attracts neutrophils to site of inflammation

chemotactic factor
Leukotrienes C4, D4, Secondary Membrane lipid Vasodilator; increases vascular permeability; bronchial
and E4 smooth muscle contractant
Prostaglandin D2 Secondary Membrane lipid Causes contraction of bronchial smooth muscle; increases
mucus secretion; vasoconstriction
Thromboxane A2 Secondary Membrane lipid Causes platelet aggregation, vasoconstriction
Bradykinins Secondary Formed by activity of Causes vascular permeability and is responsible for pain
enzymes located in sensation
granules
Platelet-activating Secondary Activated by Attracts neutrophils and eosinophils; causes vascular

factor (PAF) phospholipase A2 permeability and contraction of bronchial smooth muscle
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Macrophages
Macrophages belong to the mononuclear phagocytic
Victims of hay fever attacks suffer from the system and are subdivided into two groups of cells,
effects of histamine being released by the mast phagocytes and antigen-presenting cells.
cells of the nasal mucosa, which causes local-
ized edema from increased permeability of the As noted earlier, some macrophages behave as fixed
small blood vessels. The swelling of the mucosa cells and some as transient cells. Because macrophages
results in feeling “stuffed up” and hinders are active phagocytes, they function in removing cellu-
breathing. lar debris and in protecting the body against foreign
Victims of asthma attacks suffer from diffi- invaders.
culty in breathing as a result of bronchospasm Macrophages measure about 10 to 30 µm in diame-
caused by leukotrienes released in the lungs. ter and are irregularly shaped (Fig. 6-12). Their cell
Because degranulation of mast cells usually is surface is uneven, varying from short, blunt projections
a localized phenomenon, the typical inflammatory to finger-like filopodia. More active macrophages have
response is mild and site-specific. However, a risk pleats and folds in their plasma membranes as a conse-
also exists for hyperallergic persons who may quence of cell movement and phagocytosis. Their cyto-
experience a systemic and severe immediate plasm is basophilic and contains many small vacuoles
hypersensitivity reaction (systemic anaphylaxis) and small dense granules. The eccentric nucleus of
following a secondary exposure to an allergen macrophages is smaller and more darkly stained than
(e.g., insect stings, antibiotics). This reaction that of fibroblasts, and it usually does not display nucle-
(anaphylactic shock), which includes shortness oli. The macrophage nucleus is somewhat distinctive in
of breath and a sudden decrease in blood pres- that it is ovoid and usually indented on one side, so that
sure, may occur within seconds to a few minutes it resembles a kidney. Electron microscopic studies
and and can result in the person’s death (in a demonstrate a well-developed Golgi apparatus, promi-
matter of a few hours) if left untreated. Persons nent RER, and an abundance of lysosomes that appear
susceptible to this condition often wear a medical as small, dense granules in light micrographs.
emergency bracelet informing those giving assis- As young macrophages mature they increase in size,
tance of the need for immediate medical and there are concomitant increases in RER profiles,
attention. Golgi complex, microtubules, lysosomes, microfila-
ments, and protein synthesis.
Figure 6–12 Electron micrograph

of a macrophage in the rat epididymis.
(From Flickinger CJ, Herr CJ, Sisak
JR, Howards SS: Ultrastructure of epi-
didymal interstitial reactions following
vasectomy and vasovasostomy. Anat Rec
235:61-73, 1993.)
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Macrophage Development Under chronic inflammatory conditions, macro-

and Distribution phages congregate, greatly enlarge, and become poly-
gonal epithelioid cells. When the particulate matter
Histologists once believed that macrophages were to be removed is excessively large, several to many
derived from precursor cells in the reticuloendothe- macrophages may fuse to form a foreign-body giant
lial system, which included nonphagocytic cells such cell, a giant multinucleated macrophage.
as reticulocytes. This classification has been replaced by Macrophages residing in the connective tissues were
the mononuclear phagocyte system. All members of previously called fixed macrophages, and those that
the mononuclear phagocyte system arise from a developed as a result of an exogenous stimulus and
common stem cell in the bone marrow, possess lyso- migrated to the particular site were called free
somes, are capable of phagocytosis, and display FcεRI macrophages. These names have been replaced by the
receptors and receptors for complement. more descriptive terms resident macrophages and
Monocytes develop in the bone marrow and circu- elicited macrophages, respectively.
late in the blood. At the proper signal, they leave the
bloodstream by migrating through the endothelium of Macrophage Function
capillaries or venules. In the connective tissue com-
partment they mature into macrophages, which nor- Macrophages phagocytose foreign substances and
mally have a life span of about 2 months. Macrophages damaged and senescent cells as well as cellular debris;
arise from monocytes, activated by the macrophage they also assist in the initiation of the immune response.
colony-stimulating factor (M-CSF) (see Chapter 10 and
Table 10-6). Macrophages phagocytose senescent, damaged, and
Macrophages localized in certain regions of the body dead cells and cellular debris and digest the ingested
were given specific names before their origin was material through the action of hydrolytic enzymes in
completely understood. Thus, Kupffer cells of the their lysosomes (see Chapter 2). Macrophages also
liver (Fig. 6-13), dust cells of the lung, Langerhans assist in defense of the body by phagocytosing and
cells of the skin, monocytes of the blood, and destroying foreign substances, including microorga-
macrophages of the connective tissue, spleen, lymph nisms. During the immune response, factors released
nodes, thymus, and bone marrow are all members of by lymphocytes activate macrophages, increasing their
the mononuclear phagocyte system and possess similar phagocytic activity. Activated macrophages vary con-
morphology and functions. Additionally, osteoclasts of siderably in shape, possess microvilli and lamellipodia,
bone and microglia of the brain, although morpholog- and exhibit more locomotion compared with unacti-
ically different, belong to the mononuclear phagocyte vated macrophages. Macrophages also play a key role in
system. presenting antigens to lymphocytes (see Chapter 12).
KC
KC

of liver of an animal injected with
India ink demonstrating the presence
of cells known as Kuppfer cells (KC)
that preferentially phagocytose the ink
(×540).
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Transient Connective Tissue Cells Leukocytes

All transient connective tissue cells are derived from Leukocytes exit the bloodstream during inflammation,
precursors in the bone marrow (see Fig. 6-1). These invasion by foreign elements, and immune responses in
cells are discussed in greater detail in other chapters. order to perform various functions.
Plasma Cells
Plasma cells are derived from B lymphocytes and
manufacture antibodies.
Although plasma cells are scattered throughout the con-

nective tissues, they are present in greatest numbers in
areas of chronic inflammation and in areas where
foreign substances or microorganisms have entered the
tissues. These differentiated cells, which are derived
from B lymphocytes that have interacted with antigen,
produce and secrete antibodies and are responsible
for humorally mediated immunity (see Chapters 10
and 12).
Plasma cells are large, ovoid cells, 20 µm in diame-
ter, with an eccentrically placed nucleus, that have a rel-
atively short life span of 2 to 3 weeks. Their cytoplasm
is intensely basophilic as a result of a well-developed
RER with closely spaced cisternae (Fig. 6-14). Only a
few mitochondria are scattered between the profiles of
RER. Electron micrographs display a large, juxtanu-
clear Golgi complex and a pair of centrioles (Figs. 6-15
and 6-16). In light micrographs, these structures are
located in the pale-staining regions adjacent to the
nucleus. The spherical nucleus possesses heterochro-
matin radiating out from the center, giving it a charac- Figure 6–14 Light micrograph of plasma cells in the lamina
teristic “clock face” or “spoked” appearance under the propria of the monkey jejunum (×540). Observe the “clock face”
light microscope. nucleus (arrows).
Golgi
apparatus
Rough
endoplasmic
reticulum
Mitochondrion
Heterochromatin
Figure 6–15 Drawing of a

plasma cell as seen in an electron
micrograph. The arrangement of
heterochromatin gives the nucleus a
“clock face” appearance. (From
Lentz TL: Cell Fine Structure: An
Atlas of Drawings of Whole-Cell
Structure. Philadelphia, WB Saun-
ders, 1971.)
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graph of a plasma cell from the
lamina propria of the rat duodenum
displaying abundant rough endo-
plasmic reticulum (RER) and pro-
minent Golgi complex (×10,300). G, RER
Golgi apparatus; M, mitochondria;
N, nucleus. Arrowheads represent
small vesicles; arrows represent
dense granules. (From Rambourg A,
Clermont Y, Hermo L, Chretien M:
Formation of secretion granules in
the Golgi apparatus of plasma cells
in the rat. Am J Anat 184:52-61,
1988.)
Leukocytes are white blood cells that circulate in the

bloodstream. However, they frequently migrate through CLASSIFICATION OF
the capillary walls to enter the connective tissues, espe- CONNECTIVE TISSUE
cially during inflammation, when they carry out various As noted earlier, connective tissue is classified into
functions. (See Chapter 10 for more comprehensive dis- connective tissue proper—the major subject of this
cussions; also see summary in Table 10-3.) chapter—and specialized connective tissue, embracing
Monocytes have been discussed under cartilage, bone, and blood. The third recognized cate-
“Macrophages.” gory of connective tissue is embryonic connective
Neutrophils phagocytose and digest bacteria in tissue. Table 6-2 summarizes the major classes of con-
areas of acute inflammation, resulting in formation nective tissue and their subclasses.
of pus, an accumulation of dead neutrophils and
debris. Embryonic Connective Tissue
Eosinophils, like neutrophils, are attracted to areas
of inflammation by leukocyte chemotactic factors. Embryonic connective tissue includes both mesenchymal
Eosinophils combat parasites by releasing cytotoxins. tissue and mucous tissue.
They also are attracted to sites of allergic inflammation,
where they moderate the allergic reaction and phago- Mesenchymal connective tissue is present only in
cytose antibody-antigen complexes. the embryo and consists of mesenchymal cells in a gel-
Basophils (similar to mast cells) release preformed like, amorphous ground substance containing scattered
and newly synthesized pharmacological agents that ini- reticular fibers. Mesenchymal cells possess an oval
tiate, maintain, and control the inflammatory process. nucleus exhibiting a fine chromatin network and promi-
Lymphocytes are present only in small numbers in nent nucleoli. The sparse, pale-staining cytoplasm
most connective tissue, except at sites of chronic inflam- extends small processes in several directions. Mitotic
mation, where they are abundant. Chapter 10 describes figures frequently are observed in mesenchymal cells
leukocytes in more detail, and Chapter 12 discusses because they give rise to most of the cells of loose con-
lymphocytes. nective tissue. It is generally believed that most if not
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Loose connective tissue is characterized by abundant

Table 6–2 Classification of Connective ground substance and tissue fluid (extracellular fluid)
Tissues housing the fixed connective tissue cells: fibroblasts,
adipose cells, macrophages, and mast cells as well
A. Embryonic connective tissues as some undifferentiated cells. Also scattered
1. Mesenchymal connective tissue throughout the ground substance are loosely woven col-
2. Mucous connective tissue lagen, reticular, and elastic fibers. Coursing in this
B. Connective tissue proper amorphous tissue are small nerve fibers as well as blood
1. Loose (areolar) connective tissue vessels that supply the cells with oxygen and nutrients.
2. Dense connective tissue Because this tissue lies immediately beneath the
a. Dense irregular connective tissue
thin epithelia of the digestive and respiratory tracts, this
b. Dense regular connective tissue
(1) Collagenous is where the body first attacks antigens, bacteria,
(2) Elastic and other foreign invaders. Therefore, loose connective
3. Reticular tissue tissue contains many transient cells responsible for
4. Adipose tissue inflammation, allergic reactions, and the immune
C. Specialized connective tissue response. These cells, which originally circulate in the
1. Cartilage bloodstream, are released from blood vessels in
2. Bone response to an inflammatory stimulus. Pharmacological
3. Blood agents released by mast cells increase the permeability
of small vessels so that excess plasma enters the loose
connective tissue spaces, causing it to swell.
all of the mesenchymal cells, once scattered throughout

the embryo, are eventually depleted and do not exist as CLINICAL CORRELATIONS
such in the adult except in the pulp of teeth. In adults, Under normal circumstances, extracellular fluid
however, pluripotential pericytes, which reside along returns to the blood capillaries or enters lymph
capillaries, can differentiate into other cells of connec- vessels to be returned to the blood. A potent
tive tissue. and prolonged inflammatory response, however,
Mucous tissue is a loose, amorphous connective causes accumulation of excess tissue fluid within
tissue exhibiting a jelly-like matrix primarily composed loose connective tissue beyond what can be
of hyaluronic acid and sparsely populated with type I returned via the capillaries and lymph vessels.
and type III collagen fibers and fibroblasts. This tissue, This results in gross swelling, or edema, in the
also known as Wharton’s jelly, is found only in the affected area. Edema can result from excessive
umbilical cord and subdermal connective tissue of the release of histamine and leukotrienes C4 and D4,
embryo. which all increase capillary permeability, as well as
from obstruction of venous or lymphatic vessels.
Connective Tissue Proper
The four recognized types of connective tissue proper
(loose, dense, and reticular connective tissues and
adipose tissue), differ in their histology, location, and Dense Connective Tissue
functions.
Dense connective tissue contains a greater abundance of
Loose (Areolar) Connective Tissue fibers and fewer cells than loose connective tissue.
Loose (areolar) connective tissue is composed of a loose Dense connective tissue contains most of the same
arrangement of fibers and dispersed cells embedded in a components found in loose connective tissue, except
gel-like ground substance. that it has many more fibers and fewer cells. The ori-
entation and the arrangements of the bundles of colla-
Loose connective tissue, also known as areolar con- gen fibers in this tissue make it resistant to stress. When
nective tissue, fills in the spaces of the body just deep the collagen fiber bundles are arranged randomly, the
to the skin, lies below the mesothelial lining of the inter- tissue is called dense irregular connective tissue. When
nal body cavity, is associated with the adventitia of blood fiber bundles of the tissue are arranged in parallel or
vessels, and surrounds the parenchyma of glands. The organized fashion, the tissue is called dense regular con-
loose connective tissue of mucous membranes (as in the nective tissue, which is divided into collagenous and
alimentary canal) is called the lamina propria. elastic types.
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CF
Figure 6–18 Light micrograph of dense regular collagenous

connective tissue from monkey tendon (×270). Note the ordered, par-
Figure 6–17 Light micrograph of dense irregular collagenous allel array of collagen bundles and the elongated nuclei (N) of the
connective tissue from monkey skin (×132). Observe the many fibroblasts lying between collagen bundles.
bundles of collagen (CF) in random orientation.
in large blood vessels, ligamenta flava of the vertebral

column, and the suspensory ligament of the penis.
Dense irregular connective tissue contains mostly
coarse collagen fibers interwoven into a meshwork that Reticular Tissue
resists stress from all directions (Fig. 6-17). The collagen
bundles are packed so tightly that space is limited for Type III collagen is the major fiber component of retic-
ground substance and cells. Fine networks of elastic ular tissue. The collagen fibers form mesh-like networks
fibers are often scattered about the collagen bundles. interspersed with fibroblasts and macrophages (Fig.
Fibroblasts, the most abundant cells of this tissue, are 6-20). It is the fibroblasts that synthesize the type III
located in the interstices between collagen bundles. collagen. Reticular tissue forms the architectural frame-
Dense irregular connective tissue constitutes the dermis work of liver sinusoids, adipose tissue, bone marrow,
of skin, the sheaths of nerves, and the capsules of the lymph nodes, spleen, smooth muscle, and the islets of
spleen, testes, ovary, kidney, and lymph nodes. Langerhans.
Dense regular collagenous connective tissue is
composed of coarse collagen bundles densely packed Adipose Tissue
and oriented into parallel cylinders or sheets that resist Adipose tissue is classified into two types according to
tensile forces (Fig. 6-18). Because of the tight packing whether it is composed of unilocular or multilocular
of the collagen fibers, little space can be occupied by adipocytes. Other differences between the two types
ground substance and cells. Thin, sheet-like fibroblasts of adipose tissue are color, vascularity, and metabolic
are located between bundles of collagen with their long activity.
axes parallel to the bundles. Tendons (Fig. 6-19), liga-
ments, and aponeuroses are examples of dense regular White (Unilocular) Adipose Tissue
collagenous connective tissue.
Dense regular elastic connective tissue possesses Each unilocular fat cell contains a single lipid droplet,
coarse branching elastic fibers with only a few collagen giving the adipose tissue composed of such cells a white
fibers forming networks. Scattered throughout the inter- color. (In a person whose diet is especially rich in foods
stitial spaces are fibroblasts. The elastic fibers are containing carotenoids, such as carrots, this adipose
arranged parallel to one another and form either thin tissue is yellow.) White adipose tissue is heavily supplied
sheets or fenestrated membranes. The latter are present with blood vessels, which form capillary networks
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Figure 6–19 Light micrograph of

a cross section of monkey tendon. The
scattered, small black structures repre-
sent nuclei of fibroblasts (×270).
norepinephrine, and glucocorticoids, that facilitate

the uptake and release of free fatty acids and glycerol.
Unilocular fat is present in the subcutaneous layers
throughout the body. It also occurs in masses in char-
acteristic sites influenced by sex and age. In men, fat is
stored in the neck, in the shoulders, about the hips, and
in the buttocks. As men age, the abdominal wall
becomes an additional storage area. In women, fat is
stored in the breasts, buttocks, hips, and lateral aspects
of the thighs. Additionally, fat is stored in both sexes in
the abdominal cavity about the omental apron and the
mesenteries.
Brown (Multilocular) Adipose Tissue

Brown adipose tissue (brown fat) is composed of mul-
tilocular fat cells, which store fat in multiple droplets.
This tissue may appear tan to reddish brown because of
its extensive vascularity and the chytochromes present
in its abundant mitochondria (see Fig. 6-7).
Multilocular adipose tissue has a lobular organization
and vascular supply similar to those of a gland. Brown
fat tissue is very vascular because the vessels are located
near the adipocytes. Unmyelinated nerve fibers enter
Figure 6–20 Light micrograph of reticular tissue (stained with the tissue, with the axons ending on the blood vessels
silver) displaying the networks of reticular fibers (×270). Many lym- as well as on fat cells, whereas in white fat tissue, the
phoid cells are interspersed between the reticular fibers (arrows). neurons end only on the blood vessels.
Although it has long been known that multilocular
fat is found in many mammalian species, especially
throughout the tissue. The vessels gain access via those that hibernate, and in the infants of most
connective tissue septa that partition the fat into mammals, it was unclear whether multilocular fat exists
lobules (see Fig. 6-6). The plasma membranes of the in adult humans. However, in the newborn human,
unilocular adipose cells contain receptors for several brown fat is located in the neck region and in the inter-
substances, including insulin, growth hormone, scapular region. As humans mature, the fat droplets in
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These cells can oxidize fatty acids at up to 20 times the

CLINICAL CORRELATIONS rate of white fat, increasing body heat production three-
fold in cold environments. Sensory receptors in the skin
Obesity increases the risks for many health prob- send signals to the temperature-regulating center of the
lems, including non–insulin-dependent diabetes brain, resulting in the relaying of sympathetic nerve
mellitus, as well as problems involving the car- impulses directly to the brown fat cells. The neurotrans-
diovascular system. mitter norepinephrine activates the enzyme that cleaves
In adults, obesity develops in two ways. triglycerides into fatty acids and glycerol, initiating heat
Hypertrophic obesity results from the accu- production by oxidation of fatty acids in the mitochon-
mulation and storage of fat in unilocular fat cells, dria. Thermogenin, a transmembrane protein located
which may increase their size by as much as on the inner membrane of mitochondria, permits back-
four times. Hypercellular obesity, as the name flow of protons instead of utilizing them for synthesis of
implies, results from an overabundance of adenosine triphosphate (ATP); as a result of uncoupling
adipocytes. This type of obesity usually is severe. oxidation from phosphorylation, the proton flow gener-
Although mature adipocytes do not divide, ates energy that is dispersed as heat.
their precursors proliferate in early postnatal
life. There is substantial evidence that overfeed- Histogenesis of Adipose Tissue
ing newborn infants for a few weeks may
actually increase the number of adipocyte pre- It is believed that adipose cells are derived from undif-
cursors, leading to an increase in the number of ferentiated embryonic stem cells that develop into
adipocytes and setting the stage for hypercellu- preadipocytes, cells that, under the influence of a
lar obesity in the adult. Overweight infants are at series of activating factors, differentiate into adipocytes.
least three times more likely to exhibit obesity as The predominant view is that adipose tissue develops
adults than infants of average weight. Presently, via two separate processes. In primary fat formation,
it is understood that persons exhibiting severe which occurs early in fetal life, groups of epithelioid
obesity also exhibit an increase in the adipocyte precursor cells, probably preadipocytes, are distrib-
population, although it is not understood how uted at certain locations in the developing fetus; in these
this recruitment is driven. tissues, lipid droplets begin to accumulate in the form of
There also appears to be a genetic basis in brown adipose tissue. Near the end of fetal life, other
some cases of obesity. Mutations in the gene fusiform precursor cells differentiate in many areas of
responsible for the coding for leptin produces an the connective tissues within the fetus and begin to
inactive form of that hormone. Because leptin accumulate lipids that coalesce into the single droplet in
regulates the appetite center of the hypothala- each cell, thus forming the unilocular fat cells found in
mus, people who either do not produce leptin or adults. The latter process has been named secondary
who produce a biologically inactive form of this fat formation. It should be understood, however, that
hormone have a voracious appetite and suffer brown adipose tissue is present in the embryo but white
from an almost uncontrollable weight gain. adipose tissue appears only after birth.
brown fat cells coalesce and form into one droplet Tumors of the adipose tissues may be benign or
(similar to the droplets in white fat cells) and the cells malignant. Lipomas are common benign tumors
become more like those in unilocular fat tissue. Thus, of adipocytes, whereas liposarcomas are malig-
although adults appear to contain only unilocular fat, nant tumors of adipocytes. The latter form most
there is evidence that they also possess brown fat. This commonly in the leg and in retroperitoneal
feature can be demonstrated in some of the wasting dis- tissues, although they may form anywhere in the
eases of older people, in which multilocular fat tissue body. The tumor cells may resemble either
forms again and in the same areas as in the newborn. unilocular adipocytes or multilocular adipocytes,
Brown adipose tissue is associated with production of another indication that adult humans do indeed
body heat because of the large number of mitochondria possess the two kinds of adipose tissue.
in the multilocular adipocytes composing this tissue.
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7 䡲䡲䡲
Cartilage and Bone
Cartilage and bone are both specialized connective 䡲 Hyaline cartilage contains type II collagen in its
tissues. Cartilage possesses a firm pliable matrix that matrix; it is the most abundant cartilage in the body
resists mechanical stresses. Bone matrix is one of the and serves many functions.
hardest tissues of the body, and it too resists stresses 䡲 Elastic cartilage contains type II collagen and
placed upon it. Both of these connective tissues have abundant elastic fibers scattered throughout its
cells that are specialized to secrete the matrix in which, matrix, giving it more pliability.
subsequently, the cells become trapped. Although car- 䡲 Fibrocartilage possesses dense, coarse type I colla-
tilage and bone have many varied functions, some of the gen fibers in its matrix, allowing it to withstand strong
functions are similar and related. Both are involved in tensile forces.
supporting the body because they are intimately associ-
The perichondrium is a connective tissue sheath
ated in the skeletal system. Most of the long bones of
the body are formed first in the embryo as cartilage, covering that overlies most cartilage. It has an outer
which then acts as a template that is later replaced by fibrous layer and inner cellular layer whose cells secrete
bone; this process is referred to as endochondral bone cartilage matrix. The perichondrium is vascular, and its
formation. Most of the flat bones are formed within vessels supply nutrients to the cells of cartilage. In areas
preexisting membranous sheaths; thus this method of where the cartilage has no perichondrium (e.g., the
osteogenesis is known as intramembranous bone articular surfaces of the bones forming a joint), the car-
tilage cells receive their nourishment from the synovial
formation.
fluid that bathes the joint surfaces. Perichondria are
present in elastic and most hyaline cartilages, but absent
CARTILAGE in fibrocartilage.
Cartilage possesses cells called chondrocytes, which
occupy small cavities called lacunae within the extra- Hyaline Cartilage
cellular matrix they secreted. The substance of carti-
lage is neither vascularized nor supplied with nerves or Hyaline cartilage, the most abundant cartilage in the
lymphatic vessels; however, the cells receive their nour- body, forms the template for endochondral bone
ishment from blood vessels of surrounding connective formation.
tissues by diffusion through the matrix. The extracellu-
lar matrix is composed of glycosaminoglycans and Hyaline cartilage, a bluish-gray, semitranslucent, pliable
proteoglycans, which are intimately associated with substance, is the most common cartilage of the body. It
the collagen and elastic fibers embedded within the is located in the nose and larynx, on the ventral ends of
matrix. The flexibility and resistance of cartilage to com- the ribs where they articulate with the sternum, in the
pression permit it to function as a shock absorber, and tracheal rings and bronchi, and on the articulating
its smooth surface permits almost friction-free move- surfaces of the movable joints of the body. Also, it is
ment of the joints of the body as it covers the articulat- this cartilage that forms the cartilage template of many
ing surfaces of the bones. of the bones during embryonic development and con-
There are three types of cartilage according to the stitutes the epiphyseal plates of growing bones (see
fibers present in the matrix (Fig. 7-1 and Table 7-1): Table 7-1).
131
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132 䡲䡲䡲 Chapter 7 䡲 Cartilage and Bone
HYALINE CARTILAGE Histogenesis and Growth of

Perichondrium Hyaline Cartilage
Cells responsible for hyaline cartilage formation
Interterritorial
matrix differentiate from mesenchymal cells.
Territorial In the region where cartilage is to form, individual mes-

matrix enchymal cells retract their processes, round up, and
Lacunae without congregate in dense masses called chondrification
chondrocytes centers. These cells differentiate into chondroblasts
Isogenous group
and commence secreting the typical cartilage matrix
around themselves. As this process continues, the chon-
Chondrocytes droblasts become entrapped in their own matrix in small
in lacunae individual compartments called lacunae. Chondrob-
lasts that are surrounded by this matrix are referred to as
chondrocytes (Fig. 7-2). These cells are still capable of
ELASTIC CARTILAGE cell division, forming a cluster of two to four or more
Perichondrium
cells in a lacuna. These groups are known as isogenous
groups and represent one, two, or more cell divisions
from an original chondrocyte (see Fig. 7-1). As the cells
of an isogenous group manufacture matrix, they are
Chondrocytes pushed away from each other, forming separate lacunae
and thus enlarging the cartilage from within. This type
Elastic fibers
of growth is called interstitial growth.
Mesenchymal cells at the periphery of the develop-
ing cartilage differentiate to form fibroblasts. These
cells manufacture a dense irregular collagenous con-
nective tissue, the perichondrium, responsible for
the growth and maintenance of the cartilage. The peri-
chondrium has two layers, an outer fibrous layer com-
posed of type I collagen, fibroblasts, and blood vessels
and an inner cellular layer composed mostly of chon-
drogenic cells. The chondrogenic cells undergo divi-
FIBROCARTILAGE
sion and differentiate into chondroblasts, which begin
to elaborate matrix. In this way cartilage also grows by
adding to its periphery, a process called appositional
growth.
Chondrocyte Interstitial growth occurs only in the early phase of
hyaline cartilage formation. Articular cartilage lacks a
perichondrium and increases in size only by interstitial
growth. This type of growth also occurs in the epiphy-
Collagen fibers
seal plates of long bones, where the lacunae are
arranged in a longitudinal orientation parallel to the long
axis of the bone; therefore, interstitial growth serves to
lengthen the bone. The cartilage in the remainder of the
body grows mostly by apposition, a controlled process
that may continue during the life of the cartilage.
It is interesting that mesenchymal cells located within
the chondrification centers are induced to become
Figure 7–1 Types of cartilage. secreting chondroblasts by their attachments and the
chemistry of the surrounding extracellular matrix. Also, if
chondroblasts are removed from their secreted cartilage
matrix and are grown in a monolayer in a low-density
substrate, they will cease to secrete “cartilage matrix”
containing type II collagen. Instead they will become
fibroblast-like and start secreting type I collagen.
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Chapter 7 䡲 Cartilage and Bone ■ ■ ■ 133
TABLE 7–1 Types of Cartilage
Type Identifying Characteristics Perichondrium Location
Hyaline Type II collagen, basophilic matrix, Perichondrium present in Articular ends of long bones,
chondrocytes usually arranged in most places (exceptions: nose, larynx, trachea, bronchi,
groups articular cartilages and ventral ends of ribs
epiphyses)
Elastic Type II collagen, elastic fibers Perichondrium present Pinna of ear, walls of auditory
canal, auditory tube, epiglottis,
cuneiform cartilage of larynx
Fibrocartilage Type I collagen, acidophilic matrix; Perichondrium absent Intervertebral disks, articular
chondrocytes arranged in parallel disks, pubic symphysis,
rows between bundles of collagen; insertion of some tendons
always associated with dense
regular collagenous connective
tissue or hyaline cartilage
Cartilage Cells
Three types of cells are associated with cartilage: chon-
drogenic cells, chondroblasts, and chondrocytes (see
P Fig. 7-2).
Chondrogenic cells are spindle-shaped, narrow
cells that are derived from mesenchymal cells. They
Cg possess an ovoid nucleus with one or two nucleoli. Their
cytoplasm is sparse, and electron micrographs of chon-
Cb drogenic cells display a small Golgi apparatus, a few
mitochondria, some profiles of rough endoplasmic
reticulum (RER), and an abundance of free ribo-
somes. These cells can differentiate into both chon-
droblasts and osteoprogenitor cells.
Chondroblasts are derived from two sources: mes-
enchymal cells located within the center of chondrifi-
C
C cation and chondrogenic cells of the inner cellular
layer of the perichondrium (as in appositional growth).
Chondroblasts are plump, basophilic cells that display
the organelles required for protein synthesis. Electron
micrographs of these cells demonstrate a rich network
of RER, a well-developed Golgi complex, numerous
mitochondria, and an abundance of secretory vesicles.
Chondrocytes are chondroblasts that are sur-
rounded by matrix. Those near the periphery are ovoid,
whereas those deeper in the cartilage are more
rounded, with a diameter of 10 to 30 µm. Histological
Figure 7–2 Light micrograph of hyaline cartilage (×270). processing creates artifactual shrinkage and distortion
Observe the large ovoid chondrocytes (C) trapped in their lacunae.
Above them are the elongated chondroblasts (Cb), and at the very top of the cells. Chondrocytes display a large nucleus with
is the perichondrium (P) and the underlying chondrogenic (Cg) cell a prominent nucleolus and the usual organelles of
layer. protein-secreting cells. Young chondrocytes have a
pale-staining cytoplasm with many mitochondria, an
elaborate RER, a well-developed Golgi apparatus, and
glycogen. Older chondrocytes, which are relatively
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quiescent, display a greatly reduced complement of becomes hydrated to such an extent that up to 80% of
organelles, with an abundance of free ribosomes. Thus, the wet weight of cartilage is water, accounting for the
these cells can resume active protein synthesis if they ability of cartilage to resist forces of compression.
revert to chondroblasts. Not only do hydrated proteoglycans fill the inter-
stices among the collagen fiber bundles, but their gly-
Matrix of Hyaline Cartilage cosaminoglycan side chains form electrostatic bonds
with the collagen. Thus, the ground substance and
The matrix of hyaline cartilage is composed of type II fibers of the matrix form a cross-linked molecular
collagen, proteoglycans, glycoproteins, and extracellular framework that resists tensile forces.
fluid. Cartilage matrix also contains the adhesive glycopro-
tein chondronectin. This large molecule, similar to
The semitranslucent blue-gray matrix of hyaline carti- fibronectin, has binding sites for type II collagen, chon-
lage contains up to 40% of its dry weight in collagen. In droitin 4-sulfate, chondroitin 6-sulfate, hyaluronic acid,
addition, it contains proteoglycans, glycoproteins, and and integrins (transmembrane proteins) of chondro-
extracellular fluid. Because the refractive index of the blasts and chondrocytes. Chondronectin thus assists
collagen fibrils and that of the ground substance are these cells in maintaining their contact with the fibrous
nearly the same, the matrix appears to be an amor- and amorphous components of the matrix.
phous, homogeneous mass with the light microscope.
The matrix of hyaline cartilage contains primarily Histophysiology of Hyaline Cartilage
type II collagen, but types IX, X, and XI and other
minor collagens are also present in small quantities. The smoothness of hyaline cartilage and its ability to
Type II collagen does not form large bundles, although resist forces of both compression and tension are essen-
the bundle thickness increases with distance from the tial to its function at the articular surfaces of joints.
lacunae. Fiber orientation appears to be related to the Because cartilage is avascular, nutrients and oxygen
stresses placed on the cartilage. For example, in articu- must diffuse through the water of hydration present in
lar cartilage, the fibers near the surface are oriented the matrix. The inefficiency of such a system necessi-
parallel to the surface, whereas deeper fibers seem to tates a limit on the width of cartilage. There is a con-
be oriented in curved columns. stant turnover in the proteoglycans of cartilage that
The matrix is subdivided into two regions: the terri- changes with age. Hormones and vitamins also exert
torial matrix, around each lacuna, and the interterritor- influence on the growth, development, and function of
ial matrix (see Fig. 7-1). The territorial matrix, cartilage. Many of these substances also affect skeletal
formation and growth (Table 7-2).
a 50-µm-wide band, is poor in collagen and rich in
chondroitin sulfate, which contributes to its basophilic
and intense staining with periodic acid–Schiff (PAS)
reagent. The bulk of the matrix is interterritorial CLINICAL CORRELATIONS
matrix, which is richer in type II collagen and poorer
in proteoglycans than the territorial matrix. Hyaline cartilage degenerates when the chon-
A small region of the matrix, 1- to 3-mm thick, imme- drocytes hypertrophy and die and the matrix
diately surrounding the lacuna is known as the peri- begins to calcify. This process is a normal and
cellular capsule. It displays a fine meshwork of integral part of endochondral bone formation;
collagen fibers embedded in a basal lamina-like sub- however, it is also a natural process of aging,
stance. These fibers may represent some of the other often resulting in less mobility and in joint pain.
minor collagens present in hyaline cartilage; it has been Cartilage regeneration is usually poor except
suggested that the pericellular capsule may protect in children. Chondrogenic cells from the peri-
chondrocytes from mechanical stresses. chondrium enter the defect and form new carti-
Cartilage matrix is rich in aggrecans, large proteo- lage. If the defect is large, the cells form dense
glycan molecules composed of protein cores to which connective tissue to repair the scar.
glycosaminoglycan molecules (chondroitin 4-sulfate,
chondroitin 6-sulfate, and heparan sulfate) are cova-
lently linked (see Fig. 4-3). As many as 100 to 200 aggre- Elastic Cartilage
can molecules are linked noncovalently to hyaluronic
acid, forming huge aggrecan composites that can be 3- Elastic cartilage greatly resembles hyaline cartilage, except
to 4-µm long. The abundant negative charges associated that its matrix and perichondrium possess elastic fibers.
with these exceedingly large proteoglycan molecules
attract cations, predominantly Na+ ions, which in turn Elastic cartilage is located in the pinna of the ear, the
attract water molecules. In this way, the cartilage matrix external and internal auditory tubes, the epiglottis, and
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Table 7–2 Effects of Hormones and P

Vitamins on Hyaline Cartilage
Hormone Effect
Thyroxine, testosterone, Stimulate cartilage growth

and somatotropin and matrix formation
(via insulin-like
growth factors) C
Cortisone, Inhibit cartilage growth
hydrocortisone, and and matrix formation
estradiol
Vitamin Effect
Hypovitaminosis A Reduces width of

epiphyseal plates
Hypervitaminosis A Accelerates ossification of

epiphyseal plates
Hypovitaminosis C Inhibits matrix synthesis

and deforms architecture
of epiphyseal plate, Figure 7–3 Light micrograph of elastic cartilage (×132). Observe
leading to scurvy the perichondrium (P) and the chondrocytes (C) in their lacunae
(shrunken from the walls because of processing), some of which
Absence of vitamin D, Proliferation of contain more than one cell, evidence of interstitial growth. Elastic
resulting in deficiency chondrocytes is normal fibers (arrows) are scattered throughout.
in absorption of but matrix does not
calcium and become calcified
phosphorus properly, resulting in Fibrocartilage is present in intervertebral disks, in the
rickets pubic symphysis, in articular disks, and attached to
bone. It is associated with hyaline cartilage and with
dense connective tissue, which it resembles. Unlike
the other two types of cartilage, fibrocartilage does
the larynx (cuneiform cartilage). Because of the pres- not possess a perichondrium. It displays a scant amount
ence of elastic fibers, elastic cartilage is somewhat of matrix (rich in chondroitin sulfate and dermatan
yellow and is more opaque than hyaline cartilage in the sulfate), and exhibits bundles of type I collagen, which
fresh state (see Table 7-1). stain acidophilic (Fig. 7-4). Chondrocytes are often
In most respects, elastic cartilage is identical to aligned in alternating parallel rows with the thick,
hyaline cartilage and is often associated with it. The coarse bundles of collagen, which parallel the tensile
outer fibrous layer of the perichondrium is rich in elastic forces attendant on this tissue (see Table 7-1).
fibers. The matrix of elastic cartilage possesses abun- Chondrocytes of fibrocartilage usually arise from
dant, fine to coarse branching elastic fibers interposed fibroblasts that begin to manufacture proteoglycans. As
with type II collagen fiber bundles, giving it much more the ground substance surrounds the fibroblast, the cell
flexibility than the matrix of hyaline cartilage (Fig. 7-3). becomes incarcerated in its own matrix and differenti-
The chondrocytes of elastic cartilage are more abundant ates into a chondrocyte.
and larger than those of hyaline cartilage. The matrix is Intervertebral disks represent an example of the organ-
not as ample as in hyaline cartilage, and the elastic fiber ization of fibrocartilage. They are interposed between the
bundles of the territorial matrix are larger and coarser hyaline cartilage coverings of the articular surface of suc-
than those of the interterritorial matrix. cessive vertebrae. Each disk contains a gelatinous center,
called the nucleus pulposus, which is composed of cells,
Fibrocartilage derived from the notochord, lying within a hyaluronic
acid-rich matrix. These cells disappear by the 20th year of
Fibrocartilage, unlike hyaline and elastic cartilage, does
life. Much of the nucleus pulposus is surrounded by the
not possess a perichondrium and its matrix includes type
annulus fibrosus, layers of fibrocartilage whose type I col-
I collagen.
lagen fibers run vertically between the hyaline cartilages
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Although bone is one of the hardest substances of the

body, it is a dynamic tissue that constantly changes
shape in relation to the stresses placed on it. For
example, pressures applied to bone lead to its resorp-
tion, whereas tension applied to it results in develop-
ment of new bone. In applying these facts, the
orthodontist is able to remodel the bone of the dental
C arches by moving and straightening the teeth to correct
malocclusion, thus providing the patient with a more
C natural and pleasant smile.
Bone is the primary structural framework for support
and protection of the organs of the body, including
the brain and spinal cord and the structures within the
thoracic cavity, namely the lungs and heart. The bones
also serve as levers for the muscles attached to them,
thereby multiplying the force of the muscles to attain
movement. Bone is a reservoir for several minerals of
the body; for example, it stores about 99% of the body’s
calcium. Bone contains a central cavity, the marrow
cavity, which houses the bone marrow, a hemopoietic
organ.
Bone is covered on its external surface, except at
synovial articulations, with periosteum, which consists
of an outer layer of dense fibrous connective tissue and
Figure 7–4 Light micrograph of fibrocartilage (×132). Note
alignment of the chondrocytes (C) in rows interspersed with thick an inner cellular layer containing osteoprogenitor
bundles of collagen fibers (arrows). (osteogenic) cells. The central cavity of a bone is lined
with endosteum, a specialized thin, connective tissue
composed of a monolayer of osteoprogenitor cells
of the two vertebrae. The fibers of adjacent lamellae are and osteoblasts.
oriented obliquely to each other, providing support to Bone is composed of cells lying in an extracellular
the gelatinous nucleus pulposus. The annulus fibrosus matrix that has become calcified. The calcified matrix is
provides resistance against tensile forces, whereas the composed of fibers and ground substance. The fibers
nucleus pulposus resists forces of compression. constituting bone are primarily type I collagen. The
ground substance is rich in proteoglycans with chon-
droitin sulfate and keratan sulfate side chains. In
addition, glycoproteins such as osteonectin, osteocalcin,
CLINICAL CORRELATIONS osteopontin, and bone sialoprotein are present.
A ruptured disk refers to a tear or break in the The cells of bone include osteoprogenitor cells,
laminae of the annulus fibrosus through which which differentiate into osteoblasts. Osteoblasts are
the gel-like nucleus pulposus extrudes. This con- responsible for secreting the matrix. When these cells
dition occurs more often on the posterior por- are surrounded by matrix, they become quiescent and
tions of the intervertebral disks, particularly in are known as osteocytes. The spaces osteocytes occupy
the lumbar portion of the back, where the disk are known as lacunae (Fig. 7-5). Osteoclasts, multinu-
may dislocate, or slip. A “slipped disk” leads to cleated giant cells derived from fused bone marrow
severe, intense pain in the lower back and precursors, are responsible for bone resorption and
extremities as the displaced disk compresses the remodeling.
lower spinal nerves. Because bone is such a hard tissue, two methods are
employed to prepare it for study. Decalcified sections
can be prepared by decalcifying the bone in an acid
solution to remove the calcium salts. The tissue can
BONE then be embedded, sectioned, and routinely stained for
study. Ground sections are prepared by sawing the
bone into thin slices, followed by grinding the sections
Bone is a specialized connective tissue whose
with abrasives between glass plates. When the section
extracellular matrix is calcified, incarcerating the cells
is sufficiently thin for study with light microscope, it is
that secreted it.
mounted for study.
Ch007-X2945.qxd 12/8/06 3:27 PM Page 137
deposited into the gap regions of the collagen but also

are present along the overlap region. The free surface
of the crystals is surrounded by amorphous ground sub-
stance. The surface ions of the crystals attract H2O and
form a hydration shell, which permits ion exchange
with the extracellular fluid.
Bone is one of the hardest and strongest substances
in the body. Its hardness and strength are due to the
Op association of hydroxyapatite crystals with collagen. If
bone is decalcified (i.e., all of the mineral is removed
from the bone), it still retains its original shape but
becomes so flexible that it can be bent like a piece of
tough rubber. If the organic component is extracted
Os from bone, the mineralized skeleton still retains its orig-
inal shape, but it becomes extremely brittle and can be
L fractured with ease.
Oc
Organic Component
Cl The predominant organic component of bone is type I
collagen.
The organic component of bone matrix, constituting

approximately 35% of the dry weight of bone, includes
fibers that are almost exclusively type I collagen.
Collagen, most of which is type I, makes up about
80% to 90% of the organic component of bone. It is
Figure 7–5 Light micrograph of decalcified compact bone formed in large (50 to 70 nm in diameter) bundles dis-
(×540). Osteocytes (Oc) may be observed in lacunae (L). Also note
the osteon (Os), osteoprogenitor cells (Op), and the cementing lines playing a typical 67-nm periodicity. Type I collagen in
(Cl). bone is highly cross-linked, which prevents it from
being easily extracted.
The fact that bone matrix stains with PAS reagent
Each system has disadvantages. In decalcified sec- and displays slight metachromasia indicates the pres-
tions, osteocytes are distorted by the decalcifying acid ence of sulfated glycosaminoglycans, namely chon-
bath; in ground sections, the cells are destroyed, and the droitin sulfate and keratan sulfate. These form small
lacunae and canaliculi are filled in with bone debris. proteoglycan molecules with short protein cores to
which the glycosaminoglycans are covalently bound.
Bone Matrix The proteoglycans are noncovalently bound, via link
proteins, to hyaluronic acid, forming very large aggre-
Bone matrix has inorganic and organic constituents. can composites. The abundance of collagen, however,
causes the matrix to be acidophilic.
Inorganic Component Several glycoproteins are also present in the bone
matrix. These appear to be restricted to bone and
The inorganic constituents of bone are crystals of
include osteocalcin, which binds to hydroxyapatite,
calcium hydroxyapatite, composed mostly of calcium and
and osteopontin, which also binds to hydroxyapatite
phosphorus.
but has additional binding sites for other components
The inorganic portion of bone, which constitutes about as well as for integrins present on osteoblasts and osteo-
65% of its dry weight, is composed mainly of calcium clasts. Vitamin D stimulates the synthesis of these gly-
and phosphorus along with other components, includ- coproteins. Bone sialoprotein, another matrix protein,
ing bicarbonate, citrate, magnesium, sodium, and potas- has binding sites for matrix components and integrins
sium. Calcium and phosphorus exist primarily in the of osteoblasts and osteocytes, suggesting its involvement
form of hydroxyapatite crystals [Ca10(PO4)6(OH)2], in the adherence of these cells to bone matrix.
but calcium phosphate is also present in an amorphous
Cells of Bone
form. Hydroxyapatite crystals (40-nm long by 25-nm
wide by 1.5- to 3-nm thick) are arranged in an ordered The cells of bone are osteoprogenitor cells, osteoblasts,
fashion along the type I collagen fibers; they are osteocytes, and osteoclasts.
Ch007-X2945.qxd 12/8/06 3:27 PM Page 138
Osteoprogenitor Cells
Osteoprogenitor cells are derived from embryonic
mesenchymal cells and retain their ability to undergo
mitosis.
Osteoprogenitor cells are located in the inner cellular Oc

layer of the periosteum, lining haversian canals, and in the
endosteum (see Fig. 7-5). These cells, derived from
embryonic mesenchyme, remain in place throughout
postnatal life and can undergo mitotic division and have
the potential to differentiate into osteoblasts. Moreover,
under certain conditions of low oxygen tension, these
cells may differentiate into chondrogenic cells. Osteopro-
genitor cells are spindle-shaped and have a pale-staining
oval nucleus; their scant pale-staining cytoplasm displays
sparse RER and a poorly developed Golgi apparatus but
Ob
an abundance of free ribosomes. These cells are most
active during the period of intense bone growth.
Osteoblasts
Osteoblasts not only synthesize the organic matrix of
bone but also possess receptors for parathyroid Figure 7–6 Light micrograph of intramembranous ossification
hormone. (×540). Osteoblasts (Ob) line the bony spicule where they are secret-
ing osteoid onto the bone. Osteoclasts (Oc) may be observed housed
Osteoblasts are derived from osteoprogenitor cells and in Howship’s lacunae.
develop under the influence of the bone morphogenic
protein (BMP) family and transforming growth
factor-b.Osteoblasts are responsible for the synthesis of
the organic protein components of the bone matrix, with processes of osteocytes. Although these processes
including type I collagen, proteoglycans, and glycopro- form gap junctions with one another, the number of
teins. Additionally, they produce RANKL (receptor for gap junctions between osteoblasts is much fewer than
activation of nuclear factor kappa B), osteocalcin (for those between osteocytes.
bone mineralization), osteopontin (for formation of
sealing zone between osteoclasts and the subosteoclas-
tic compartment), osteonectin (related to bone miner- CLINICAL CORRELATIONS
alization), bone sialoprotein (binding osteoblasts to
extracellular matrix), and macrophage colony-stimulat- Osteoblast cell membranes are rich in the
ing factor (M-CSF) (discussed later). Osteoblasts are enzyme alkaline phosphatase. During active
located on the surface of the bone in a sheet-like bone formation, these cells secrete high levels of
arrangement of cuboidal to columnar cells (Fig. 7-6). alkaline phosphatase, elevating the levels of this
When actively secreting matrix, they exhibit a basophilic enzyme in the blood. Thus, the clinician can
cytoplasm. monitor bone formation by measuring the blood
The organelles of osteoblasts are polarized so that alkaline phosphatase level.
the nucleus is located away from the region of secretory
activity, which houses secretory granules believed to
contain matrix precursors. The contents of these vesi- As osteoblasts exocytose their secretory products,
cles stain pink with PAS reagent. each cell surrounds itself with the bone matrix it has just
Electron micrographs exhibit abundant RER, a well- produced; when this occurs, the incarcerated cell is
developed Golgi complex (Fig. 7-7A), and numerous referred to as an osteocyte, and the space it occupies is
secretory vesicles containing flocculent material that known as a lacuna. Most of the bone matrix becomes
accounts for the PAS pink-staining vacuoles observed in calcified; however, osteoblasts as well as osteocytes are
the light microscope. Osteoblasts extend short always separated from the calcified substance by a thin,
processes that make contact with those of neighboring noncalcified layer known as the osteoid (uncalcified
osteoblasts, as well as long processes that make contact bone matrix).
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Op
4 5
1 2 3
Figure 7–7 Electron micrographs of

bone-forming cells. A, Five osteoblasts (1 to
5) lined up on the surface of bone (B) dis-
playing abundant rough endoplasmic reticu-
lum. Observe the process of an osteocyte in a
canaliculus (arrow). The cell with the elon-
gated nucleus lying above the osteoblasts
is an osteoprogenitor cell (Op) (×2500).
B, Note the osteocyte in its lacuna (L)
with its processes extending into canaliculi
(arrows) (×1000). B, bone; C, cartilage.
(From Marks SC Jr, Popoff SN: Bone cell
biology: The regulation of development,
structure, and function in the skeleton. Am
J Anat 183:1-44, 1988.) B
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Surface osteoblasts that cease to form matrix revert the periosteocytic space, is occupied by extracellular
to a more flattened-shaped quiescent state and are fluid. Considering the extensive network of the canali-
called bone-lining cells. Although these cells appear culi and the sheer number of osteocytes present in the
to be similar to osteoprogenitor cells, they are most skeleton of an average person, the volume of the perios-
likely incapable of dividing but can be reactivated to the teocytic space and the surface area of the walls have
secreting form with the proper stimulus. been calculated to be a staggering 1.3 L and as much
Osteoblasts have several factors on their cell mem- as 5000 m2, respectively. It has been suggested that the
branes, the most significant of which are integrins and 1.3 L of extracellular fluid occupying the periosteocytic
parathyroid hormone receptors. When parathyroid space is exposed to as much as 20 g of exchangeable
hormone binds to these receptors, it stimulates osteo- calcium that can be resorbed from the walls of these
blasts to secrete osteoprotegerin ligand (OPGL), a spaces. The resorbed calcium gains access to the blood-
factor that induces the differentiation of preosteoclasts stream and ensures the maintenance of adequate blood
into osteoclasts and it increases RANKL expression. calcium levels.
Also osteoblasts secrete an osteoclast-stimulating
factor, which activates osteoclasts to resorb bone. Osteoclasts
Osteoblasts also secrete enzymes responsible for
removing osteoid so that osteoclasts can make contact Osteoclasts are multinucleated cells originating from
with the mineralized bone surface. granulocyte-macrophage progenitors. They play a role in
bone resorption.
Osteocytes
The precursor of the osteoclast originates in the bone
Osteocytes are mature bone cells derived from marrow. Osteoclasts have receptors for osteoclast-
osteoblasts that became trapped in their lacunae. stimulating factor, colony-stimulating factor-1, osteopro-
tegerin (OPG), and calcitonin, among others. Osteoclasts
Osteocytes are mature bone cells, derived from are responsible for resorbing bone, and after they finish
osteoblasts, that are housed in lacunae within the cal- doing so, these cells probably undergo apoptosis.
cified bony matrix (see Figs. 7-5 and 7-7B). There are
as many as 20,000 to 30,000 osteocytes per mm3 of Morphology of Osteoclasts
bone. Radiating out in all directions from the lacunaa
are narrow, tunnel-like spaces (canaliculi) that house Osteoclasts are large, motile, multinucleated cells
cytoplasmic processes of the osteocyte. These processes 150 µm in diameter; they contain up to 50 nuclei and
make contact with similar processes of neighboring have an acidophilic cytoplasm (see Fig. 7-6). Osteoclasts
osteocytes, forming gap junctions through which ions were once thought to be derived from the fusion of
and small molecules can move between the cells. The many blood-derived monocytes, but the newest evi-
canaliculi also contain extracellular fluid carrying nutri- dence shows that they have a bone marrow precursor
ents and metabolites that nourish the osteocytes. in common with monocytes termed the mononuclear-
Osteocytes conform to the shape of their lacunae. phagocyte system. These precursor cells are stimu-
Their nucleus is flattened, and their cytoplasm is poor lated by macrophage colony–stimulating factor to
in organelles, displaying scant RER and a greatly undergo mitosis. In the presence of bone, these osteo-
reduced Golgi apparatus. Although osteocytes appear to clast precursors fuse to produce the multinucleated
be inactive cells, they secrete substances necessary for osteoclasts.
bone maintenance. These cells have also been impli- Osteoblasts secrete three signaling molecules that
cated in mechanotransduction, in that they respond regulate the differentiation of osteoclasts. The first of
to stimuli that place tension on bone by releasing cyclic these signals, the macrophage colony–stimulating
adenosine monophosphate (cAMP), osteocalcin, and factor (M-CSF) binds to a receptor on the
insulin-like growth factor. The release of these factors macrophage, inducing it to become a proliferating
facilitates the recruitment of preosteoblasts to assist in osteoclast precursor, and it induces the expression of
the remodeling of the skeleton (adding more bone) not the receptor for activation of nuclear factor kappa B
only during growth and development but also during (RANK) on the precursor. Another osteoblast signaling
the long-term redistribution of forces acting on the molecule, RANKL, binds to the RANKL receptor on
skeleton. An example of such remodeling is evident in the osteoclastic precursor, inducing it to differentiate
the comparison of male and female skeletons, in which into the multinucleated osteoclast, activating it, and
the muscle attachments of the male skeleton are usually enhancing bone resorption. The third signaling mole-
better defined than those of the female skeleton. cule, OPG, a member of the tumor necrosis factor
The interval between the osteocyte plasmalemma receptor (TNFR) family, can serve as a decoy by inter-
and the walls of the lacunae and canaliculi, known as acting with RANKL, thus prohibiting it from binding to
Ch007-X2945.qxd 12/8/06 3:27 PM Page 141
the macrophage and thus inhibiting osteoclast forma- resorption compartment, known as the subosteo-
tion. In this way, RANKL, RANK, and OPG regulate clastic compartment. The cytoplasmic aspect of the
bone metabolism and osteoclastic activity. OPG is ruffled border plasmalemma displays a regularly
produced not only by osteoblasts but by cells of many spaced, bristle-like coat that increases the thickness
other tissues, including the cardiovascular system, lung, of the plasma membrane of this region.
kidney, intestines, as well as hematopoietic and immune 3 The clear zone is the region of the cell that imme-
cells. Therefore it is not surprising that its expression is diately surrounds the periphery of the ruffled border.
modulated by various means by cytokines, peptides, It is organelle-free but contains many actin microfil-
hormones, drugs, and so forth. In bone, OPG not only aments that form an actin ring and appear to
inhibits the differentiation of precursor cells into osteo- function in helping integrins of the clear zone plas-
clasts but also suppresses the osteoclast’s bone resorp- malemma maintain contact with the bony periphery
tive capacities. Also, tensional forces on bone trigger of the Howship lacunae. In fact, the plasma mem-
OPG and mRNA synthesis. brane of this region is so closely applied to the bone
Osteoclasts occupy shallow depressions, called that it forms the sealing zone of the subosteoclastic
Howship’s lacunae, that identify regions of bone compartment. Thus, the clear zone isolates the
resorption. An osteoclast active in bone resorption may subosteoclastic compartment from the surrounding
be subdivided into four morphologically recognizable region, establishing a microenvironment whose con-
regions: tents may be modulated by cellular activities. For the
osteoclast to be able to resorb bone, the actin ring
1 The basal zone, located farthest from the Howship must first be formed, and its formation may be facil-
lacunae, houses most of the organelles, including the itated by OPGL. Then the ruffled border is formed,
multiple nuclei and their associated Golgi complexes whose finger-like processes increase the surface area
and centrioles. Mitochondria, RER, and polysomes of the plasmalemma in the region of bone resorption,
are distributed throughout the cell but are more facilitating the resorptive process.
numerous near the ruffled border. 4 The vesicular zone of the osteoclast consists of
2 The ruffled border is the portion of the cell that is numerous endocytotic and exocytotic vesicles that
directly involved in resorption of bone. Its finger-like ferry lysosomal enzymes and metalloproteinases into
processes are active and dynamic, changing their the subosteoclastic compartment and the products
configuration continuously as they project into the of bone degradation into the cell (Fig. 7-8). The
Cz
Figure 7–8 Electron micrograph of

an osteoclast. Note the clear zone (Cz)
on either side of the ruffled border (B)
of this multinucleated cell. (From Marks
Cz
SC Jr, Walker DG: The hematogenous
origin of osteoclasts. Experimental evi-
dence from osteopetrotic [microph-
thalmic] mice treated with spleen cells
from beige mouse donors. Am J Anat
161:1-10, 1981.)
Ch007-X2945.qxd 12/8/06 3:27 PM Page 142
vesicular zone is between the basal zone and the

ruffled border. CLINICAL CORRELATIONS
Mechanism of Bone Resorption Osteopetrosis, not to be confused with osteo-
porosis, is a genetic disorder where osteoclasts do
Within osteoclasts, the enzyme carbonic anhydrase not possess a ruffled border. Consequently, these
catalyzes the intracellular formation of carbonic acid osteoclasts cannot resorb bone and persons with
(H2CO3) from carbon dioxide and water. Carbonic acid osteopetrosis display increased bone density.
dissociates within the cells into H+ ions and bicarbon- Individuals suffering from this disease may
ate ions, HCO3−. The bicarbonate ions, accompanied by exhibit anemia resulting from decreased marrow
Na+ ions, cross the plasmalemma and enter nearby space, as well as blindness, deafness, and cranial
capillaries. Proton pumps in the plasmalemma of the nerve involvement because of impingement of
ruffled border of the osteoclasts actively transport H+ the nerves due to narrowing of the foramina.
ions into the subosteoclastic compartment, reducing the
pH of the microenvironment (Cl− ions follow passively).
The inorganic component of the matrix is dissolved as
the environment becomes acidic; the liberated miner- Hormonal Control of Bone Resorption
als enter the osteoclast cytoplasm to be delivered to
nearby capillaries. The bone-resorbing activity of osteoclasts is regulated
Lysosomal hydrolases and metalloproteinases, by two hormones, parathyroid hormone and calcitonin,
such as collagenase and gelatinase, are secreted produced by the parathyroid and thyroid gland,
by osteoclasts into the subosteoclastic compartment to respectively.
degrade the organic components of the decalcified bone
matrix. The degradation products are endocytosed by Bone Structure
the osteoclasts and further broken down into amino
Bones are classified according to their anatomical shape:
acids, monosaccharides, and disaccharides, which then
long, short, flat, irregular, and sesamoid.
are released into nearby capillaries (Fig. 7-9).
OSTEOCLAST
Nucleus
Nucleolus
Golgi
RER
Mitochondria
Capillary
_
CO2 + H2O H2CO3 H+ + HCO3
Endocytic
vesicle
Actin filaments
Bone
Section of
Lysosomes circumferential
Microenvironment of low pH clear zone
and lysosomal enzymes
Ruffled border
Figure 7–9 Osteoclastic function. RER, rough endoplasmic reticulum. (From Gartner LP, Hiatt JL, Strum JM: Cell Biology and Histology
[Board Review Series]. Philadelphia, Lippincott Williams & Wilkins, 1998, p 100.)
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Bones are classified according to their shape: external surface and inserting into it via Sharpey’s fibers
䡲 Long bones display a shaft located between two (see Fig. 7-10). Periosteum is composed of two layers.
heads (e.g., tibia). The outer fibrous layer helps distribute vascular and
䡲 Short bones have more or less the same width and nerve supply to bone, whereas the inner cellular layer
length (e.g., carpal bones of the wrist). possesses osteoprogenitor cells and osteoblasts.
䡲 Flat bones are flat, thin, and plate-like (e.g., bones The flat bones of the skull develop by a method dif-
forming the brain case of the skull). ferent from that of most of the long bones of the body.
䡲 Irregular bones have an irregular shape that does The inner and outer surfaces of the calvaria (skull cap)
not fit into the other classes (e.g., sphenoid and possess two relatively thick layers of compact bone
ethmoid bones within the skull). called the inner and outer tables, which surround
䡲 Sesamoid bones develop within tendons, where the spongy bone (diploë) sandwiched between them.
they increase the mechanical advantage for the The outer table possesses a periosteum, identified as the
muscle (e.g., patella) across a joint. pericranium, whereas internally the inner table is
lined with dura mater, which serves as a periosteum
Gross Observation of Bone for the inner table and as a protective covering for the
brain.
Gross observations of the femur (a long bone) cut in
longitudinal section reveal two different types of bone Bone Types Based on
structure. The very dense bone on the outside surface Microscopic Observations
is compact bone, whereas the porous portion lining
the marrow cavity is cancellous or spongy bone (Fig. Microscopically, bone is classified as either primary
7-10). Closer observation of the spongy bone reveals (immature) or secondary (mature) bone.
branching bony trabeculae and spicules jutting out
from the internal surface of the compact bone into Microscopic observations reveal two types of bone:
the marrow cavity. There are no haversian systems in primary bone, or immature or woven bone, and sec-
spongy bone, but there are irregular arrangements of ondary bones, or mature or lamellar bone.
lamellae. These contain lacunae housing osteocytes that Primary bone is immature in that it is the first bone
are nourished by diffusion from the marrow cavity, to form during fetal development and during bone
which is filled with bone marrow. repair. It has abundant osteocytes and irregular bundles
Bone marrow exists as two types: red bone marrow, of collagen, which are later replaced and organized as
in which blood cells are forming, and yellow bone secondary bone except in certain areas (e.g., at sutures of
marrow, composed mostly of fat. the calvaria, insertion sites of tendons, and bony alveoli
The shaft of a long bone is called the diaphysis, and surrounding the teeth). The mineral content of primary
the articular ends are called the epiphyses (singular, bone is also much less than that of secondary bone.
epiphysis). In a person who is still growing, the diaph- Secondary bone is mature bone composed of paral-
ysis is separated from each epiphysis by the epiphyseal lel or concentric bony lamellae 3- to 7-µm thick. Osteo-
plate of cartilage. The articular end of the bone is cytes in their lacunae are dispersed at regular intervals
enlarged and sculpted to articulate with its bony coun- between, or occasionally within, lamellae. Canaliculi,
terpart of the joint. The surface of the articulating end housing osteocytic processes, connect neighboring
is covered with only a thin layer of compact bone over- lacunae with one another, forming a network of inter-
lying spongy bone. On top of this is the highly polished communicating channels that facilitate the flow of nutri-
articular hyaline cartilage, which reduces friction as it ents, hormones, ions, and waste products to and from
moves against the articular cartilage of the bony coun- osteocytes. In addition, osteocytic processes within
terpart of the joint. The area of transition between the these canaliculi make contact with similar processes of
epiphyseal plate and the diaphysis is called the meta- neighboring osteocytes and form gap junctions, permit-
physis, where columns of spongy bone are located. It ting these cells to communicate with each other.
is from the epiphyseal plate and the metaphysis that Because the matrix of secondary bone is more calci-
bone grows in length. fied, it is stronger than primary bone. In addition, the
The diaphysis is covered by a periosteum except collagen fibers of secondary bone are arranged so that
where tendons and muscles insert into the bone. There is they parallel each other within a given lamella.
no periosteum on the surfaces of bone covered by articu-
lar cartilage. Periosteum is also absent from sesamoid Lamellar Systems of Compact Bone
bones (e.g., patella), which are formed within tendons
There are four lamellar systems in compact bone: outer
and function to increase the mechanical advantage across
circumferential lamellae, inner circumferential lamellae,
a joint. The periosteum is a noncalcified, dense, irregular,
osteons, and interstitial lamellae.
collagenous connective tissue covering the bone on its
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Canaliculi
Concentric
lamellae
Haversian
Osteon canal
Lacuna
Haversian canal
Volkmann’s canal
(with blood vessel)
Sharpey’s fibers
Periosteum
Blood vessels
Outer circumferential
lamellae
Inner circumferential
lamellae
Marrow cavity
Compact bone
Cancellous bone
(spongy bone)
Figure 7–10 Diagram of bone illustrating compact cortical bone, osteons, lamellae, Volkmann’s canals, haversian canals, lacunae, canali-
culi, and spongy bone.
Compact bone is composed of wafer-like thin layers OUTER AND INNER

of bone, lamellae, that are arranged in lamellar sys- CIRCUMFERENTIAL LAMELLAE
tems that are especially evident in the diaphyses of
long bones. These lamellar systems are the outer cir- The outer circumferential lamellae are just deep to
cumferential lamellae, inner circumferential lamellae, the periosteum, forming the outermost region of the
osteons (haversian canal systems), and interstitial diaphysis, and contain Sharpey’s fibers anchoring the
lamellae. periosteum to the bone (see Fig. 7-10).
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The inner circumferential lamellae, analogous to bundle with its associated connective tissue. Haversian
but not as extensive as outer circumferential lamellae, canals of adjacent osteons are connected to each other
completely encircle the marrow cavity. Trabeculae of by Volkmann’s canals (Fig. 7-12; also see Fig. 7-10).
spongy bone extend from the inner circumferential These vascular spaces are oriented oblique to or per-
lamellae into the marrow cavity, interrupting the pendicular to haversian canals.
endosteal lining of the inner circumferential lamellae. The diameter of haversian canals varies from approx-
imately 20 µm to about 100 µm. During the formation
HAVERSIAN CANAL SYSTEMS (OSTEONS) of osteons, the lamella closest to the cementing line is
the first one to be formed. As additional lamellae are
The bulk of compact bone is composed of an abundance
added to the system, the diameter of the haversian canal
of haversian canal systems (osteons); each system is
is reduced, and the thickness of the osteon wall
composed of cylinders of lamellae, concentrically
increases. Because nutrients from blood vessels of the
arranged around a vascular space known as the haver-
haversian canal must traverse canaliculi to reach osteo-
sian canal (Fig. 7-11; also see Fig. 7-10). Frequently,
cytes, an inefficient process, most osteons possess only
osteons bifurcate along their considerable length. Each
4 to 20 lamellae.
osteon is bounded by a thin cementing line, composed
mostly of calcified ground substance with a scant
amount of collagen fibers (see Fig. 7-5).
Collagen fiber bundles are parallel to each other
within a lamella but are oriented almost perpendicular
to those of adjacent lamellae. This arrangement is pos-
sible because the collagen fibers follow a helical
arrangement around the haversian canal within each
lamella but are pitched differently in adjacent lamellae.
Each haversian canal, lined by a layer of osteoblasts
and osteoprogenitor cells, houses a neurovascular
Oc
Os
C
Figure 7–11 Light micrograph of undecalcified ground bone Figure 7–12 Light micrograph of decalcified compact bone
(×270). Observe the haversian system containing the haversian canal (×162). Several osteons (Os) are displayed with their concentric lamel-
(C) and concentric lamellae (L) with lacunae with their canaliculi lae (L). A Volkmann’s canal (V) is also displayed. The dark-staining
(arrows). structures scattered throughout represent nuclei of osteocytes (Oc).
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As bone is being remodeled, osteoclasts resorb Intramembranous Bone Formation

osteons and osteoblasts replace them. Remnants of
osteons remain as irregular arcs of lamellar fragments, Intramembranous bone formation occurs within
known as interstitial lamellae, surrounded by osteons. mesenchymal tissue.
Like osteons, interstitial lamellae are also surrounded
by cementing lines. Most flat bones are formed by intramembranous bone
formation. This process occurs in a richly vascularized
Histogenesis of Bone mesenchymal tissue, whose cells make contact with
each other via long processes.
Bone formation during embryonic development may Mesenchymal cells differentiate into osteoblasts
be of two types: intramembranous and endo- that secrete bone matrix, forming a network of
chondral. Bone that is formed by either of the two spicules and trabeculae whose surfaces are populated
methods is identical histologically. The first bone by these cells (Figs. 7-13 and 7-14). This region of initial
formed is primary bone, which is later resorbed and osteogenesis is known as the primary ossification
replaced by secondary bone. Secondary bone continues center. The collagen fibers of these developing spicules
to be resorbed throughout life, although at a slower and trabeculae are randomly oriented, as expected in
rate. primary bone. Calcification quickly follows osteoid
Skin
Connective tissue
Spongy bone
Connective tissue
Mesenchyme Osteoblasts Osteocytes

Collagen Osteoid Primary bone tissue Figure 7–13 Intramembranous bone
fiber (trabeculae) formation.
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D
A B C
Os
E
Os
F
Figure 7–14 Light micrograph of intramembranous bone for-

mation (ossification) (×132). Trabeculae of bone are being formed by
osteoblasts lining their surface (arrows). Observe osteocytes trapped
in lacunae (arrowheads). Primitive osteons (Os) are beginning to form.
formation, and osteoblasts trapped in their matrices

become osteocytes. The processes of these osteocytes
are also surrounded by forming bone, establishing a
system of canaliculi. Continuous mitotic activity of mes-
enchymal cells provides a supply of undifferentiated
osteoprogenitor cells, which form osteoblasts.
As the sponge-like network of trabeculae is estab-
lished, the vascular connective tissue in their interstices
is transformed into bone marrow. The addition of tra-
beculae to the periphery increases the size of the
forming bone. Larger bones, such as the occipital bone Figure 7–15 Endochondral bone formation. Blue represents the
of the base of the skull, have several ossification centers, cartilage model upon which bone is formed. The bone then replaces
which fuse with each other to form a single bone. The the cartilage. A, Hyaline cartilage model. B, Cartilage at the midriff
fontanelles (“soft spots”) on the frontal and parietal (diaphysis) is invaded by vascular elements. C, Subperiosteal bone
collar is formed. D, Bone collar prevents nutrients from reaching car-
bones of a newborn infant represent ossification centers tilage cells so they die leaving confluent lacunae. Osteoclasts invade
that are not fused prenatally. and etch bone to permit periosteal bud to form. E, Calcified bone/cal-
Regions of the mesenchymal tissues that remain cified cartilage complex at epiphyseal ends of the growing bone.
uncalcified differentiate into the periosteum and endos- F, Enlargement of the epiphyseal plate at the end of the bone where
teum of developing bone. Moreover, the spongy bone bone replaces cartilage.
deep to the periosteum and the periosteal layer of the
dura mater of flat bones are transformed into compact Most of the long and short bones of the body develop
bone, forming the inner and outer tables with the by endochondral bone formation (Table 7-3). This type
intervening diploë. of bone formation occurs in several phases, the most
critical of which are (1) formation of a miniature hyaline
Endochondral Bone Formation cartilage model, (2) continued growth of the model,
which serves as a structural scaffold for bone develop-
Endochondral bone formation requires the presence of a
ment, and (3) eventual resorption and replacement by
cartilage template.
bone (Fig. 7-15).
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TABLE 7–3 Events in Endochondral Bone Formation
Event Description
Hyaline cartilage model formed. Miniature hyaline cartilage model formed in region of developing
embryo where bone is to develop; some chondrocytes mature,
hypertrophy, and die; cartilage matrix becomes calcified
Primary Center of Ossification
Perichondrium at the midriff of diaphysis Vascularization of perichondrium changes it to periosteum

becomes vascularized. Chondrogenic cells become osteoprogenitor cells
Osteoblasts secrete matrix, forming The subperiosteal bone collar is formed of primary bone
subperiosteal bone collar. (intramembranous bone formation)
Chondrocytes within the diaphysis core Presence of periosteum and bone prevents diffusion of nutrients to
hypertrophy, die, and degenerate. chondrocytes; their degeneration leaves lacunae, opening large
spaces in septa of cartilage
Osteoclasts etch holes in subperiosteal bone Holes permit osteoprogenitor cells and capillaries to invade cartilage
collar, permitting entrance of osteogenic bud model, now calcified, and begin elaborating bone matrix
Calcified cartilage/calcified bone complex is Bone matrix laid down on septa of calcified cartilage forms this
formed. complex (histologically, calcified cartilage stains blue, calcified
bone stains red)
Osteoclasts begin resorbing the calcified Destruction of the calcified cartilage/calcified bone complex enlarges
cartilage/calcified bone complex. the marrow cavity
Subperiosteal bone collar thickens, begins This event, over a period of time, completely replaces diaphyseal
growing toward the epiphyses. cartilage with bone
Secondary Center of Ossification
Ossification begins at epiphysis. Process begins in same way as at primary center, except that there
is no bone collar; osteoblasts lay down bone matrix on calcified
cartilage scaffold
Growth of bone occurs at epiphyseal plate. Cartilaginous articular surface of bone remains; epiphyseal plate
persists—growth added at epiphyseal end of plate. Bone is added
at diaphyseal end of plate
Epiphysis and diaphysis become continuous. At the end of bone growth, cartilage of epiphyseal plate ceases
proliferation; bone development continues to unite the diaphysis
and epiphysis
EVENTS OCCURRING AT THE the chondrocytes results in enlargement of their

PRIMARY CENTER OF OSSIFICATION lacunae and reduction in the intervening cartilage
matrix septae, which become calcified.
1 In the region where bone is to grow within the 2 Concurrently, the perichondrium at the midriff of
embryo, a hyaline cartilage model of that bone the diaphysis of cartilage becomes vascularized
develops. This event begins in exactly the same way (Fig. 7-17). When this happens, chondrogenic cells
that hyaline cartilage at any location would develop become osteoprogenitor cells forming osteoblasts, and
(discussed earlier). For a period this model grows the overlying perichondrium becomes a periosteum.
both appositionally and interstitially. Eventually, the 3 The newly formed osteoblasts secrete bone
chondrocytes in the center of the cartilage model matrix, forming the subperiosteal bone collar on
hypertrophy, accumulate glycogen in their cytoplasm, the surface of the cartilage template by intramem-
and become vacuolated (Fig. 7-16). Hypertrophy of branous bone formation (see Fig. 7-17).
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graph of hypertrophic chondrocytes
in the growing mandibular condyle
(×83,000). Observe the abundant
rough endoplasmic reticulum and
developing Golgi apparatus (G).
Note also glycogen (gly) deposits in
one end of the cells, a characteristic
of these cells shortly before death.
Col, collagen fibers; Fw, territorial
matrix. (From Marchi F, Luder HU,
Leblond CP: Changes in cells’ secre-
tory organelles and extracellular
matrix during endochondral ossifica-
tion in the mandibular condyle of the
growing rat. Am J Anat 190:41-73,
1991.)
4 The bone collar prevents the diffusion of nutrients to toward the epiphyses, osteoclasts begin resorbing the
the hypertrophied chondrocytes within the core of calcified cartilage/calcified bone complex, enlarging
the cartilage model, causing them to die. This process the marrow cavity. As this process continues, the car-
is responsible for the presence of empty, confluent tilage of the diaphysis is replaced by bone except for
lacunae forming large concavities—the future the epiphyseal plates, which are responsible for the
marrow cavity in the center of the cartilage model. continued growth of the bone for 18 to 20 years.
5 Holes etched in the bone collar by osteoclasts permit
a periosteal bud (osteogenic bud), composed of
EVENTS OCCURRING AT
osteoprogenitor cells, hemopoietic cells, and blood
SECONDARY CENTERS
vessels, to enter the concavities within the cartilage
OF OSSIFICATION
model (see Fig. 7-15).
6 Osteoprogenitor cells divide to form osteoblasts. Secondary centers of ossification begin to form at the
These newly formed cells elaborate bone matrix on epiphysis at each end of the forming bone by a process
the surface of the calcified cartilage. The bone matrix similar to that in the diaphysis, except that a bone
becomes calcified to form a calcified cartilage/cal- collar is not formed. Rather, osteoprogenitor cells
cified bone complex. This complex can be appre- invade the cartilage of the epiphysis, differentiate into
ciated in routinely stained histological sections osteoblasts, and begin secreting matrix on the cartilage
because calcified cartilage stains basophilic, whereas scaffold (see Fig. 7-15). These events take place and
calcified bone stains acidophilic (Figs. 7-18 and 7-19). progress much as they do in the diaphysis, and eventu-
7 As the subperiosteal bone becomes thicker and grows ally the cartilage of the epiphysis is replaced with bone
in each direction from the midriff of the diaphysis except at the articular surface and at the epiphyseal
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MC
Tr
BV
Figure 7–18 Light micrograph of endochondral bone formation

b (×132). Observe the blood vessel (BV), bone-covered trabeculae (Tr)
of calcified cartilage, and medullary cavity (MC).
Ob
Figure 7–17 Light micrograph of endochondral bone formation
(×14). The upper half demonstrates cartilage (C) containing chon-
drocytes that mature, hypertrophy, and calcify at the interface; the
lower half shows where calcified cartilage/bone complex (arrows) is
being resorbed and bone (b) is being formed. P, periosteum. CC
plate. The articular surface of the bone remains carti-

laginous throughout life. The process at the epiphyseal
plate, which controls bone length, is described in the
next section.
These events are a dynamic continuum that is com- Figure 7–19 Higher magnification of endochondral bone for-
pleted over a number of years as bone growth and mation (×270). The trabeculae of calcified cartilage (CC) are covered
development progress toward the growing epiphyses at by a thin layer of bone (darker red) with osteocytes embedded in it
each end of the bone (see Table 7-3). At the same time, (arrows) and with osteoblasts (Ob) lying next to the bone.
the bone is constantly being remodeled to meet the
changing forces placed on it.
side of the plate. Histologically, the epiphyseal plate is
BONE GROWTH IN LENGTH divided into five recognizable zones. These zones,
beginning at the epiphyseal side, are as follows:
The continued lengthening of bone depends on the
epiphyseal plate. 䡲 Zone of reserve cartilage: Chondrocytes randomly
distributed throughout the matrix are mitotically
The chondrocytes of the epiphyseal plate proliferate active.
and participate in the process of endochondral bone for- 䡲 Zone of proliferation: Chondrocytes, rapidly pro-
mation. Proliferation occurs at the epiphyseal aspect, liferating, form rows of isogenous cells that parallel
and replacement by bone takes place at the diaphyseal the direction of bone growth.
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䡲 Zone of maturation and hypertrophy: Chondro- Exactly how calcification occurs is unclear, although
cytes mature, hypertrophy, and accumulate glycogen it is known to be stimulated by certain proteoglycans
in their cytoplasm (see Fig. 7-16). The matrix and the Ca2+-binding glycoprotein osteonectin as
between their lacunae narrows with a corresponding well as bone sialoprotein. One theory, called het-
growth of lacunae. erogeneous nucleation, is that collagen fibers in
䡲 Zone of calcification: Lacunae become confluent, the matrix are nucleation sites for the metastable
hypertrophied chondrocytes die, and cartilage matrix calcium and phosphate solution and that the solution
becomes calcified. begins to crystallize into the gap region of the colla-
䡲 Zone of ossification: Osteoprogenitor cells invade gen. Once this region has “nucleated,” calcification
the area and differentiate into osteoblasts, which proceeds.
elaborate matrix that becomes calcified on the surface The most commonly accepted theory of calcification
of calcified cartilage. This is followed by resorption of is based on the presence of matrix vesicles within the
the calcified cartilage/calcified bone complex. osteoid. Osteoblasts release these small, membrane-
bounded matrix vesicles, 100 to 200 nm in diameter,
As long as the rate of mitotic activity in the zone of
which contain a high concentration of Ca2+ and PO43−
proliferation equals the rate of resorption in the zone ions, cAMP, adenosine triphosphate (ATP), adenosine
of ossification, the epiphyseal plate remains the same triphosphatase (ATPase), alkaline phosphatase,
width and the bone continues to grow longer. At about pyrophosphatase, calcium-binding proteins, and phos-
the 20th year of age, the rate of mitosis decreases in the phoserine. The matrix vesicle membrane possesses
zone of proliferation and the zone of ossification over- numerous calcium pumps, which transport Ca2+ ions
takes the zones of proliferation and cartilage reserve.
into the vesicle. As the concentration of calcium Ca2+
The cartilage of the epiphyseal plate is replaced by
ions within the vesicle increases, crystallization occurs
a plate of calcified cartilage/calcified bone complex,
and the growing calcium hydroxyapatite crystal pierces
which is resorbed by osteoclastic activity, and the
the membrane, bursting the matrix vesicle and releas-
marrow cavity of the diaphysis becomes confluent with
ing its contents.
the bone marrow cavity of the epiphysis. Once the epi-
Alkaline phosphatase cleaves pyrophosphate groups
physeal plate is resorbed, growth in length is no longer
from the macromolecules of the matrix. The liberated
possible.
pyrophosphate molecules are inhibitors of calcification,
but they are cleaved by the enzyme pyrophosphatase
BONE GROWTH IN WIDTH into PO43− ions, increasing the concentration of this ion
in the microenvironment.
Bone growth in width takes place by appositional
The calcium hydroxyapatite crystals released from
growth.
the matrix vesicles act as nidi of crystallization. The
The events just described detail how bone lengthening high concentration of ions in their vicinity, along with
is accomplished by the proliferation and interstitial the presence of calcification factors and calcium-
growth of cartilage, which is eventually replaced by binding proteins, fosters the calcification of the matrix.
bone. Growth of the diaphysis in girth, however, takes As crystals are deposited into the gap regions on the
place by appositional growth. The osteoprogenitor surface of collagen molecules, water is resorbed from
cells of the osteogenic layer of the periosteum prolif- the matrix.
erate and differentiate into osteoblasts that begin elab- Mineralization occurs around numerous closely
orating bone matrix on the subperiosteal bone surface. spaced nidi of crystallization; as it progresses, these
This process occurs continuously throughout the total centers enlarge and fuse with each other. In this fashion,
period of bone growth and development, so that in a an increasingly large region of the matrix is dehydrated
mature long bone the shaft is built via subperiosteal and calcified.
intramembranous bone formation.
During bone growth and development, bone resorp-
tion is as important as bone deposition. Formation of Bone Remodeling
bone on the outside of the shaft must be accompanied
by osteoclastic activity internally so that the marrow In the adult, bone development is balanced with bone
space can be enlarged. resorption as bone is remodeled to meet stresses placed
on it.
Calcification of Bone In a young person, bone development exceeds bone

resorption because new haversian systems are being
Calcification begins when there are deposits of calcium
developed much faster than old ones are being
phosphate on the collagen fibril.
resorbed. Later, in adulthood, when the epiphyseal
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plates close and bone growth has been attained, new Bone Repair
bone development is balanced with bone resorption.
Growing bones largely retain their general architec- Bone repair involves both intramembranous and
tural shape from the beginning of bone development in endochondral bone formation.
the fetus to the end of bone growth in the adult. This
is accomplished by surface remodeling, a process A bone fracture causes damage and destruction to the
involving bone deposition under certain regions of the bone matrix, death to cells, tears in the periosteum and
periosteum with concomitant bone resorption under endosteum, and possible displacement of the ends of
other regions of the periosteum. Similarly, bone is being the broken bone (fragments). Blood vessels are severed
deposited in certain regions of the endosteal surface, near the break, and localized hemorrhaging fills in the
whereas it is being resorbed in other regions. The bones zone of the break, resulting in blood clot formation at
of the calvarium are being reshaped in a similar way to the site of injury. Soon the blood supply is shut down in
accommodate the growing brain; however, how this a retrograde fashion from the injury site back to regions
process is regulated is unclear. of anastomosing vessels, which can establish a new cir-
Cortical bone and cancellous bone, however, are not culation route. As a consequence there is a widening
remodeled in the same fashion, probably because zone of injury, on either side of the original break,
osteoblasts and osteoprogenitor cells of cancellous bone resulting in a lack of a blood supply to many haversian
are located within the confines of bone marrow and, systems, thus causing the zone of dead and dying osteo-
therefore, they are under the direct, paracrine influence cytes to increase appreciably. Because bone marrow and
of nearby bone marrow cells. The factors produced by the periosteum are highly vascularized, the initial injury
these bone marrow cells include interleukin-1 (IL-1), site in either of these two areas does not grow signifi-
tumor necrosis factor, colony-stimulating factor-1, cantly, nor is there a notable increase in dead and dying
osteoprotegrin (OPG), osteoprotegrin ligand (OPGL), cells much beyond the original injury site. Whenever
and transforming growth factor-β. The osteoprogenitor the bone’s haversian systems are without a blood supply,
cells and osteoblasts of compact bone are located in the osteocytes become pyknotic and undergo lysis, leaving
cellular layer of the periosteum and in the lining of empty lacunae.
haversian canals and thus are too far from the cells of The blood clot filling the site of the fracture is
bone marrow to be under their paracrine influence. invaded by small capillaries and fibroblasts from the
Instead, these cells of compact bone respond to sys- surrounding connective tissue, forming granulation
temic factors, such as calcitonin and parathyroid tissue. A similar event occurs in the marrow cavities as
hormone. a clot forms; the clot is soon invaded by osteoprogeni-
The internal structure of adult bone is continually tor cells of the endosteum and multipotential cells of
being remodeled as new bone is formed and dead and the bone marrow, forming an internal callus of bony
dying bone is resorbed; for example, trabeculae within a week or so (Fig. 7-20). Within
䡲 Haversian systems are continually being replaced. 48 hours after injury, osteoprogenitor cells build up
䡲 Bone must be resorbed from one area and added to because of increased mitotic activity of the osteogenic
another to meet changing stresses placed on it (e.g., layer of the periosteum and the endosteum and from
weight, posture, fractures). undifferentiated cells of the bone marrow. The deepest
layer of proliferating osteoprogenitor cells of the perios-
As haversian systems are resorbed, their osteocytes teum (those closest to the bone), which are in the vicin-
die; in addition, osteoclasts are recruited to the area to ity of capillaries, differentiate into osteoblasts and begin
resorb the bone matrix, forming absorption cavities. elaborating a collar of bone, cementing it to the dead
Continual osteoclastic activity increases the diameter bone about the injury site.
and length of these cavities, which are invaded by blood Although the capillaries are growing, their rate of
vessels. At this point, bone resorption ceases and proliferation is much slower than that of the osteo-
osteoblasts deposit new concentric lamellae around the progenitor cells; thus the osteoprogenitor cells in the
blood vessels, forming new haversian systems. Although middle of the proliferating mass are now without a
primary bone is remodeled in this fashion, which profuse capillary bed. This results in lowered oxygen
strengthens the bone by ordered collagen alignment tension, and these cells become chondrogenic cells,
about the haversian system, remodeling continues giving rise to chondroblasts that form cartilage in the
throughout life as resorption is replaced by deposition outer parts of the collar.
and the formation of new haversian systems. This The outermost layer of the proliferating osteoprog-
process of bone resorption, followed by bone replace- enitor cells (those adjacent to the fibrous layer of the
ment, is known as coupling. The interstitial lamellae periosteum), having some capillaries in their midst, con-
observed in adult bone are remnants of remodeled tinue to proliferate as osteoprogenitor cells. Thus, the
haversian systems. collar exhibits three zones that blend together: (1) a
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Periosteum Periosteum proliferation Bone The cartilage matrix adjacent to the new bone
formed in the deepest region of the collar becomes cal-
cified and is eventually replaced with cancellous bone.
Ultimately, all of the cartilage is replaced with primary
bone by endochondral bone formation.
Once the fragments of bone are united by bridging
with cancellous bone, it is necessary to remodel the
injury site by replacing the primary bone with second-
ary bone and resolving the callus.
A Endosteum
The first bone elaborated against injured bone devel-
ops by intramembranous bone formation, and the new
Hyaline cartilage trabeculae become firmly cemented to the injured or
dead bone. Matrices of dead bone, located in the empty
spaces between newly developing bony trabeculae, are
resorbed, and the spaces are filled in by new bone.
Eventually, all of the dead bone is resorbed and
replaced by new bone formed by the osteoblasts that
invade the region. These events are concurrent, result-
ing in repair of the fracture with cancellous bone sur-
rounded by a bony callus.
B Through the events of remodeling, the primary bone
Newly formed of intramembranous bone formation is replaced with
primary bone Callus
secondary bone, further reinforcing the mended frac-
ture zone; at the same time, the callus is resorbed. It
appears that the healing and remodeling processes at
the fracture site are in direct response to the stresses
placed on it; eventually, the repaired zone is restored to
its original shape and strength. It is interesting that bone
repair involves cartilage formation and both intramem-
branous and endochondral bone formation.
Newly formed
C secondary bone
Healed fracture CLINICAL CORRELATIONS

If segments of bone are lost or damaged so
severely that they have to be removed, a “bony
union” is not possible; that is, the process of
bone repair cannot occur because a bony callus
does not form. In cases of this sort, a bone graft
is required. Since the 1970s, bone banks have
D become available to supply viable bone for graft-
ing purposes. The bone fragments are harvested
Figure 7–20 Events in bone fracture repair. and frozen to preserve their osteogenic potential
and are then utilized as transplants by orthope-
dic surgeons. Autografts are the most success-
ful because the transplant recipient is also the
layer of new bone cemented to the bone of the frag- donor. Homografts are from different individu-
ment, (2) an intermediate layer of cartilage, and (3) a als of the same species and may be rejected
proliferating osteogenic surface layer. In the meantime, because of immunological response. Hetero-
the collars formed on the ends of each fragment fuse grafts, grafts from different species, are least
into one collar, known as the external callus, leading successful, although it has been shown that calf
to union of the fragments. Continued growth of the bone loses some of its antigenicity after being
external collar is derived mainly from proliferation of refrigerated, making it a worthy bone graft when
osteoprogenitor cells and, to some degree, from inter- necessary.
stitial growth of the cartilage in its intermediate zone.
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Histophysiology of Bone The growth hormone somatotropin, secreted by

cells in the anterior lobe of the pituitary gland, influ-
Bone supports soft tissues of the body and protects the ences bone development via somatomedins (insulin-like
central nervous system and hemopoietic tissue. It also growth factors), especially stimulating growth of the
is the site for attachment of the tendons of muscle that epiphyseal plates. Children deficient in this hormone
use the bone as levers to increase the mechanical advan- exhibit dwarfism, whereas persons with an excess of
tage needed for locomotion. Just as important, bone somatotropin in their growing years display pituitary
serves as a reservoir of calcium and phosphate for main- gigantism.
taining adequate levels of these elements in the blood Many additional factors are involved in bone metab-
and other tissues of the body. olism, only a few of which are indicated in the follow-
ing list. Moreover, many of these factors are released by
Maintenance of Blood Calcium Levels a variety of cells and have numerous target cells;
however, only their bone-related functions are listed:
Calcium is vital for the activity of many enzymes and
also functions in membrane permeability, cell adhe- 䡲 Interleukin-1, released by osteoblasts, activates
sion, blood coagulation, nerve impulse transmission, osteoclast precursors to proliferate; it also has an indi-
muscle contraction, among other bodily processes. To rect role in osteoclast stimulation.
fulfill all of the necessary functional requirements 䡲 Tumor necrosis factor, released by activated
for which calcium is responsible, a tightly controlled macrophages, acts in a fashion similar to interleukin-
blood plasma concentration of 9 to 11 mg/dL must be 1.
maintained. 䡲 Colony-stimulating factor-1, released by bone
Because 99% of the calcium in the body is stored in marrow stromal cells, induces osteoclast formation.
bone as hydroxyapatite crystals, the remaining 1% must 䡲 OPG inhibits osteoclast differentiation.
be available for mobilization from the bone on short 䡲 Interleukin-6, released by various bone cells, espe-
notice. Indeed, there is a constant turnover between the cially by osteoclasts, stimulates the formation of other
calcium ions in bone and in blood. The calcium ions osteoclasts.
retrieved from bone to maintain blood calcium levels 䡲 Interferon-g, released by T lymphocytes, inhibits
come from new and young osteons, where mineraliza- differentiation of osteoclast precursors into osteo-
tion is incomplete. Because bone remodeling is con- clasts.
stant, new osteons are always forming where labile 䡲 Transforming growth factor-b, liberated from
calcium ions are available for this purpose. It seems that bone matrix during osteoclasia, induces osteoblasts to
older osteons are more heavily mineralized; because of manufacture bone matrix and enhances the process
this, their calcium ions are less available. of matrix mineralization; also, it inhibits proliferation
of osteoclast precursors and their differentiation into
mature osteoclasts.
Hormonal Effects
Osteoclastic activity is necessary for maintaining a con-
stant supply of calcium ions for the body. Parenchymal CLINICAL CORRELATIONS
cells of the parathyroid gland are sensitive to the blood
calcium level; when calcium levels fall below normal, Acromegaly occurs in adults who produce an
parathyroid hormone (PTH) is secreted. As discussed excess of somatotropin, causing an abnormal
earlier, this hormone activates receptors on osteoblasts, increase in bone deposition without normal bone
suppressing matrix formation and initiating manufac- resorption. This condition creates thickening of
ture and secretion of OPGL and osteoclast-stimulat- the bones, especially those of the face, in addi-
ing factor by the osteoblasts. These factors induce tion to disfiguring soft tissue.
osteoclast formation and stimulate quiescent osteoclasts
to become active, leading to bone resorption and the
release of calcium ions. Skeletal maturation is also influenced by hormones
Parafollicular cells (C cells) of the thyroid gland produced in the male and female gonads. Closure of the
also monitor calcium ion levels in the plasma. When epiphyseal plates is normally rather stable and constant
calcium ion levels become elevated, these cells secrete and is related to sexual maturation. Precocious sexual
calcitonin, a polypeptide hormone that activates re- maturation stunts skeletal development because the
ceptors on osteoclasts, inhibiting them from resorb- epiphyseal plates are stimulated to close too early. In
ing bone. Additionally, osteoblasts are stimulated to other people whose sexual maturation is retarded,
increase osteoid synthesis and calcium deposition is skeletal growth continues beyond normal limits because
increased. the epiphyseal plates do not close.
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protein, minerals, and vitamins is sufficient, the amino

CLINICAL CORRELATIONS acids essential for collagen synthesis by osteoblasts are
lacking and collagen formation is reduced. Insufficient
Osteoporosis affects about 10 million chroni- intake of calcium or phosphorus leads to poorly calcified
cally immobilized Americans. It often affects bone, which is subject to fracture. A deficiency of vitamin
women older than 40 years of age, especially post- D prevents calcium absorption from the intestines,
menopausal women. Osteoporosis is related to causing rickets in children. Vitamins A and C are also
decreasing bone mass, which becomes more necessary for proper skeletal development (Table 7-4).
serious after menopause, when estrogen secre-
tion drops appreciably. Binding of estrogen to
specific receptors on osteoblasts activates the cells
to manufacture and secrete bone matrix. With CLINICAL CORRELATIONS
diminished secretion of estrogen, osteoclastic
activity is greater than bone deposition, poten- Rickets is a disease in infants and children who
tially reducing bone mass to the point at which the are deficient in vitamin D. Without vitamin D,
bone cannot withstand stresses and breaks easily. the intestinal mucosa cannot absorb calcium even
For decades estrogen replacement therapy though there may be adequate dietary intake.
coupled with calcium supplements and pain- This results in disturbances in ossification of the
killers were used to alleviate or eliminate this epiphyseal cartilages and disorientation of the
condition. However, in 2004 it was determined cells at the metaphysis, giving rise to poorly calci-
that estrogen replacement therapy increases the fied bone matrix. Children with rickets display
risk for heart disease, stroke, breast cancer, and deformed bones, particularly in the legs, simply
blood clots. A newly developed group of drugs because the bones cannot bear their weight.
called the bisphosphonates reduces the inci- Osteomalacia, or adult rickets, results from
dence of osteoporosis fractures without the risks prolonged deficiency of vitamin D. When this
of estrogen replacement therapy. An early diag- occurs, the newly formed bone in the process of
nostic tool, dual-energy x-ray absorptiometry remodeling does not calcify properly. This con-
(DEXA), is being employed as a reliable method dition may become severe during pregnancy
for assessing increasing bone density even in because the fetus requires calcium, which must
individuals with osteoporosis. be supplied by the mother.
Scurvy is a condition resulting from a defi-
ciency of vitamin C. One effect is deficient
collagen production, causing a reduction in for-
Nutritional Effects mation of bone matrix and bone development.
Normal bone growth is sensitive and dependent on Healing is also delayed.
several nutritional factors. Unless a person’s intake of
TABLE 7–4 Vitamins Affecting Skeletal Development
Deficiency/Excess Effect
Vitamin A deficiency Inhibits proper bone formation as coordination of osteoblast and osteoclast activities fails;
failure of resorption and remodeling of cranial vault to accommodate the brain results in
serious damage to the central nervous system
Hypervitaminosis A Erosion of cartilage columns without increases of cells in proliferation zone; epiphyseal plates
may become obliterated, ceasing growth prematurely
Vitamin C deficiency Mesenchymal tissue is affected because connective tissue is unable to produce and maintain
extracellular matrix; deficient production of collagen and bone matrix results in retarded
growth and delayed healing (scurvy)
Vitamin D deficiency Ossification of epiphyseal cartilages is disturbed; cells become disordered at metaphysis,
leading to poorly calcified bones, which become deformed by weight bearing (in children,
termed rickets; in adults, osteomalacia)
Ch007-X2945.qxd 12/8/06 3:27 PM Page 156
Joints
Bones articulate or come into close proximity with one
Periosteum
another at joints, which are classified according to the
degree of movement available between the bones of the
joint. Those that are closely bound together with only Fibrous layer
of capsule
a minimum of movement between them are called
synarthroses; joints in which the bones are free to
articulate over a fairly wide range of motion are classi- Synovial
membrane
fied as diarthroses.
There are three types of synarthrosis joints accord-
ing to the tissue making up the union: Articular
cavity
1 Synostosis. There is little if any movement, and
joint-uniting tissue is bone (e.g., skull bones in
adults). Articular
2 Synchondrosis. There is little movement, and joint- cartilage
uniting tissue is hyaline cartilage (e.g., joint of first
rib and sternum). Spongy bone
3 Syndesmosis. There is little movement, and bones
are joined by dense connective tissue (e.g., pubic
Compact bone
symphysis).
Most of the joints of the extremities are diarthroses Marrow cavity
(Fig. 7-21). The bones making up these joints are
covered by persistent hyaline cartilage, or articular
cartilage. Usually, ligaments maintain the contact
between the bones of the joint, which is sealed by the Figure 7–21 Anatomy of a diarthrodial joint.
joint capsule. The capsule is composed of an outer
fibrous layer of dense connective tissue, which is
continuous with the periosteum of the bones, and an 2 Type B cells resemble fibroblasts, exhibiting a well-
inner cellular synovial layer, which covers all non- developed RER; these cells are thought to secrete
articular surfaces. Some prefer to call this a synovial the synovial fluid.
membrane.
Synovial fluid contains a high concentration of
Two kinds of cells are located in the synovial
hyaluronic acid and the glycoprotein lubricin com-
layer:
bined with filtrate of plasma. In addition to supplying
1 Type A cells are macrophages displaying a well- nutrients and oxygen to the chondrocytes of the articu-
developed Golgi apparatus and many lysosomes but lar cartilage, this fluid has a high content of hyaluronic
only a small amount of RER. These phagocytic cells acid and lubricin that permits it to function as a lubri-
are responsible for removing debris from the joint cant for the joint. Moreover, macrophages in the syn-
space. ovial fluid act to phagocytose debris in the joint space.
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8 䡲䡲䡲
Muscle
Although many cells of multicellular organisms have During embryonic development, several hundred
limited contractile abilities, it is the capability of muscle myoblasts, precursors of skeletal muscle fibers, line
cells, which are specialized for contraction, that permits up end to end, fusing with one another to form
animals to move. Organisms harness the contraction of long multinucleated cells known as myotubes. These
muscle cells and the arrangement of the extracellular newly formed myotubes manufacture cytoplasmic con-
components of muscle to permit locomotion, constric- stituents as well as contractile elements, called myofi-
tion, pumping, and other propulsive movements. brils. Myofibrils are composed of specific arrays of
Cells of muscle are elongated and are called either myofilaments, the proteins responsible for the con-
striated muscle cells or smooth muscle cells, depending tractile capability of the cell.
on the respective presence or absence of a regularly Muscle fibers are arranged parallel to one another,
repeated arrangement of myofibrillar contractile pro- with their intervening intercellular spaces housing
teins, the myofilaments. Striated muscle cells display parallel arrays of continuous capillaries. Each skele-
characteristic alternations of light and dark cross-bands, tal muscle fiber is long, cylindrical, multinucleated,
which are absent in smooth muscle (Fig. 8-1). There are and striated. The diameters of the fibers vary, ranging
two types of striated muscle: skeletal, accounting for from 10 to 100 µm, although hypertrophied fibers
most of the voluntary muscle mass of the body, and invol- may exceed the latter figure. The relative strength
untary cardiac, limited almost exclusively to the heart. of a muscle fiber directly depends on its diameter,
Smooth muscle cells are located in the walls of blood whereas the strength of the entire muscle is a function
vessels and the viscera as well as in the dermis of the skin. of the number and thickness of its component
Unique terms are often used to describe the compo- fibers.
nents of muscle cells. Thus, muscle cell membrane is Skeletal muscle is pink to red because of its rich vas-
referred to as sarcolemma; the cytoplasm, as sarco- cular supply as well as the presence of myoglobin pig-
plasm; the smooth endoplasmic reticulum, as sarco- ments, oxygen-transporting proteins that resemble, but
plasmic reticulum; and occasionally, the mitochondria, are smaller than, hemoglobin. Depending on the fiber
as sarcosomes. Because they are much longer than they diameter, quantity of myoglobin, number of mitochon-
are wide, muscle cells frequently are called muscle fibers; dria, extensiveness of the sarcoplasmic reticulum, con-
unlike collagen fibers, however, they are living entities. centration of various enzymes, and rate of contraction,
All three muscle types are derived from mesoderm. the muscle fiber may be classified as red, white, or
Cardiac muscle originates in splanchnopleuric meso- intermediate (Table 8-1).
derm, most smooth muscle is derived from splanchnic Usually, a gross anatomical muscle (e.g., biceps) con-
and somatic mesoderm, and most skeletal muscles tains all three types of muscle fibers (red, white, and
originate from somatic mesoderm. intermediate) in relatively constant proportions that are
characteristic of that particular muscle. In chickens, for
SKELETAL MUSCLE instance, thigh muscle fibers are predominantly red,
and breast muscle fibers are predominantly white. The
innervation of the muscle fiber appears to be the factor
Skeletal muscle is composed of long, cylindrical,
that determines fiber type. If the innervation is experi-
multinucleated cells that undergo voluntary contraction
mentally switched, the fiber accommodates itself to the
to facilitate movement of the body or its parts.
new nerve supply.
157
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158 䡲䡲䡲 Chapter 8 䡲 Muscle
TABLE 8–1 Comparison of Types of Skeletal Muscle Fibers*
Characteristics Red Muscle Fibers White Muscle Fibers
Vascularization Rich vascular supply Poorer vascular supply
Innervation Smaller nerve fibers Larger nerve fibers
Fiber diameter Smaller Larger
Contraction Slow but repetitive; not easily Fast but easily fatigued; stronger
fatigued; weaker contraction contraction
Sarcoplasmic reticulum Not extensive Extensive
Mitochondria Numerous Few
Myoglobin Rich Poor
Enzymes Rich in oxidative enzymes; poor Poor in oxidative enzymes; rich in

in adenosine triphosphatase phosphorylases and adenosine
triphosphatase
*Intermediate muscle fibers have characteristics between those of red and white fibers.
Investments
The investments of skeletal muscle are the epimysium,
perimysium, and endomysium.
The entire muscle is surrounded by epimysium, a

dense irregular collagenous connective tissue. Peri-
Z
mysium, a less dense collagenous connective tissue
A
derived from epimysium, surrounds bundles (fascicles)
of muscle fibers. Endomysium, composed of reticular
fibers and an external lamina (basal lamina), sur-
rounds each muscle cell (Fig. 8-2).
Because these connective tissue elements are inter-
connected, contractile forces exerted by individual
muscle cells are transferred to them. Tendons and
aponeuroses, which connect muscle to bone and to
other tissues, are continuous with the connective tissue
encasements of muscle and, therefore, act in harness-
ing the contractile forces for motion.
N Light Microscopy
Light microscopy of skeletal muscle fibers displays long,
cylindrical, multinucleated cells whose nuclei are
Figure 8–1 Light micrograph of a longitudinal section of skele- peripherally located.
tal muscle (×540). Note the peripherally located nuclei (N) as well as
the very fine connective tissue elements between individual muscle Skeletal muscle fibers are multinucleated cells, with
fibers. A, band; Z, disk. their numerous nuclei peripherally located just beneath
the cell membrane (Fig. 8-3). Each cell is surrounded
by endomysium, whose fine reticular fibers intermingle
with those of neighboring muscle cells. Small satellite
cells, which have a single nucleus and act as regenera-
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Chapter 8 䡲 Muscle ■ ■ ■ 159
Epimysium Perimysium Endomysium
Total muscle Fascicle

Endomysium Sarcolemma
Sarcoplasm
SKELETAL MUSCLE
Nucleus
Fiber
SMOOTH MUSCLE
Nucleus in central
sarcoplasm
Intercalated disk
Endomysium
Myofibril
CARDIAC MUSCLE
Nucleus
Sarcoplasm
Endomysium
Figure 8–2 Three types of muscle. Top, Skeletal muscle; center, smooth muscle; bottom, cardiac muscle.
Ch008-X2945.qxd 15/8/06 2:45 PM Page 160
During muscle contraction, the various transverse

bands behave characteristically. The I band becomes
narrower, the H band is extinguished, and the Z disks
move closer together (approaching the interface
C between the A and I bands), but the width of the A
bands remains unaltered.
N
Fine Structure of Skeletal
Muscle Fibers
Electron microscopy has helped reveal the functional
and morphological significance of skeletal muscle cross-
striations and other structural components.
T Tubules and Sarcoplasmic Reticulum

P T tubules and sarcoplasmic reticulum are essential
components involved in skeletal muscle contraction.
The fine structure of the sarcolemma is similar to that

of other cell membranes. A distinguishing feature of this
membrane, however, is that it is continued within the
E skeletal muscle fiber as numerous T tubules (trans-
verse tubules), long, tubular invaginations that inter-
twine among the myofibrils (see Fig. 8-5).
In mammalian skeletal muscle, T tubules pass
transversely across the fiber and lie specifically in the
Figure 8–3 Light micrograph of a cross section of skeletal
muscle (×540). Note the peripheral location of the nuclei (N) as well plane of the junction of the A and I bands. These
as the capillary (C) located in the slender connective tissue elements tubules branch and anastomose but usually remain
of the endomysium (E). Also observe the perimysium (P) that in a single plane; hence, each sarcomere possesses
envelops bundles of muscle fibers. two sets of T tubules, one at each interface of the A
and I bands. Thus, T tubules extend deep into the
interior of the fiber and facilitate the conduction of
tive cells, are located in shallow depressions on the waves of depolarization along the sarcolemma (Figs.
muscle cell’s surface, sharing the muscle fiber’s external 8-6 and 8-7).
lamina. The chromatin network of the satellite cell Associated with this system of T tubules is the sar-
nucleus is denser and coarser than that of the muscle coplasmic reticulum, which is maintained in close
fiber. register with the A and I bands as well as with the
Much of the skeletal muscle cell is composed of T tubules. The sarcoplasmic reticulum, which stores
longitudinal arrays of cylindrical myofibrils, each 1 to intracellular calcium, forms a meshwork around each
2 µm in diameter (Fig. 8-4). They extend the entire myofibril and displays dilated terminal cisternae at
length of the cell and are aligned precisely with their each A–I junction. Thus, two of these cisternae are
neighbors. This strictly ordered parallel arrangement of always in close apposition to a T tubule, forming a
the myofibrils is responsible for the cross-striations of triad in which a T tubule is flanked by two terminal
light and dark banding that are characteristic of skele- cisternae. This arrangement permits a wave of depolar-
tal muscle viewed in longitudinal section (see Fig. 8-1). ization to spread, almost instantaneously, from the
The dark bands are known as A bands (anisotropic surface of the sarcolemma throughout the cell, reach-
with polarized light) and the light bands as I bands ing the terminal cisternae, which have voltage-gated
(isotropic with polarized light). The center of each A calcium release channels (junctional feet) in their
band is occupied by a pale area, the H band, which is membrane.
bisected by a thin M line. Each I band is bisected by a The sarcoplasmic reticulum regulates muscle con-
thin dark line, the Z disk (Z line). The region of the traction through controlled sequestering (leading to
myofibril between two successive Z disks, known as a relaxation) and release (leading to contraction) of
sarcomere, is 2.5 µm in length and is considered the calcium ions (Ca2+) within the sarcoplasm. The trigger
contractile unit of skeletal muscle fibers (Fig. 8-5; also for the calcium ion release is the wave of depolarization
see Fig. 8-4). transmitted by T tubules, which causes opening of the
Ch008-X2945.qxd 15/8/06 2:45 PM Page 161
Bundle of
muscle fibers
One muscle fiber
I band
Z disk
H band
A band
One myofibril
Sarcomere
Figure 8–4 Organization of myofibrils and sarcomeres within a skeletal muscle cell. Note that the entire gross muscle is surrounded by a
thick connective tissue investment, known as the epimysium, which provides finer connective tissue elements (the perimysium) that surround
bundles of skeletal muscle fibers. Individual muscle cells are surrounded by still finer connective tissue elements, the endomysium. Individual
skeletal muscle fibers possess a sarcolemma that has tubular invaginations (T tubules) that course through the sarcoplasm and are flanked by
terminal cisternae of the sarcoplasmic reticulum. The contractile elements of the skeletal muscle fiber are organized into discrete cylindrical
units called myofibrils. Each myofibril is composed of thousands of sarcomeres with their characteristic A, I, and H bands and Z disk.
calcium release channels of the terminal cisternae, numerous mitochondria are located just deep to the
resulting in release of calcium ions into the cytosol in sarcoplasm.
the vicinity of the myofibrils.
Myofibrils are held in register with one another by Structural Organization of Myofibrils
the intermediate filaments desmin and vimentin, which
secure the periphery of the Z disks of neighboring Myofibrils are composed of interdigitating thick and thin
myofibrils to each other. These bundles of myofibrils are myofilaments.
attached to the cytoplasmic aspect of the sarcolemma
by various proteins, including dystrophin, a protein Electron microscopy reveals the same banding as noted
that binds to actin. by light microscopy but also demonstrates the presence
Deep to the sarcolemma and interspersed between of parallel, interdigitating, rod-like thick myofila-
and among myofibrils are numerous elongated mito- ments and thin myofilaments. The thick filaments
chondria with many highly interdigitating cristae. The (15 nm in diameter and 1.5 µm long) are composed of
mitochondria may either parallel the longitudinal axis of myosin II, whereas the thin filaments (7 nm in diam-
the myofibril or wrap around the myofibril. Moreover, eter and 1.0 µm long) are composed primarily of actin.
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Terminal
cisternae of
Nucleus Transverse sarcoplasmic
tubule reticulum Sarcolemma
Myofibril
Mitochondrion
Z line Z line
A band I band
Figure 8–5 Organization of triads and sarcomeres of skeletal muscle. Note that in skeletal muscle the triad is always located at the junc-
tion of the A and I bands, permitting the quick release of calcium ions from the terminal cisternae of the sarcoplasmic reticulum just in the
region where the interaction of the thick and thin filaments can produce efficient sarcomere shortening. Observe the presence of mitochondria
around the periphery of the myofibrils.
Thin filaments originate at the Z disk and project the thick filaments (Huxley’s sliding filament
toward the center of the two adjacent sarcomeres, thus theory). Thus, when contraction occurs, the motion of
pointing in opposite directions. Hence, a single sar- the thin filaments toward the center of the sarcomere
comere has two groups of parallel arrays of thin fila- creates a greater overlap between the two groups
ments, each attached to one Z disk, with all of the of filaments, effectively reducing the widths of the I
filaments in each group pointing toward the middle of and H bands without influencing the width of the
the sarcomere (Fig. 8-8). Thick filaments also form par- A band.
allel arrays, interdigitating with the thin filaments in a The arrangement of the thick and thin filaments
specific fashion. bears a specific and constant relationship. In mam-
In a relaxed skeletal muscle fiber, the thick filaments malian skeletal muscle, each thick filament is sur-
do not extend the entire length of the sarcomere, and rounded equidistantly by six thin filaments. Cross
the thin filaments projecting from the two Z disks of the sections through the region of overlapping thin and
sarcomere do not meet in the midline. Therefore, there thick filaments display a hexagonal pattern, with thin fil-
are regions of each sarcomere, on either side of each Z aments for the apices of each hexagon, the center of
disk, where only thin filaments are present. These adja- which is occupied by a thick filament (Fig. 8-9; also see
cent portions of two successive sarcomeres correspond Fig. 8-8). Thick filaments are separated from each other
to the I band seen by light microscopy; for instance, the by a distance of 40 to 50 nm, whereas the distance
region of each sarcomere that encompasses the entire between thick and thin filaments is only 15 to 20 nm.
length of the thick filaments is the A band, and the zone The structural organization of myofibrils is main-
in the middle of the A band, which is devoid of thin fil- tained largely by five proteins:
aments, is the H band. As noted earlier, the H band is 䡲 Titin
bisected by the M line, which consists of myomesin, C 䡲 α-Actinin
protein, and other as yet poorly characterized proteins
䡲 Cap Z
that interconnect thick filaments to maintain their spe- 䡲 Nebulin
cific lattice arrangement (Table 8-2). 䡲 Tropomodulin
During contraction, individual thick and thin fila-
ments do not shorten; instead, the two Z disks are Thick filaments are positioned precisely within the
brought closer together as the thin filaments slide past sarcomere with the assistance of titin, a large, linear,
Ch008-X2945.qxd 15/8/06 2:45 PM Page 163
Figure 8–6 Electron micrograph of longitudinal

section of rat skeletal muscle (×19,330). (Courtesy of
Dr. J. Strum.)
†
S S

graph of triads and sarcoplasmic
reticulum in skeletal muscle
(×57,847). Evident are a T tubule
(t) and terminal cisternae of the
sarcoplasmic reticulum (S). Note
the cross-section of a T tubule
flanked by terminal cisternae (arrow).
(From Leeson TS, Leeson CR,
Papparo AA. Text/Atlas of Histology.
Ch008-X2945.qxd 15/8/06 2:45 PM Page 164
Sarcomere
A band
H band Tropomodulin
Z disk
M band Nebulin Titin
Figure 8–8 The sarcomere and its components. A, The

Myofilaments myosin molecules are arranged in an antiparallel fashion so that
Tropomyosin their heads are projecting from each end of the thick filament, and
each thick filament is anchored in position by four titin molecules
Tropomodulin that extend from the Z disk to the center of the thick filament at
the M line. Additionally, each thin filament is fixed in place by
Actin nebulin molecules that extend from the Z disk to the distal end of
Troponin the thin filament. B, Cross-sectional profiles of a sarcomere at indi-
cated regions. Each thick filament is surrounded equidistally by six
Myosin II thin filaments, so that there are always two thin filaments between
neighboring thick filaments. C, Myofilaments (thick and thin fila-
C ments). Each thin filament is composed of two chains of F-actins,
where each F-actin is composed of numerous G-actin molecules
assembled head to toe. Each groove of a thin filament is occupied
Myosin II molecule by a linear protein called tropomyosin; these proteins are posi-
tioned in such a fashion that they block the myosin-binding site of
Light chain each G-actin molecule. Additionally the tripartite molecule, tro-
ponin, is associated with each tropomyosin molecule. When the
troponin C moiety of troponin binds calcium, the conformational
change in the troponin molecule pushes the tropomyosin deeper
into the groove, unmasking the myosin-binding site of the G-actin
and permitting muscle contraction to occur. D, Myosin II mole-
S1 S2 Light meromyosin cule. Each myosin II molecule is composed of two light chains and
two heavy chains. The heavy chains can be cleaved by trypsin into
Heavy meromyosin
light and heavy meromyosin, and each heavy meromyosin can be
D cleaved by papain into S1 and S2 fragments.
elastic protein. Two titin molecules extend from each addition, two molecules of nebulin, a long, nonelastic
half of a thick filament to the adjacent Z disk; thus four protein, are wrapped around the entire length of each
titin molecules anchor a thick filament between the two thin filament, further anchoring it in the Z disk and
Z disks of each sarcomere. ensuring the maintenance of the specific array of the
Thin filaments are held in register by the rod-shaped thin filaments. Moreover, nebulin acts as a “ruler,”
protein a-actinin, a component of the Z disk that can ensuring the precise length of the thin filament. It is
bind thin filaments in parallel arrays. The plus end of assisted in this function by the protein tropomodulin,
the thin filament is held in place by a protein known as a cap on the minus end of the thin filament that, simi-
Cap Z that also prevents the addition or subtraction of larly to Cap Z, prevents the addition or the deletion of
G-actin molecules to or from the thin filament, thus G-actin molecules to or from the thin filament (see
assisting in the maintenance of its precise length. In Table 8-2 and Fig. 8-8).
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TABLE 8–2 Proteins Associated with Skeletal Muscle
Molecular Subunits and Their

Protein Weight (kD) Molecular Weight Function
Myosin II 510 2 heavy chains, 222 kD Major protein of thick filament; its interaction with actin
each; 2 pairs of light hydrolyzes ATP and produces contraction
chains, 18 kD and
22 kD
Myomesin 185 None Cross-links thick filaments that are next to each other at
M line
Titin 2500 None Forms an elastic lattice that anchors thick filaments to
Z disks
C protein 140 None Binds to thick filaments at the M line
G actin 42 None Polymerizes to form thin filaments of F-actin; interaction

of G-actin with myosin II assists in hydrolyzing ATP,
resulting in contraction
Tropomyosin 64 2 chains, 32 kD each Occupies grooves of the thin filaments
Troponin 78 TnC, 18 kD Binds calcium

TnT, 30 kD Binds to tropomyosin
TnI, 30 kD Binds to actin, thus inhibiting actinmyosin interaction
α-Actinin 190 2 units, each 95 kD Anchors plus ends of thin filaments to Z disk
Nebulin 600 None Z disk protein that may assist α-actinin to anchor thin
filaments to Z disk
Cap Z Forms part of the Z disk and caps the plus end of the
thick filament
Tropomodulin 43 kD Caps the minus end of the thin filament
ATP, adenosine triphosphate; kD, kilodalton.
THICK FILAMENTS Light meromyosin functions in the proper assembly

of the molecules into the bipolar thick filament. Heavy
Thick filaments are composed of myosin II molecules meromyosin is cleaved by papain into two globular
aligned end to end. (S1) moieties and a short, helical, rod-like segment (S2)
(see Fig. 8-8). The S1 subfragment binds adenosine
Every thick filament consists of 200 to 300 myosin II triphosphate (ATP) and functions in the formation of
molecules. Each myosin II molecule (150 nm in cross-bridges between the thick and thin myofilaments.
length; 2 to 3 nm in diameter) is composed of two iden- Light chains (not to be confused with light meromyosin)
tical heavy chains and two pairs of light chains. The are of two types, and one of each type is associated with
heavy chains resemble two golf clubs, whose rod-like each S1 subfragment of the myosin II molecule. For
polypeptide chains are wrapped around each other in each heavy chain, therefore, there are two light chains.
an α-helix. The heavy chains can be cleaved by trypsin A myosin II molecule is composed of two heavy chains
into: and four light chains.
䡲 Light meromyosin, a rod-like tail composed of most Myosin II molecules are closely packed in a specific
of the two rod-like polypeptide chains wrapped fashion in the thick filament. They are lined up in a par-
around each other allel but staggered manner, spaced at regular intervals,
䡲 Heavy meromyosin, the two globular heads with lying arranged head to tail, so that the middle of each
the attendant short proximal portions of the two rod- thick filament is composed solely of tail regions, whereas
like polypeptide chains wrapped around each other the two ends of the thick filament consist of both heads
Ch008-X2945.qxd 15/8/06 2:45 PM Page 166
sr
*
*
* m
gly Figure 8–9 Electron micrograph of cross section
of skeletal muscle fiber. Asterisks represent thick and
thin filaments. gly, glycogen; m, mitochondria; pm,
plasma membrane. (Electron micrograph courtesy of
Dr. C. Peracchia; in Hopkins CR: Structure and
Function of Cells. Philadelphia, WB Saunders,
1978.)
and tails. The spatial orientation of the myosin II mole- THIN FILAMENTS
cules permits the heavy meromyosin portion to project
from the thick filament at a 60-degree angle relative to Thin filaments are composed of two chains of F-actin
neighboring heavy meromyosin, so that the head regions filaments wrapped around each other in association
are always in register with the thin filaments. with tropomyosin and troponin.
Each myosin II molecule appears to have two flexible
regions, one at the junction of the heavy meromyosin and The major component of each thin filament is F-actin,
the light meromyosin and the other at the junction of the a polymer of globular G-actin units. Although G-actin
S1 and S2 subfragments. The flexible region between the molecules are globular, they all polymerize in the same
heavy and light meromyosins permits each myosin II mol- spatial orientation, imparting a distinct polarity to the
ecule to contact the thin filament, forming a cross-bridge filament. The plus end of each filament is bound to the
between the two filament types. As discussed later, the Z disk by α-actinin; the minus end extends toward
flexible region between the S1 and S2 subfragments the center of the sarcomere. Each G-actin molecule also
enables the myosin II molecule to drag the thin filament, contains an active site, where the head region (S1 sub-
incrementally, toward the middle of the sarcomere. fragment) of myosin II binds. Two chains of F-actin are
Ch008-X2945.qxd 15/8/06 2:45 PM Page 167
wound around each other in a tight helix (36-nm peri- and inorganic phosphate (Pi) remain attached to the
odicity) like two strands of pearls (see Fig. 8-8). S1 subfragment, and the complex binds to the active
Running along the length of the F-actin double- site on actin (Fig. 8-10).
stranded helix are two shallow grooves. Pencil-shaped 5 Pi is released, resulting not only in a greater bond
tropomyosin molecules, about 40-nm long, polymer- strength between the actin and myosin II but also in
ize to form head-to-tail filaments that occupy the a conformational alteration of the S1 subfragment.
shallow grooves of the double-stranded actin helix. 6 ADP is also released, and the thin filament is dragged
Bound tropomyosin masks the active sites on the actin toward the center of the sarcomere (“power stroke”).
molecules by partially overlapping them. 7 A new ATP molecule binds to the S1 subfragment,
Approximately 25 to 30 nm from the beginning of causing the release of the bond between actin and
each tropomyosin molecule is a single troponin mole- myosin II.
cule, composed of three globular polypeptides: TnT, The attachment and release cycles must be repeated
TnC, and TnI. The TnT subunit binds the entire tro- numerous times for contraction to be completed. Each
ponin molecule to tropomyosin; TnC has a great affin- attachment and release cycle requires ATP for the
ity for calcium; and TnI binds to actin, preventing the conversion of chemical energy into motion.
interaction between actin and myosin II. Binding of
calcium by TnC induces a conformational shift in
tropomyosin, exposing the previously blocked active CLINICAL CORRELATIONS
sites on the actin filament so that myosin II molecules
can flex, forming cross-bridges, and so that the S1 moi- Shortly after the death of an animal, or of a human
eties (myosin heads) can bind to the active site on the being, the joints become immoveable. This stiffen-
actin molecule (see later). ing of the joints is referred to as rigor mortis and,
depending on the ambient temperature, it may last
Muscle Contraction and Relaxation as long as three days. Because the dead cells are
unable to manufacture ATP, the dissociation of the
Muscle contraction obeys the “all-or-none law” and is thick and thin filaments cannot occur, and the
followed by muscle relaxation. myosin heads will remain bound to the active site of
the actin molecule until the muscle begins to
Contraction effectively reduces the resting length of the decompose. The time of death may be estimated by
muscle fiber by an amount that is equal to the sum of all the state of rigor mortis, when it is correlated with
shortenings that occur in all sarcomeres of that particu- the record of the ambient temperature fluctuations.
lar muscle cell. The process of contraction, usually trig- It is interesting to note that the facial muscles are
gered by neural impulses, obeys the all-or-none law, in the first to undergo rigor mortis and that the
that a single muscle fiber either contracts as a result of maximal rigor occurs 12 to 24 hours after death.
stimulation or does not respond at all. The strength of
contraction of a gross anatomical muscle, such as the
biceps, is a function of the number of muscle fibers that As long as the cytosolic calcium concentration is
undergo contraction. The stimulus is transferred at the high enough, actin filaments remain in the active state
neuromuscular junction. During muscle contraction, and contraction cycles continue. Once the stimulating
the thin filaments slide past the thick filaments, as pro- impulses cease, however, muscle relaxation occurs,
posed by Huxley’s sliding filament theory. involving a reversal of the steps that led to contraction.
The following sequence of events leads to contrac- First, calcium pumps in the membrane of the sar-
tion in skeletal muscle: coplasmic reticulum actively drive Ca2+ back into the ter-
minal cisternae, where the ions are bound by the protein
1 An impulse, generated along the sarcolemma, is
calsequestrin. The reduced levels of Ca2+ in the cytosol
transmitted into the interior of the fiber via the T
tubules, where it is conveyed to the terminal cister- cause TnC to lose its bound Ca2+; tropomyosin then
reverts to the position in which it masks the active site of
nae of the sarcoplasmic reticulum (see Fig. 8-5).
actin, preventing the interaction of actin and myosin II.
2 Calcium ions leave the terminal cisternae through
voltage-gated calcium release channels, enter Energy Sources for Muscle Contraction
the cytosol, and bind to the TnC subunit of troponin,
altering its conformation. Energy sources for muscle contraction are the phosphogen
3 Conformational change in troponin shifts the position energy system, glycolysis, and the aerobic energy system.
of tropomyosin deeper into the groove, unmasking the
active site (myosin-binding site) on the actin molecule. Because the process of muscle contraction consumes a
4 ATP present on the S1 subfragment of myosin II is great deal of energy, skeletal muscle cells maintain a
hydrolyzed, but both adenosine diphosphate (ADP) high concentration of the energy-rich compounds ATP
Ch008-X2945.qxd 15/8/06 2:45 PM Page 168
Actin
ADP
P
Myosin
Pi is released, resulting in a
conformational alteration of the
ATP present on the S1 subfragment S1 subfragment.
is hydrolyzed, and the complex binds
to the active site on actin.
P
ADP
ATP
ADP is also released and the thin

ADP
filament is dragged toward the
center of the sarcomere.
ATP
Power Stroke
A new ATP molecule binds to the S1

subfragment, which causes the
release of the bond between actin
and myosin.
Figure 8–10 The role of adenosine triphosphate (ATP) in muscle contraction. ADP, adenosine diphosphate; P, phosphate; Pi, inorganic
phosphate; S1 subfragment, fragment of myosin. (Modified from Alberts B, Bray D, Lewis J, et al: Molecular Biology of the Cell. New York,
Garland Publishing, 1994.)
and creatine phosphate (or phosphocreatine). Because ity modalities. During bursts of muscle contraction, the
both ATP and creatine phosphate contain high-energy ADP that is generated is rephosphorylated by two means:
phosphate bonds, they constitute the phosphogen (1) glycolysis, leading to accumulation of lactic acid, and
energy system, and can provide enough energy for (2) transfer of high-energy phosphate from creatine phos-
about a total of 9 seconds of maximal muscle activity (3 phate (phosphogen system) catalyzed by phosphocrea-
seconds for ATP and 6 seconds for creatine phosphate). tine kinase. During prolonged muscle activity, however,
Additional energy can be derived from anaerobic the aerobic system of energy production is employed.
metabolism of glycogen (glycolysis), which results in
the formation and buildup of lactic acid. This is known Myotendinous Junctions
as the glycogen-lactic acid system. This system provides
about 90 to 100 seconds’ worth of energy at almost The connective tissue elements of the muscle fiber are
maximal muscle activity. continuous with the tendon to which the muscle is
The third system, known as the aerobic energy attached. At the myotendinous junctions, the cells
system, uses the normal diet for the manufacture of become tapered and highly fluted. Collagen fibers of
ATP. The aerobic system does not support maximal the tendon penetrate deep into these infoldings and
muscle activity, but it can sustain normal muscle activ- probably become continuous with the reticular fibers of
ity indefinitely if the dietary intake is maintained and the endomysium. Within the cell, the myofilaments are
the nutrients persist. anchored to the internal aspect of the sarcolemma so
ATP is manufactured via oxidative phosphorylation that the force of contraction is transmitted to the colla-
within the abundant mitochondria of muscle cells during gen fibers of the tendon.
periods of inactivity or low activity. Lipid droplets and
glycogen, which abound in the sarcoplasm, also are readily Innervation of Skeletal Muscle
converted into energy sources. The three metabolic
Skeletal muscle cells and the single motor neuron that
systems of skeletal muscle are harnessed to supply the
innervates them constitute a motor unit.
energy requirement of the muscle according to their activ-
Ch008-X2945.qxd 15/8/06 2:45 PM Page 169
Each skeletal muscle receives at least two types of Impulse Transmission at the
nerve fibers: motor and sensory. The motor nerve Neuromuscular Junction
functions in eliciting contraction, whereas the sensory
fibers pass to muscle spindles (see later). Additionally, Impulse transmission from the motor neuron to the
autonomic fibers supply the vascular elements of skele- skeletal muscle fiber occurs at the neuromuscular
tal muscle. The specificity of motor innervation is a junction.
function of the muscle innervated. If the muscle acts
fastidiously, as do some muscles of the eye, a single Motor fibers are myelinated axons of a-motor
motor neuron may be responsible for as few as 5 to neurons, which pass in the connective tissue of the
10 skeletal muscle fibers, whereas a muscle located in muscle. The axon arborizes, eventually losing its myelin
the abdominal wall may have as many as 1000 fibers sheath (but not its Schwann cells). The terminal of each
under the control of a single motor neuron. Each arborized twig becomes dilated and overlies the motor
motor neuron and the muscle fibers it controls form a end plates of individual muscle fibers. Each of these
motor unit. The muscle fibers of a motor unit contract muscle–nerve junctions, known as a neuromuscular
in unison and follow the all-or-none law of muscle junction, is composed of an axon terminal, a synaptic
contraction. cleft, and the muscle cell membrane (Figs. 8-11 to 8-13).
Figure 8–11 Scanning electron micrograph of a

neuromuscular junction (MJ) from the tongue of a
cat (×2315). N, nerve fiber. Arrows indicate stria-
tions. (Courtesy of Dr. L. Litke.)
Ch008-X2945.qxd 15/8/06 2:45 PM Page 170
Figure 8–12 Electron micrograph of a

mouse neuromuscular junction. (From Feczko
D, Klueber KM: Cytoarchitecture of muscle in a
genetic model of murine diabetes. Am J Anat
182:224-240, 1988.)
The muscle cell membrane (postsynaptic mem- Stimulus transmission across a synaptic cleft
brane) is modified, forming the primary synaptic involves the following sequence of events (Fig. 8-14):
cleft, a trough-like structure occupied by the axon ter-
minal. Opening into the primary synaptic clefts are 1 A stimulus, traveling along the axon, depolarizes the
numerous secondary synaptic clefts (junctional membrane of the axon terminal, thus opening the
folds), a further modification of the sarcolemma. Both voltage-gated calcium channels, located in the vicinity
the primary synaptic cleft and the junctional folds are of linearly arranged structures known as dense bars.
lined by a basal lamina–like external lamina. The sar- 2 The influx of calcium into the axon terminal results
coplasm in the vicinity of the secondary synaptic cleft is in the fusion of about 120 synaptic vesicles per nerve
rich in glycogen, nuclei, ribosomes, and mitochondria. impulse with the axon terminal’s membrane (presy-
The axon terminal, covered by Schwann cells, houses naptic membrane) and subsequent release of
mitochondria, smooth endoplasmic reticulum, and as acetylcholine (along with proteoglycans and ATP)
many as 300,000 synaptic vesicles (each 40 to 50 nm into the primary synaptic cleft. Fusion occurs along
in diameter) containing the neurotransmitter acetyl- specific regions of the presynaptic membrane, known
choline. The function of the neuromuscular junction is as active sites, adjoining the dense bars.
to transmit a stimulus from the nerve fiber to the muscle 3 The neurotransmitter acetylcholine (ligand) is liber-
cell. ated in large quantities, known as quanta (equal
Ch008-X2945.qxd 15/8/06 2:45 PM Page 171
Axon
Schwann cell Myelin
nucleus sheath
Terminal nerve
branches Schwann cell
Synaptic sheath
vesicles
Junctional
folds
Myofibril
Muscle nucleus
Figure 8–13 Neuromuscular junction. Note that the myelin sheath stops as the axon arborizes over the skeletal muscle fiber, but the
Schwann cell sheath continues to insulate the nerve fiber. The terminal nerve branches expand to form axon terminals that overlie the motor
endplates of individual muscle fibers.
to 10,000 to 20,000 molecules), from the nerve nal, the acetylcholine is synthesized from activated
terminal. acetate (produced in mitochondria) and the recycled
4 Acetylcholine then diffuses across the synaptic cleft choline, a reaction catalyzed by choline acetyl trans-
and binds to postsynaptic acetylcholine receptors ferase. The newly formed acetylcholine is transported,
in the muscle cell membrane. These receptors, through the use of an antiport system powered by a
located in the vicinity of the presynaptic active sites, proton concentration gradient, into newly formed
are ligand-gated ion channels, which open in synaptic vesicles.
response to the binding of acetylcholine. The result- In addition to the recycling of choline, the synaptic
ing ion influx leads to depolarization of the sar- vesicle membrane is recycled to conserve the surface
colemma and generation of an action potential (see area of the presynaptic membrane. This membrane
Chapter 9). recycling is accomplished by the formation of clathrin-
5 The impulse generated spreads quickly throughout coated endocytotic vesicles, which become the newly
the muscle fiber via the system of T tubules, initiat- formed synaptic vesicles.
ing muscle contraction.
Muscle Spindles and Golgi
To prevent a single stimulus from eliciting multiple Tendon Organs
responses, acetylcholinesterase, an enzyme located in
the external lamina lining the primary and secondary Muscle spindles and Golgi tendon organs are sensory
synaptic clefts, degrades acetylcholine into acetate and receptors that monitor muscle contraction.
choline, thus permitting the reestablishment of the
resting potential. Degradation is so rapid that all of The neural control of muscle function requires not
the released acetylcholine is cleaved within a few only the capability of inducing or inhibiting muscle
hundred milliseconds. contraction but also the ability to monitor the status
Choline is transported back into the axon terminal by of the muscle and its tendon during muscle activity.
a sodium-choline symport protein powered by the This monitoring is performed by two types of sensory
sodium concentration gradient. Within the axon termi- receptors:
Ch008-X2945.qxd 15/8/06 2:45 PM Page 172
Na+
Voltage-gated Ca2+
Na+ channel
Voltage-gated
Ca2+ Ca2+ channel
Smooth ER
Na+ Membrane is
AcCoA
reclaimed as
+ clathrin coated
CHOLINE vesicle
Choline
CHOLINE acetyltransferase ACh
ACh
ATP
AChE PG Synaptic
H+ vesicle
ACETATE
h
AC PG
ACETATE CHOLINE
P Synaptic
AT h
AC cleft
AChE
ACh
ACh ATP
Muscle PG
Acetylcholine
cell receptors
Figure 8–14 Diagram depicting events occurring at the neuromuscular junction during the release of acetylcholine. AcCoA, acetyl CoA;
Ach, acetylcholine; AchE, acetylcholinesterase; ATP, adenosine triphosphate; PG, proteoglycan. (Modified from Katzung BG: Basic and
Clinical Pharmacology, 4th ed. East Norwalk, Conn, Appleton & Lange, 1989.)
䡲 Muscle spindles, which provide feedback about the When muscle is stretched, it normally undergoes reflex
changes in muscle length as well as the rate of contraction, or stretch reflex. This proprioceptive
alteration in muscle length response is initiated by the muscle spindle, an encap-
䡲 Golgi tendon organs, which monitor the tension as sulated sensory receptor located among, and in paral-
well as the rate at which the tension is being pro- lel with, the muscle cells (Fig. 8-15). Each muscle
duced during movement spindle is composed of 8 to 10 elongated, narrow, very
small, modified muscle cells called intrafusal fibers,
Information from these two sensory structures is
surrounded by the fluid-containing periaxial space,
generally processed at unconscious levels, within the
which in turn is enclosed by the capsule. The connec-
spinal cord. The information also reaches the cerebel-
tive tissue elements of the capsule are continuous with
lum and even the cerebral cortex, however, so a person
the collagen fibers of the perimysium and endomysium.
may sense muscle position.
The skeletal muscle fibers surrounding the muscle
spindle are unremarkable and are called extrafusal
Muscle Spindles fibers.
Intrafusal fibers are of two types: nuclear bag
Muscle spindles continuously monitor the length and the
fibers and the more numerous, thinner nuclear chain
changes in length of the muscle.
fibers. Furthermore, there are two categories of
Ch008-X2945.qxd 15/8/06 2:45 PM Page 173
Within a specific muscle spindle, a single, myeli-

CLINICAL CORRELATIONS nated, large, sensory nerve fiber (group Ia) wraps
spirally around the nuclear regions of each of the
Botulism is usually caused by ingestion of three types of intrafusal fibers, forming the primary
improperly preserved canned foods. The toxin, sensory endings (also known as dynamic and Ia
produced by the microbe Clostridium botu- sensory endings). Additionally, secondary sensory
linum, interferes with the release of acetyl- nerve endings (also known as static and II sensory
choline, with resultant muscle paralysis and, nerve endings) are formed by group II nerve fibers,
without treatment, death. which wrap around every nuclear chain fiber as well as
Myasthenia gravis is an autoimmune disease around the static nuclear bag fibers.
in which autoantibodies attach to acetylcholine The contractile regions of the intrafusal fibers
receptors, blocking their availability to acetyl- receive two types of γ-motor neurons. Dynamic nuclear
choline. Receptors thus inactivated are endocy- bag fibers are innervated by a dynamic g-motor
tosed and replaced by new receptors, which neuron, whereas all nuclear chain fibers as well as all
are also inactivated by the autoantibodies. Thus, of the static nuclear bag fibers are innervated by a static
the number of locations for the initiation of g-motor neuron.
muscle depolarization is reduced and the skele- The extrafusal fibers receive their normal nerve
tal muscles (including the diaphragm) weaken fibers, which are the large, rapidly conducting axons of
gradually. Certain neurotoxins, such as the a-efferent (motor) neurons.
bungarotoxin of some poisonous snakes, also As a muscle is stretched, the intrafusal muscle fibers
bind to acetylcholine receptors, causing paral- of its muscle spindle are also stretched, causing the
ysis and eventual death due to respiratory primary (group Ia, dynamic) and secondary (group II,
compromise. static) sensory nerve fibers to initiate an action poten-
Botulinum toxin type A, produced by tial; with increased stretching, these nerve fibers
Clostridium botulinum, is an inhibitor of acetyl- accelerate their rate of firing. Group Ia and group II
choline release by motor fibers that cause skele- fibers both respond to a stretching of the muscle
tal muscle contraction. For cosmetic purposes, at a constant rate. Only group Ia fibers, however,
“Botox” is injected into the procerus and corru- respond to a change in the rate at which stretching
gator muscles to diminish the frown lines that occurs, thus furnishing information concerning both
the contraction of those facial muscles otherwise the rapidity of movement and unanticipated stretching
produces. By eradicating these “wrinkles,” the of the muscle.
face appears smoother and younger looking. In Firing of the γ-motor neurons causes the polar
2001, almost 2 million people were injected with regions of the intrafusal fibers to contract. When this
Botox for cosmetic purposes. The effect lasts for occurs, the noncontractile regions of the intrafusal
less than 3 months, and many patients repeat the fibers are stretched from both directions, resulting
procedure two to three times per year. There in activation of the primary and secondary sensory
appear to be no serious side effects, but if nerve endings. Modulation of γ-motor neuron activity
injected into the wrong muscles, ptosis of the sensitizes the muscle spindle so that it can react
eyelids could persist for several months. Occa- even to a small degree of muscle stretching, as
sionally individuals suffer headaches, cold-like follows:
symptoms, and nausea, as well as muscle weak-
ness, pain, and inflammation in the area of the 䡲 Firing of dynamic γ-motor neurons primes the
injection for as long as 4 months. dynamic nerve endings but not the static nerve
endings (because their firing does not cause contrac-
tion of the static nuclear bag fibers).
䡲 Firing of static γ-motor neurons increases the con-
tinuous, steady response of both group Ia and group
II sensory fibers (because both fibers form sensory
nerve endings on static nuclear bag and all nuclear
nuclear bag fibers: static and dynamic. The nuclei of
chain intrafusal fibers). However, the dynamic
both types of fibers occupy the centers of the cells; their
sensory fiber response decreases (because static γ-
myofibrils are located on either side of the nuclear
motor neurons do not innervate dynamic nuclear
region, limiting contraction to the polar regions of these
bag fibers).
spindle-shaped cells. The central regions of the intra-
fusal fibers do not contract. The nuclei are aggregated Thus, modulation of the γ-motor neuron activity
in the nuclear bag fibers, whereas they are aligned in a gives the nervous system the ability to adjust the sensi-
single row in nuclear chain fibers. tivity of the muscle spindle.
Ch008-X2945.qxd 15/8/06 2:45 PM Page 174
Nuclear bag fiber External capsule
Group II sensory
fibers
Nuclear chain fiber
Static γ motor
neuron
Primary ending
of group Ia
afferent fiber
Nuclei
Internal capsule
α motor fiber
Subcapsular space
Extrafusal fiber
A
Static nuclear
bag fiber
Dynamic nuclear
Nuclear bag fiber
chain fiber
II
Figure 8–15 Muscle spindle.

Ia A, Schematic diagram showing com-
ponents of a muscle spindle. B, The
various fiber types of a muscle spindle
Static - γ and their innervation are presented in
a spread-out fashion. Ia, group Ia
sensory fiber; II, group II sensory
Dynamic - γ fiber. (A, Modified from Krstic RV:
Die Gewebe des Menschen und der
Saugertiere. Berlin, Springer-Verlag,
1978. B, Modified from Hulliger M:
The mammalian muscle spindle
and its central control. Rev Physiol
B Biochem Pharmacol 101:1-110, 1984.)
Ch008-X2945.qxd 15/8/06 2:45 PM Page 175
CARDIAC MUSCLE
The simple reflex arc, such as the knee jerk, is Cardiac muscle is nonvoluntary striated muscle limited to
an example of the function of muscle spindles. the heart and the proximal portions of the pulmonary
Tapping on the patellar tendon results in a veins.
sudden stretching of the muscle (and of the
muscle spindles). The primary and secondary Cardiac muscle (heart muscle), another form of striated
nerve endings are stimulated, relaying the stim- muscle, is found only in the heart and in pulmonary
ulus to the g-motor neurons of the spinal veins where they join the heart. Cardiac muscle is
cord, resulting in muscle contraction. derived from a strictly defined mass of splanchnic mes-
enchyme, the myoepicardial mantle, whose cells give
rise to the epicardium and myocardium.
The adult myocardium consists of an anastomosing
Golgi Tendon Organs network of branching cardiac muscle cells arranged in
(Neurotendinous Spindles) layers (laminae). Laminae are separated from one
another by slender connective tissue sheets that convey
Golgi tendon organs monitor the intensity of muscle blood vessels, nerves, and the conducting system of the
contraction. heart. Capillaries, derived from these branches, invade
the intercellular connective tissue, forming a rich, dense
Golgi tendon organs, also called neurotendinous spin- network of capillary beds surrounding every cardiac
dles, are cylindrical structures about 1 mm in length and muscle cell.
0.1 mm in diameter. They are located at the juncture of Cardiac muscle differs from skeletal and smooth
a muscle with its tendon and are positioned in series muscles in that it possesses an inherent rhythmicity as
with the muscle fibers. Golgi tendon organs are com- well as the ability to contract spontaneously. A system
posed of wavy collagen fibers and the nonmyelinated of modified cardiac muscle cells has been adapted to
continuation of a single type Ib axon that ramifies as ensure the coordination of its contractile actions. This
free nerve endings in the interstices between the colla- specialized system, as well as the associated autonomic
gen fibers. When the muscle contracts, it places tensile nerve supply, is discussed in Chapter 11.
forces on the collagen fibers, straightening them, with Almost half the volume of the cardiac muscle cell is
a consequent compression and firing of the entwined occupied by mitochondria, attesting to its great energy
nerve endings. The rate of firing is directly related to consumption. Glycogen, to a certain extent, but mostly
the amount of tension placed on the tendon. triglycerides (~60% during basal rate) form the energy
When a muscle undergoes strenuous contraction, it supply of the heart. Because the oxygen requirement of
may generate a great amount of force. To protect the cardiac muscle cells is high, they contain an abundant
muscle, bone, and tendon, Golgi tendon organs provide supply of myoglobin.
an inhibitory feedback to the γ-motor neuron of the Although the resting lengths of individual cardiac
muscle, resulting in relaxation of the contracting muscle cells vary, on average they are 15 µm in diame-
tendon’s muscle. Thus, the Golgi tendon organs monitor ter and 80 µm in length. Each cell possesses a single,
the force of muscle contraction, whereas muscle spin- large, oval, centrally placed nucleus, although two
dles monitor the stretching of the muscle in which they nuclei are occasionally present (Figs. 8-16 to 8-18).
are located. These two sensory organs act in concert to Muscle cells of the atria are somewhat smaller than
integrate spinal reflex systems. those of the ventricles. These cells also house granules
(especially in the right atrium) containing atrial natri-
uretic peptide, a substance that functions to lower
CLINICAL CORRELATIONS blood pressure (Fig. 8-19). This peptide acts by decreas-
The ability of a person to touch his or her nose in ing the capabilities of renal tubules to resorb (conserve)
absolute darkness is due to the integrative activi- sodium and water.
ties of muscle spindles and, possibly, to Golgi
tendon organs. These structures provide not only Intercalated Disks
feedback about the amount of tension placed on Cardiac muscle cells form highly specialized end-to-end
the muscle and tendon but also input to the cere- junctions, referred to as intercalated disks (Figs. 8-20 to
bellum and cerebral cortex supplying information 8-22; also see Fig. 8-16). The cell membranes involved
about the body’s position in three-dimensional in these junctions approximate each other, so that in
space; this ability is referred to as proprioception. most areas they are separated by a space of less than 15
to 20 nm.
Ch008-X2945.qxd 15/8/06 2:45 PM Page 176
N Gl
D D
Figure 8–17 Light micrograph of cardiac muscle in cross-

Figure 8–16 Light micrograph of cardiac muscle in longitudinal section (×540). The nucleus (N) is centrally located, and at each pole
section (×540). Note the nucleus (N) and the presence of intercalated of the nucleus the glycogen deposits (Gl) have been extracted during
disks, regions where the cardiac muscle cells form desmosomes (D), the histological preparation.
fasciae adherents, and gap junctions with each other.
Gl
I
N
of cardiac muscle cells in longitudi-
nal section, displaying their charac-
teristic branching patterns and
glycogen deposits (Gl) (×270). The
branching of the cardiac muscle
fibers, the central location of the
nuclei (N), and the presence of
intercalated disks (I) are identifying
characteristics of cardiac muscle.
Ch008-X2945.qxd 15/8/06 2:45 PM Page 177
Figure 8–19 Electron micrograph of a rat atrial

muscle cell (×14,174). Observe the secretory gran-
ules containing atrial natriuretic peptide. (Courtesy
of Dr. Stephen C. Pang.)
Intercalated disks have transverse portions, where bands. Each sarcomere possesses the same substructure
fasciae adherentes and desmosomes abound, as well as as its skeletal muscle counterpart; therefore, the mode
lateral portions rich in gap junctions (see Figs. 8-20 and mechanism of contraction are virtually identical in
to 8-22). On the cytoplasmic aspect of the sarcolemma the two striated muscles. Several major differences
of intercalated disks, thin myofilaments attach to the should be noted, however; they are found in the sar-
fasciae adherens, which are thus analogous to Z disks. coplasmic reticulum, the arrangement of T tubules, the
Gap junctions, which function in permitting rapid flow Ca2+ supply of cardiac muscle, the ion channels of the
of information from one cell to the next, also form in plasmalemma, and the duration of the action potential.
regions where cells lying side by side come in close The sarcoplasmic reticulum of cardiac muscle does
contact with each other. not form terminal cisternae and is not nearly as exten-
sive as in skeletal muscle; instead, small terminals of sar-
Organelles coplasmic reticulum approximate the T tubules. These
structures do not normally form a triad, as in skeletal
The extracellular fluid is the primary calcium source for muscle; rather, the association is usually limited to two
cardiac muscle contraction. partners, resulting in a dyad. Unlike in skeletal muscle,
where the triads are located at the A-I interfaces, the
The bandings of cardiac muscle fibers are identical with dyads in cardiac muscle cells are located in the vicinity
those of skeletal muscle, including alternating I and A of the Z line. The T tubules of cardiac muscle cells are
Ch008-X2945.qxd 15/8/06 2:45 PM Page 178
A Is
Mi
M
M
Mitochondria Intercalated disk
3
2
Ri
I ba
nd
A ba
nd Tu
Z disk
Fascia Desmosome Gap junctions

B adherens
Figure 8–21 Electron micrograph of an intercalated disk from
a steer heart (×29,622). Is, intercellular space; M, M-line; Mi, mito-
chondrion; Ri, ribosomes; Tu, sarcoplasmic reticulum. The numerals
2 and 3 denote the two cardiac muscle cells, one on either side of the
intercalated disk. (From Rhodin JAG: An Atlas of Ultrastructure.
enters the cardiac muscle cells at the time of depolar-

ization. Moreover, the negatively charged external
lamina coating of the T tubule stores calcium for instan-
taneous release. An additional method whereby calcium
can enter the cardiac muscle cells is through the large
Figure 8–20 Cardiac muscle. A, Three-dimensional view of an calcium-sodium channels described later.
intercalated disk. B, Two-dimensional view of the intercalated disk Skeletal muscle cell action potential is achieved by
with a display of adhering and communicating junctions. The trans- an abundance of fast sodium channels, which open
verse portions of the intercalated disk act as a Z plate, and thin fila- and close within a few ten-thousandths of a second,
ments are embedded in them.
leading to the generation of very rapid action potentials.
In addition to fast sodium channels, cardiac muscle cell
membranes possess calcium-sodium channels (slow
almost two and one-half times the diameter of those in sodium channels). Although these channels are slow
skeletal muscle and are lined by an external lamina. to open initially, they remain open for a considerable
Because the sarcoplasmic reticulum is relatively time (several tenths of a second). During this time, a
sparse, it cannot store enough calcium to accomplish a tremendous number of sodium and calcium ions enter
forceful contraction; therefore, additional sources of the cardiac muscle cell cytoplasm, thus increasing the
calcium are available. Because the T tubules open into calcium ion concentration supplied by the T tubule and
the extracellular space and have a relatively large bore, the sarcoplasmic reticulum. An additional difference
extracellular calcium flows through the T tubules and between the movement of ions in skeletal and cardiac
Ch008-X2945.qxd 15/8/06 2:45 PM Page 179

graph of an intercalated disk from
the atrium of a mouse heart
(×57,810). Observe the gap junc-
tions (arrow). (From Forbes MS,
Sperelakis N: Intercalated disks of
mammalian heart: A review of struc-
ture and function. Tissue Cell
17:605, 1985.)
muscle cells is that potassium ions can leave the skele- tract, some of the reproductive tract, and the urinary
tal muscle cells extremely quickly, thus reestablishing tract), walls of blood vessels, larger ducts of compound
the resting membrane potential; in cardiac muscle cells, glands, respiratory passages, and small bundles within
the egress of potassium ions is retarded, thus con- the dermis of skin. Smooth muscle is not under volun-
tributing to the protracted action potential. tary control; it is regulated by the autonomic nervous
system, hormones (such as bradykinins), and local phys-
iological conditions. Hence, smooth muscle is also
referred to as involuntary muscle.
CLINICAL CORRELATIONS There are two types of smooth muscle:
During cardiac hypertrophy, the number of 䡲 Cells of multiunit smooth muscle can contract
myocardial fibers is not increased; instead, the independently of one another, because each muscle
cardiac muscle cells become longer and larger in cell has its own nerve supply.
diameter. Damage to the heart does not result in 䡲 Cell membranes of unitary (single-unit, vascular)
regeneration of muscle tissue; instead, the dead smooth muscle form gap junctions with those of
muscle cells are replaced by fibrous connective contiguous smooth muscle cells, and nerve fibers
tissue. form synapses with only a few of the muscle fibers.
Lack of Ca2+ in the extracellular compartment Thus, cells of unitary smooth muscle cannot contract
results in cessation of cardiac muscle contraction independently of one another.
within 1 minute, whereas skeletal muscle fibers
can continue to contract for several hours. In addition to its contractile functions, some smooth
Although a small amount of energy pro- muscle is capable of exogenous protein synthesis.
duction may be achieved by anaerobic meta- Among the substances manufactured by smooth muscle
bolism (up to 10% during hypoxia), totally cells for extracellular utilization are collagen, elastin,
anaerobic conditions cannot sustain ventricular glycosaminoglycans, proteoglycans, and growth factors.
contraction.
Light Microscopy of Smooth
Muscle Fibers
Light microscopy reveals that smooth muscle fibers are
SMOOTH MUSCLE short, spindle-shaped cells with a centrally placed
nucleus.
The cells of the third type of muscle exhibit no stria-
tions; therefore, they are referred to as smooth muscle. Smooth muscle fibers are fusiform, elongated cells
Additionally, smooth muscle cells do not possess a whose average length is about 0.2 mm with a diameter
system of T tubules (Table 8-3). Smooth muscle is found of 5 to 6 µm. The cells taper at either end, and the
in the walls of hollow viscera (e.g., the gastrointestinal central portion contains an oval nucleus housing two
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TABLE 8–3 Comparison of the Three Types of Muscle
Feature Skeletal Muscle Cardiac Muscle Smooth Muscle
Sarcomeres and Yes Yes No

myofibrils
Nuclei Multinucleated; One (or two); centrally located One; centrally located
peripherally located
Sarcoplasmic Well-developed with Poorly defined; some small Some smooth endoplasmic
reticulum terminal cisterns terminals reticulum
T tubules Yes; small, involved in Yes; large, involved in dyad No

triad formation formation
Cell junctions No Intercalated disks Nexus (gap junctions)
Contraction Voluntary; “all or none” Involuntary; rhythmic and Involuntary; slow and forceful;
spontaneous not “all or none”
Calcium control Calsequestrin in terminal Calcium from extracellular Calcium from extracellular
cisternae sources and the sarcoplasmic sources (via caveolae) and
reticulum the sarcoplasmic/endoplasmic
reticulum
Calcium binding Troponin C Troponin C Calmodulin
Regeneration Yes, via satellite cells No Yes
Mitosis No No Yes
Nerve fibers Somatic motor Autonomic Autonomic
Connective tissue Epimysium, perimysium, Connective tissue sheaths and Connective tissue sheaths and
and endomysium endomysium endomysium
Distinctive features Long; cylinder-shaped; Branched cells; intercalated Fusiform cells with no
many peripheral nuclei disks; one or two nuclei striations; single nucleus
or more nucleoli (Figs. 8-23 and 8-24; also see Fig. the sarcoplasm of smooth muscle cells, representing
8-2). During muscle shortening, the nucleus assumes clumped associations of myofilaments.
a characteristic “corkscrew appearance,” as a result Smooth muscle cells usually form sheets of various
of the method of smooth muscle contraction (Fig. thicknesses, although they may also occur as individual
8-25). cells. When they form sheets, the cells are arranged so
Each smooth muscle cell is surrounded by an that they form a continuous network in which their
external lamina, which invariably separates the tapered portions fit almost precisely into existing spaces
sarcolemma of contiguous muscle cells (Fig. 8-26). between the expanded regions of neighboring smooth
Embedded in the external lamina are numerous muscle cells (see Fig. 8-2). In cross section, outlines of
reticular fibers, which appear to envelop individual various diameters may be noted, some containing
smooth muscle cells and function in harnessing the nuclei, some not (see Fig. 8-24). Cross sections without
force of contraction. nuclei represent the tapered ends of smooth muscle
With hematoxylin and eosin (H&E) staining, the cells as they interdigitate with the other smooth muscle
cytoplasm of smooth muscle fibers appears unremark- fibers.
able; however, iron hematoxylin stain demonstrates the Sheets of smooth muscle cells are frequently
presence of dense bodies adhering to the cytoplasmic arranged in two layers perpendicular to each other, as
aspect of the cell membrane. In addition to dense in the digestive and urinary systems. This arrangement
bodies, thin, longitudinal striations may be evident in permits waves of peristalsis.
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N
N
Figure 8–23 Light micrograph of smooth muscle in longitudi- Figure 8–24 Light micrograph of smooth muscle in cross section
nal section (×540). The nuclei (N) are located in the midline of the (×540). The nuclei (N) are of various diameters, indicating that they
cell but off-center, so that they are closer to one lateral cell membrane are spindle-shaped and that they have been sectioned at various
than to the other. The nuclei are not corkscrew-shaped, indicating that regions along their length. Also, knowing that the nucleus of the cell
the muscle is not undergoing contraction. is located at its center and that the cell is much longer than the
nucleus, it is reasonable to expect that there will be many smooth
muscle cells in the field that do not display their nuclei, because they
have been sectioned along regions of the cell that are away from the
center.
Fine Structure of Smooth Muscle
The perinuclear cytoplasm of smooth muscle cells,
especially the regions adjacent to the two poles of thick filaments throughout the length of the filament,
the nucleus, contains numerous mitochondria, Golgi with the two ends lacking heavy meromyosin. The
apparatus, rough endoplasmic reticulum (RER), middle of the filament, unlike that of striated muscle,
smooth endoplasmic reticulum (SER), and inclusions also possesses heavy meromyosin, resulting in the avail-
such as glycogen (see Fig. 8-26). Additionally, an exten- ability of a larger surface area for the interaction of actin
sive array of interweaving thin filaments (7 nm) and with myosin II and permitting contractions of long
thick filaments (15 nm) is present. The thin filaments duration.
are composed of actin (with its associated caldesmon, The all-or-none law for striated muscle contraction
a protein that blocks the active site of F-actin, and does not apply to smooth muscle. The entire cell, or
tropomyosin, with the notable absence of troponin). only a portion of the cell, may contract at a given instant
The thick filaments are composed of the same myosin even though the method of contraction probably follows
II that is present in skeletal muscle. the sliding filament theory of contraction.
Myofilaments of smooth muscle are not arranged in The contractile forces are harnessed intracellularly
the paracrystalline fashion of striated muscle, and the by an additional system of intermediate filaments,
organization of the thick filaments is not the same. which consist of vimentin and desmin in unitary
Instead, the myosin II molecules are lined up so that smooth muscle and desmin (only) in multiunit smooth
the heavy meromyosin heads (S1) project from the muscle. These intermediate filaments as well as thin
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configuration, in that their actin-binding site is masked

by their light meromyosin moiety (Fig. 8-27), and also
their light chains are different from those of striated
muscle.
Contraction of smooth muscle fibers proceeds as
follows:
1 Calcium ions, released from the sarcoplasmic reticu-
Dense bodies lum as well as entering the cell at plasma membrane
caveolae, bind to calmodulin (a regulatory protein
ubiquitous in living organisms), thereby altering its
conformation. The Ca2+-calmodulin complex binds to
caldesmon, causing its release from the active site of
F-actin, and then activates myosin light chain
Relaxed Nucleus kinase.
2 Myosin light chain kinase phosphorylates one of the
myosin light chains, known as the regulatory chain,
permitting the unfolding of the light meromyosin
moiety to form the typical, “golf club”–shaped
myosin II molecule (see Fig. 8-27).
3 The phosphorylated light chain permits the interac-
tion between actin and the S1 subfragment of myosin
II that results in contraction.
Because both phosphorylation and the attachment-
Contracted detachment of the myosin cross-bridges occur slowly,
the process of smooth muscle contraction takes longer
Figure 8–25 A relaxed smooth muscle cell and a contracted than skeletal or cardiac muscle contraction. It is inter-
smooth muscle cell. Note that in a contracted smooth muscle cell the
nucleus appears corkscrew-shaped. esting that ATP hydrolysis also occurs much more slowly
and the myosin heads remain attached to the thin fila-
ments for a longer time in smooth muscle than in stri-
filaments insert into dense bodies, formed of a- ated muscle. Thus, smooth muscle contraction not only
actinin and other Z disk–associated proteins. Dense is prolonged but also requires less energy.
bodies may be located in the cytoplasm or associated Decrease in the sarcoplasmic calcium level results in
with the cytoplasmic aspect of the smooth muscle sar- the dissociation of the calmodulin-calcium complex,
colemma. They are believed to resemble Z disks in causing inactivation of myosin light chain kinase. The
function and in three dimensions may even be more subsequent dephosphorylation of myosin light chain,
extensive than formerly assumed, in that they form catalyzed by the enzyme myosin phosphatase, brings
interconnected branching networks that extend about masking of the myosin’s actin binding site and
throughout the cytoplasm. The force of contraction is the subsequent relaxation of the muscle.
relayed, through the association of myofilaments with
dense bodies, to the intermediate filaments, which act Innervation of Smooth Muscle
to twist and shorten the cell along its longitudinal axis.
Associated with the cell membrane domains are Neuromuscular junctions in smooth muscle are not as
structures known as caveolae that act, among other specifically organized as those in skeletal muscle. The
functions, as T tubules of skeletal and cardiac synapses may vary from 15 to 100 nm in width. The
muscle in regulating the cytosolic free calcium ion neural component of the synapse is the en passant
concentration. type, which occurs as axonal swellings that contain
synaptic vesicles, housing either norepinephrine for
Control of Smooth sympathetic innervation or acetylcholine for parasym-
Muscle Contraction pathetic innervation.
In certain cases, every smooth muscle cell receives
Although the regulation of contraction in smooth individual innervation, as in the iris and the vas defer-
muscle depends on Ca2+, the control mechanism differs ens. As indicated previously, smooth muscle innervated
from that encountered in striated muscle because in this fashion is referred to as multiunit.
smooth muscle thin filaments are devoid of troponin. Other smooth muscle cells, such as those of the gas-
Additionally, myosin II molecules assume a different trointestinal tract and uterus, do not possess individual
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Figure 8–26 Electron micrograph of smooth

muscle cells. (Courtesy of Dr. J. Strum.)
innervation; rather, only a few muscle cells are equipped muscle cells regulate their number and their size by the
with neuromuscular junctions. As discussed previously, secretion of a member of the transforming growth
impulse transmission in these muscles, referred to as factor-β (TGF-β) superfamily of extracellular signaling
unitary (single-unit or visceral smooth muscles), molecules, myostatin. Certain mutant mice, whose
occurs via nexus (gap junctions) formed between neigh- skeletal muscle fibers cannot produce myostatin have
boring smooth muscle cells. Visceral smooth muscle may enormous muscles that not only have many more cells
also be regulated by humoral or microenvironmental but whose muscle cells are much larger than those of
factors, such as oxytocin in the uterus or stretching of the normal mice.
muscle fibers in the intestines. Cardiac muscle is incapable of regeneration. Fol-
Still other smooth muscles of the body are of an lowing damage, such as a myocardial infarct, fibro-
intermediate type, in which a certain percentage (30% blasts invade the damaged region, undergo cell
to 60%) of the cells receive individual innervation. division, and form fibrous connective tissue (scar tissue)
to repair the damage.
Smooth muscle cells retain their mitotic capability
REGENERATION OF MUSCLE to form more smooth muscle cells. This ability is espe-
Although skeletal muscle cells do not have the capa- cially evident in the pregnant uterus, where the mus-
bility of mitotic activity, the tissue can regenerate cular wall becomes thicker both by hypertrophy of
because of the presence of satellite cells. These cells individual cells and by hyperplasia derived from mitotic
may undergo mitotic activity, resulting in hyperplasia, activity of the smooth muscle cells. Small defects,
subsequent to muscle injury. Under certain other con- subsequent to injury, may result in formation of new
ditions, such as “muscle building,” satellite cells may smooth muscle cells. These new cells may be derived
fuse with existing muscle cells, thus increasing muscle via mitotic activity of existing smooth muscle cells, as
mass during skeletal muscle hypertrophy. Skeletal in the gastrointestinal and urinary tracts, or from
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Inactive state differentiation of relatively undifferentiated pericytes

(light chains not phosphorylated) accompanying some blood vessels.
Myosin light chains
Myosin
MYOEPITHELIAL CELLS
heavy chains AND MYOFIBROBLASTS
Certain cells associated with glandular secretory units
possess contractile capabilities. These myoepithelial
cells are modified to assist in the delivery of the secre-
ATP
Myosin light tory products into the ducts of the gland. Myoepithelial
chain kinase
cells are flattened and possess long processes that wrap
ADP around the glandular units (see Chapter 5, Figs. 5-24
and 5-25). Myoepithelial cells contain both actin and
Active state
(light chains phosphorylated) myosin. Mechanisms and control of contraction in
myoepithelial cells resemble, but are not identical to,
those in smooth muscle.
P
Actin-binding In lactating mammary glands, myoepithelial cells
site P contract upon the release of oxytocin; in the lacri-
Myosin tail
released mal gland, they contract because of the action of
acetylcholine.
Figure 8–27 Activation of a myosin molecule of smooth muscle. Myofibroblasts resemble fibroblasts but have abun-
ADP, adenosine diphosphate; ATP, adenosine triphosphate; P, myosin dant actin and myosin. They can contract and are espe-
light chain–bound phosphate. (Modified from Alberts B, Bray D, cially prominent in wound contraction and tooth
Lewis J, et al.: Molecular Biology of the Cell. New York, Garland
Publishing, 1994.)
eruption.
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9 䡲䡲䡲
Nervous Tissue
Nervous tissue, composed of as many as a trillion

neurons with multitudes of interconnections, forms the DEVELOPMENT OF
complex system of neuronal communication within the NERVOUS TISSUE
body. Certain neurons have receptors, elaborated on
their terminals, that are specialized for receiving The nervous system develops from the ectoderm of the
different types of stimuli (e.g., mechanical, chemical, embryo in response to signaling molecules from the
thermal) and transducing them into nerve impulses that notochord.
may eventually be conducted to nerve centers. These
impulses are then transferred to other neurons for proc- As the notochord develops early in embryonic life, it
essing and transmission to higher centers for perceiving releases signaling molecules that induce the overlying
sensations or for initiating motor responses. ectoderm to form neuroepithelium, which thickens
To accomplish these functions, the nervous system and forms the neural plate. As the margins of this plate
is organized anatomically into the central nervous continue to thicken, the plate buckles, forming a neural
system (CNS), which comprises the brain and spinal groove whose edges continue to grow toward each
cord, and the peripheral nervous system (PNS). The other until they come together, forming the neural
PNS, located outside the CNS, includes cranial nerves, tube. The rostral (anterior) end of this structure devel-
emanating from the brain; spinal nerves, emanating ops into the brain; the remaining (caudal) portion of the
from the spinal cord; and their associated ganglia. neural tube develops into the spinal cord. Additionally,
Functionally, the PNS is divided into a sensory the neural tube gives rise to the neuroglia, ependyma,
(afferent) component, which receives and transmits neurons, and choroid plexus.
impulses to the CNS for processing, and a motor A small mass of cells at the lateral margins of the
(efferent) component, which originates in the CNS neural plate, which does not become incorporated into
and transmits impulses to effector organs throughout the neural tube, forms the neural crest cells. This
the body. The motor component is further subdivided group of cells begins to migrate away from the devel-
as follows: oping neural tube early in development. Once they
reach their destinations, these cells eventually form
䡲 In the somatic system, impulses originating in the many structures, including the following:
CNS are transmitted directly, via a single neuron, to
skeletal muscles. 䡲 Most of the sensory components of the PNS
䡲 In the autonomic system, in contrast, impulses from 䡲 Sensory neurons of cranial and spinal sensory ganglia
the CNS first are transmitted to an autonomic gan- (dorsal root ganglia)
glion via one neuron; a second neuron originating in 䡲 Autonomic ganglia and the postganglionic autonomic
the autonomic ganglion then transmits the impulses neurons originating in them
to smooth muscles, cardiac muscles, or glands. 䡲 Much of the mesenchyme of the anterior head and
neck
In addition to neurons, nervous tissue contains 䡲 Melanocytes of the skin and oral mucosa
numerous other cells, collectively called neuroglial 䡲 Odontoblasts (cells responsible for production of
cells, which do not receive or transmit impulses; dentin)
instead, these cells support neurons in various ways. 䡲 Chromaffin cells of the adrenal medulla
185
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186 䡲䡲䡲 Chapter 9 䡲 Nervous Tissue
䡲 Cells of the arachnoid and pia mater body of a neuron, also known as the perikaryon or
䡲 Satellite cells of peripheral ganglia soma, is the central portion of the cell where the
䡲 Schwann cells nucleus and perinuclear cytoplasm are contained. Gen-
erally, neurons in the CNS are polygonal (Fig. 9-1), with
concave surfaces between the many cell processes,
whereas neurons in the dorsal root ganglion (a sensory
CLINICAL CORRELATIONS ganglion of the PNS) have a round cell body from which
Abnormal organogenesis of the CNS results in only one process exits (Fig. 9-2). Cell bodies exhibit dif-
various types of congenital malformations. Spina ferent sizes and shapes that are characteristic for their
bifida is a defective closure of the spinal column. type and location. These different morphologies are
In severe cases, the spinal cord and meninges described later in the discussion of the various regions
may protrude through the unfused areas. Spina of the nervous system.
bifida anterior is a defective closure of the Projecting from the cell body are the dendrites,
vertebrae. Severe cases may be associated with processes specialized for receiving stimuli from sensory
defective development of the viscera of the cells, axons, and other neurons (Fig. 9-3). Often the
thorax and abdomen. dendrites are multibranched. They are arborized so that
Anencephaly is failure of the developmental they can receive multiple stimuli from many other
anterior neuropore to close, with a poorly formed neurons simultaneously. The nerve impulses received
brain and absence of the cranial vault. It usually by the dendrites are then transmitted toward the soma.
is not compatible with life. Each neuron possesses a single axon, a process of
Epilepsy may result from abnormal migra- varying diameter and up to 100 cm in length, which
tion of cortical cells, which disrupts normal usually has terminal dilatations, known as axon termi-
interneuronal functioning. nals, at or near its end. The axon conducts impulses
Hirschsprung disease, also known as con- away from the soma to other neurons, muscles, or
genital megacolon, is caused by failure of the glands, but it may also receive stimuli from other
neural crest cells to invade the wall of the gut. neurons, which may modify its behavior. Like dendrites,
The wall lacks Auerbach’s plexus, a portion of the axon arborizes. These axon terminals, also known as
the parasympathetic system innervating the
distal end of the colon. Absence of the plexus
leads to dilatation and hypertrophy of the colon.
CELLS OF THE NERVOUS SYSTEM mN

The cells of the nervous system are divided into two
categories: neurons, which are responsible for the
receptive, integrative, and motor functions of the
nervous system; and neuroglial cells, which support and
protect neurons.
Neurons
The cells responsible for the reception and transmission
of nerve impulses to and from the CNS are the neurons.
Ranging in diameter from 5 to 150 mm, neurons are
among both the smallest and the largest cells in the
body.
Structure and Function of Neurons

Neurons are composed of a cell body, dendrites, and an
axon.
Figure 9–1 Light micrograph of the gray matter of the spinal
Most neurons are composed of three distinct parts: a cord (×270). Observe the multipolar neuron (mN) cell bodies and
cell body, multiple dendrites, and a single axon. The cell their processes.
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Chapter 9 䡲 Nervous Tissue ■ ■ ■ 187
scope. RER is also present in the dendritic region of the

neuron, but only as scattered short or branching cister-
nae. RER is absent at the axon hillock, the region on
the cell body where the axon arises; however, smooth
endoplasmic reticulum (SER) is present in the axon.
Although Nissl bodies in each type of neuron have a
characteristic size, shape, and form, no pattern has been
n observed. Generally, small neurons display small gran-
ular Nissl bodies, but not all large neurons display larger
Nissl bodies. These differences may be related to
changing physiological and pathological conditions
within the neuron.
Most neurons have abundant SER throughout the
cell body; this reticulum extends into the dendrites
and the axon, forming hypolemmal cisternae directly
beneath the plasmalemma. These cisternae are contin-
uous with the RER in the cell body and weave between
N the Nissl bodies on their way into the dendrites and
axon. Although it is unclear how they function, it is
known that hypolemmal cisternae sequester calcium
and contain protein. These cisternae may serve as a
conduit for the distribution of protein throughout the
cell. Some authors theorize that transport and synaptic
vesicles bud from these cisternae, but much of this issue
Figure 9–2 Light micrograph of a sensory ganglion (×270). is still unclear.
Observe the large neuronal cell bodies (N) with singular nucleoli (n). A prominent juxtanuclear Golgi complex is present,
composed of several closely associated cisternae ex-
end bulbs (terminal boutons), approach other cells hibiting a dilated periphery, characteristic of protein-
to form a synapse, the region where impulses can be secreting cells. The Golgi complex is thought to be
transmitted between cells. Neurons can be classified responsible for the packaging of neurotransmitter sub-
according to their shape and the arrangement of their stances or enzymes essential for their production in the
processes (Fig. 9-4). axon.
Numerous mitochondria are scattered throughout
Neuronal Cell Body (Soma, Perikaryon) the cytoplasm of the soma, dendrites, and axon, but they
are most abundant at the axon terminals. Generally, the
The cell body is the region of the neuron containing the mitochondria in neurons are more slender than those in
large, pale-staining nucleus and the perinuclear other cells, and occasionally their cristae are oriented
cytoplasm. longitudinally rather than transversely. It has been
shown that neuronal mitochondria are constantly
The cell body is the most conspicuous region of the moving along microtubules in the cytoplasm.
neuron, but the largest volume of the neuron’s cyto- Most adult neurons display only one centriole asso-
plasm is located in the processes originating from the ciated with a basal body of a cilium; it possesses the
cell body. The nucleus is large, usually spherical to 9 + 0 arrangement of microtubules (see Chapter 2 con-
ovoid, and centrally located. It contains finely dispersed cerning microtubule structure). Because neurons do
chromatin, indicative of a rich synthetic activity, al- not undergo cell division, their centrioles are believed
though smaller neurons may present some condensed, to be vestigial structures.
inactive heterochromatin. A well-defined nucleolus is
also common. INCLUSIONS
The cytoplasm of the cell body has abundant rough
endoplasmic reticulum (RER) with many cisternae in Inclusions located in neuronal cell bodies encompass
parallel arrays, a characteristic especially prominent in nonliving substances such as melanin and lipofuscin
large motor neurons. Polyribosomes are also scattered pigments as well as lipid droplets.
throughout the cytoplasm. When these stacked RER
cisternae and polyribosomes are stained with basic dyes, Dark brown to black melanin granules are found in
they appear as clumps of basophilic material called neurons in certain regions of the CNS (e.g., mostly in
Nissl bodies, which are visible with the light micro- the substantia nigra and locus ceruleus, with lesser
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Dendrites
Motor neuron
Axon hillock
Axon
Myelin sheath
Node of Ranvier
Collateral
branch
End bulb
Muscle fiber
Figure 9–3 A, Typical motor neuron. B, Elec-

tron micrograph of a ventral horn neuron with several
of its dendrites (×1300). (B, From Ling EA, Wen CY,
Shieh JY, et al: Neuroglial response to neuron injury:
A study using intraneural injection of Ricinus com-
munis agglutinin-60. J Anat 164:201-213, 1989.)
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Dendrites Dendrites
Axon
Cell
Cell body
body
Axon
Axon
Bipolar Unipolar Multipolar

(retina) (pseudounipolar) (motor)
Dendrites
Cell
body
Axon
Figure 9–4 The various types of Pyramidal Purkinje

neurons. (hippocampus) (cerebellum)
amounts in the dorsal motor nucleus of the vagus and Lipid droplets sometimes are observed in the
the spinal cord) and in the sympathetic ganglia of the neuronal cytoplasm and may be the result of faulty
PNS. The function of these granules in these various metabolism or from energy reserves. Secretory gran-
locations is unknown. However, dihydroxyphenylala- ules are observed in neurosecretory cells; many of them
nine (DOPA), or methyldopa, the precursor of this contain signaling molecules.
pigment, is also the precursor of the neurotransmitters
dopamine and noradrenaline. It has been suggested, CYTOSKELETAL COMPONENTS
therefore, that melanin may accumulate as a by-product
of the synthesis of these neurotransmitters. When prepared by silver impregnation for visualization
Lipofuscin, an irregularly shaped, yellowish brown with light microscopy, the neuronal cytoskeleton
pigment granule, is more prevalent in the neuronal exhibits neurofibrils (up to 2 mm in diameter) cours-
cytoplasm of older adults and is thought to be the ing through the cytoplasm of the soma and extending
remnant of lysosomal enzymatic activity. Lipofuscin into the processes. Electron microscopic studies reveal
granules increase in number with advancing age and three different filamentous structures: microtubules
may even crowd the organelles and nucleus to one side (24 nm in diameter), neurofilaments (intermediate
in the cell, possibly affecting cellular function. It is filaments 10 nm in diameter), and microfilaments
interesting that certain cells (e.g., Purkinje cells of the (6 nm in diameter). The neurofibrils observed with light
cerebellar cortex) do not accumulate lipofuscin. Iron- microscopy possibly represent clumped bundles of neu-
containing pigments also may be observed in certain rofilaments, a suggestion supported by the fact that neu-
neurons of the CNS and may accumulate with age. rofilaments are stained by silver nitrate. Microfilaments
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(actin filaments) are associated with the plasma mem- These spines diminish with age and poor nutrition, and
brane. The microtubules in neurons are identical to they may exhibit structural changes in persons with
those in other cells, except that the microtubule- trisomy 13 and trisomy 21 (Down syndrome). Dendrites
associated protein MAP-2 is found in the cytoplasm sometimes contain vesicles and transmit impulses to
of the cell body and dendrite, whereas MAP-3 is present other dendrites.
only in the axon.
Axons
Dendrites
Axons transmit impulses to other neurons or effector
Dendrites receive stimuli from other nerve cells. cells, namely cells of muscle and glands.
Dendrites are elaborations of the receptive plasma The axon arises from the cell body at the axon hillock
membrane of the neuron. In some neurons, however, as a single, thin process extending longer distances from
the cell body and the proximal end of the axon may also the cell body than does the dendrite. In some instances,
serve in a receptive capacity. Most neurons possess mul- axons of motor neurons may be 1 meter or more in
tiple dendrites, each of which arises from the cell body, length. Axon thickness is directly related to conduction
usually as a single, short trunk that ramifies several velocity, so that velocity increases as axon diameter
times into smaller and smaller branches, tapering at the increases. Although axon thickness varies, it is constant
ends like branches of a tree. Each kind of neuron has a for a particular type of neuron. Some axons possess col-
characteristic dendrite branching pattern. The base of lateral branches, which arise at right angles from the
the dendrite arises from the cell body and contains the axonal trunk (see Fig. 9-3A). As the axon terminates,
usual complement of organelles except for Golgi com- it may ramify, forming many small branches (terminal
plexes (Fig. 9-5). Farther away from the base, toward arbor).
the distal end of the dendrite, many of the organelles The axon hillock, a pyramid-shaped region of the
become sparse or are absent. soma, is devoid of ribosomes and is usually located on
In the dendrites of most neurons, neurofilaments the opposite side of the soma from the dendrites. The
are reduced to small bundles or single filaments, which portion of the axon from its origin to the beginning of
may be cross-linked to microtubules. Mitochondria, the myelin sheath is called the initial segment. Deep
however, are abundant in dendrites. The branching of to the axolemma (plasmalemma) of the initial segment
dendrites, which results in numerous synaptic termi- is a thin, electron-dense layer whose function is not
nals, permits a neuron to receive and integrate multi- known but that resembles the layer located at the nodes
ple, perhaps even hundreds of thousands, of impulses. of Ranvier. This area of the soma lacks RER and ribo-
Spines located on the surfaces of some dendrites somes but houses abundant microtubules and neuro-
permit them to form synapses with other neurons. filaments that are believed to facilitate the regulation
Dendrite Smooth
endoplasmic
reticulum
Ribosomes
Lysosomes
Lipofuscin
granule
Nissl substance
Synapse
Synaptic vesicle
Figure 9–5 Ultrastructure of a neu-
Golgi ronal cell body. (From Lentz TL: Cell
Fine Structure: An Atlas of Drawings of
Microtubule
Whole-Cell Structure. Philadelphia, WB
Axon Saunders, 1971.)
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of the axon’s diameter. In some neurons, the number

of neurofilaments may increase three-fold in the initial CLINICAL CORRELATIONS
segment, whereas the number of microtubules
increases only slightly. It is in this initial segment, Retrograde axonal transport is used by certain
referred to as the spike trigger zone, where excitatory viruses (e.g., herpes simplex and rabies virus) to
and inhibitory impulses are summed to determine spread from one neuron to the next in a chain of
whether propagation of an action potential is to occur. neurons. It is also the method whereby toxins
The axoplasm contains short profiles of SER and (e.g., tetanus) are transported from the periph-
remarkably long, thin mitochondria and many micro- ery into the CNS.
tubules; however, it lacks RER and polyribosomes.
Thus, the axon relies on the soma for its maintenance.
Microtubules are grouped in small bundles at the origin
of the axon and in its initial segment; distally, however,
they become arranged as uniformly spaced, single Oligodendrocyte
microtubules interspersed with neurofilaments.
The plasmalemma of certain neuroglial cells forms
a myelin sheath around some axons in both the
CNS and the PNS, referred to as myelinated axons
(Figs. 9-6 and 9-7) (the process of myelination is
described in detail later). Axons lacking myelin sheaths
are called unmyelinated axons (Fig. 9-8). Nerve
impulses are conducted much faster along myelinated
Myelin
axons than along unmyelinated axons. In the fresh state, wrapping
the myelin sheath imparts a white, glistening appearance axon
to the axon. The presence of myelin permits the subdivi- Axon
sion of the CNS into white matter and gray matter.
In addition to impulse conduction, an important
function of the axon is axonal transport of materials
between the soma and the axon terminals. In antero-
grade transport, the direction is from the cell body to
the axon terminal; in retrograde transport, the direc-
tion is from the axon terminal to the cell body. Axonal
transport is crucial to trophic relationships within the
axon because it is located between neurons and muscles
or glands. If these relationships are interrupted, the
Myelination
target cells atrophy. continues
Axonal transport occurs at three velocities: fast,
intermediate, and slow. The most rapid transport (up to
400 mm/day) takes place in anterograde transport of
organelles, which move more rapidly in the cytosol. In
retrograde transport, the fastest speed is less than half
that observed in anterograde transport, with the slowest
being only about 0.2 mm/day. Axonal transport
speeds between these two extremes are considered
intermediate.
Anterograde transport is used in the translocation
of organelles and vesicles as well as of macromolecules
such as actin, myosin, and clathrin and of some enzymes
necessary for neurotransmitter synthesis at the axon Myelination
terminals. Items returned to the cell body from the complete
axon in retrograde transport include protein building
blocks of neurofilaments, subunits of microtubules,
soluble enzymes, and materials taken up by endocytosis
(e.g., viruses and toxins). Additionally, small molecules Figure 9–6 Process of myelination in the central nervous system.
and proteins destined for degradation are transported Unlike the Schwann cell of the peripheral nervous system, each oligo-
to endolysosomes of the soma. dendroglion is capable of myelinating several axons.
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Axonal transport not only distributes materials for

nerve conduction and neurotransmitter synthesis but
also serves to provide and ensure general maintenance
of the axon cytoskeleton.
Schwann cell
Since the 1970s, much has been learned about the
nature and functioning of the neuron through study of
the mechanism of axonal retrograde transport with the
use of the enzyme horseradish peroxidase. When this
Mesaxon enzyme is injected into the axon terminal, it can be
detected later by histochemical techniques that mark its
pathway to the cell body. In studying anterograde axonal
transport, researchers inject radiolabeled amino acids
into the cell body and then later determine the radioac-
tivity at the axon terminals using autoradiography.
Microtubules are important in fast anterograde
transport because they exhibit a polarity, with their
Basal lamina
plus ends directed toward the axon terminal. Tubulin
dimers, reaching the axoplasm via anterograde trans-
port, are assembled onto the microtubules at their
Figure 9–7 The fine structure of a myelinated nerve fiber and
plus ends and depolymerized at their minus ends. The
its Schwann cell. (From Lentz TL: Cell Fine Structure: An Atlas of mechanism for anterograde transport involves kinesin,
Drawings of Whole-Cell Structure. Philadelphia, WB Saunders, a microtubule-associated protein, because one end
1971.) attaches to a vesicle and the other end interacts in a
cyclical fashion with a microtubule, thus permitting
the kinesin to transport the vesicle at a speed of about
3 mm/second. Dynein, another microtubule-associated
protein, is responsible for moving vesicles along the
microtubules in retrograde transport.
Although neurological tumors account for
about 50% of intracranial tumors, those of
neurons of the CNS are rare. Most intracranial
tumors originate from neuroglial cells (e.g.,
benign oligodendrogliomas and fatal malig-
nant astrocytomas). Tumors that arise from
cells of connective tissue associated with nervous
tissue (e.g., benign fibroma or malignant
sarcoma) are connective tissue tumors and are
not related to the nervous system. Tumors of
neurons in the PNS may be extremely malignant
(e.g., neuroblastoma in the suprarenal gland,
which attacks mostly infants and young children).
Classification of Neurons
Neurons are classified morphologically into three major
types according to their shape and the arrangement of
Schwann cell
Mesaxons their processes.
Axons
There are three major types of neurons (see Fig. 9-4):
Figure 9–8 The fine structure of an unmyelinated nerve fiber.
(From Lentz TL: Cell Fine Structure. An Atlas of Drawings of Whole- 䡲 Bipolar neurons possess two processes emanating
Cell Structure. Philadelphia, WB Saunders, 1971.) from the soma, a single dendrite and a single axon.
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Bipolar neurons are located in the vestibular and Blood Perivascular

cochlear ganglia and in the olfactory epithelium of vessel foot
the nasal cavity.
䡲 Unipolar neurons (formerly called pseudounipo-
lar neurons) possess only one process emanating
from the cell body, but this process branches later
into a peripheral branch and a central branch. The
central branch enters the CNS, and the peripheral
branch proceeds to its destination in the body. Each
of the branches is morphologically axonal and can Protoplasmic Fibrous
propagate nerve impulses, although the very distal astrocyte astrocyte
aspect of the peripheral branch arborizes and dis-
plays small dendritic ends, indicating its receptor
function. Unipolar neurons develop from embryonic
bipolar neurons whose processes migrate around the
cell body during development and eventually fuse
into a single process. During impulse transmission,
the impulse passes from the dendritic (receiving) end
of the peripheral process to the central process
without involving the cell body. Unipolar neurons are Microglia Oligodendrocyte
present in the dorsal root ganglia and in some of the
cranial nerve ganglia. Figure 9–9 The various types of neuroglial cells.
䡲 Multipolar neurons, the most common type,
possess various arrangements of multiple dendrites
emanating from the soma and a single axon. They are
present throughout the nervous system, and most of Cells whose function is the metabolic and mechanical
them are motor neurons. Some multipolar neurons support and protection of neurons collectively form the
are named according to their morphology (e.g., neuroglia (Fig. 9-9). There may be as many as 10 times
pyramidal cells) or after the scientist who first more neuroglial cells than neurons in the nervous
described them (e.g., Purkinje cells). system. Neuroglial cells undergo mitosis, whereas
Neurons also are classified into three general groups neurons cannot—only their progenitors can. Although
according to their function: neuroglial cells form gap junctions with other neuro-
glial cells, they do not react to or propagate nerve
䡲 Sensory (afferent) neurons receive sensory input impulses. Neuroglial cells that reside exclusively in the
at their dendritic terminals and conduct impulses to CNS include astrocytes, oligodendrocytes, microglia
the CNS for processing. Those located in the periph- (microglial cells), and ependymal cells. Schwann cells,
ery of the body monitor changes in the environment, although located in the PNS, are now also considered
and those within the body monitor the internal neuroglial cells.
environment.
䡲 Motor (efferent) neurons originate in the CNS and Astrocytes
conduct their impulses to muscles, glands, and other
neurons. Astrocytes provide structural and metabolic support
䡲 Interneurons, located completely in the CNS, func- to neurons and act as scavengers of ions and
tion as interconnectors or integrators that establish neurotransmitters released into the extracellular space.
networks of neuronal circuits between sensory and
motor neurons and other interneurons. With evolu- Astrocytes are the largest of the neuroglial cells and
tion, the number of neurons in the human nervous exist as two distinct types: (1) protoplasmic astrocytes in
system has grown enormously, but the greatest the gray matter of the CNS and (2) fibrous astrocytes
increase has involved the interneurons, which are present mainly in the white matter of the CNS. It is
responsible for the complex functioning of the body. difficult to distinguish the two types of astrocytes in
light micrographs. Some researchers have suggested
that they may be the same cells functioning in different
Neuroglial Cells environments. Electron micrographs display distinct
cytoplasmic bundles of intermediate filaments 8- to
Neuroglial cells function in the physical and metabolic
11-nm in diameter composed of glial fibrillar acidic
support of neurons.
protein, which is unique to astrocytes.
Ch009-X2945.qxd 12/8/06 3:29 PM Page 194
*
F
r
r
* t
graph of protoplasmic astrocyte
(×11,400). Observe the nucleus (N),
m * filaments (F), mitochondria (m),
microtubules (t), free ribosomes (r),
and granular endoplasmic reticulum
(ER). Two lysosomes (L) are also
L identified in the processes of the
neuroglia. Note the irregular cell
boundary (arrowheads) and pro-
cesses of other neuroglial cells of
the neuropil (asterisks). Inset, Light
* micrograph of three highly branched
m protoplasmic astrocytes (P) sur-
N
rounding capillaries (C). (Large
image, From Peters A, Palay SL,
ER Webster HF: The Fine Structure of
the Nervous System. Philadelphia,
L WB Saunders, 1976. Inset, From
Leeson TS, Leeson CR, Paparo AA:
Text/Atlas of Histology. Philadelphia,
WB Saunders, 1988.)
Protoplasmic astrocytes are stellate cells display-

ing abundant cytoplasm, a large nucleus, and many
short branching processes (Fig. 9-10). The tips of some
processes end as pedicels (vascular feet) that come
into contact with blood vessels. Other astrocytes lie
adjacent to blood vessels with the cell body apposed to
the vessel wall. Still other protoplasmic astrocytes near
the brain or surface of the spinal cord exhibit pedicel-
tipped processes that contact the pia mater, forming
the pia-glial membrane. Some smaller protoplasmic
astrocytes located adjacent to neuronal cell bodies are
a form of satellite cells.
Fibrous astrocytes possess a euchromatic cyto-
plasm containing only a few organelles, free ribosomes, Figure 9–11 Light micrograph of a fibrous astrocyte (arrow) in
the human cerebellum (×132).
and glycogen (Fig. 9-11). The processes of these cells
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are long and mostly unbranched. These processes are Oligodendrocytes

closely associated with the pia mater and blood vessels
but are separated from these structures by their own Oligodendrocytes function in electrical insulation and in
basal lamina. myelin production in the CNS.
Astrocytes function in scavenging ions, neurotrans-
mitters, and remnants of neuronal metabolism, such as Oligodendrocytes resemble astrocytes but are smaller
potassium ions (K+), glutamate, and γ-aminobutyric acid and contain fewer processes with sparse branching. The
(GABA), accumulated in the microenvironment of the darkest-staining neuroglial cells, oligodendrocytes are
neurons, especially at the nodes of Ranvier, where they located in both the gray and the white matter of
provide a cover for the axon. These cells also contribute the CNS. Their dense cytoplasm contains a relatively
to energy metabolism within the cerebral cortex by small nucleus, abundant RER, many free ribosomes
releasing glucose from their stored glycogen when and mitochondria, and a conspicuous Golgi complex
induced by the neurotransmitters norepinephrine and (Fig. 9-12). Microtubules also are present, especially in
vasoactive intestinal peptide. Astrocytes located at the the perinuclear zone and in the processes.
periphery of the CNS form a continuous layer over Interfascicular oligodendrocytes, located in rows
the blood vessels and may assist in maintaining the beside bundles of axons, are responsible for manufac-
blood-brain barrier. Astrocytes are also recruited to turing and maintaining myelin about the axons of the
damaged areas of the CNS, where they form cellular CNS, serving to insulate them (see Fig. 9-6). In pro-
scar tissue. ducing myelin, oligodendrocytes function similarly to
As
ER
m N

graph of an oligodendrocyte
(×2925). Note the nucleus (N),
endoplasmic reticulum (ER), Golgi
apparatus (G), and mitochondria
(m). Processes of fibrous astrocytes
(As) contact the oligodendrocyte.
(From Leeson TS, Leeson CR, As
Paparo AA: Text/Atlas of Histology.
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the Schwann cells of the PNS, except that a single oligo- that facilitates the movement of cerebrospinal fluid
dendrocyte may wrap several axons with segments of (CSF). In the embryo, processes emanating from the
myelin, whereas a single Schwann cell wraps only one cell body reach the surface of the brain, but in the adult
axon with myelin. Schwann cells also differ from inter- the processes are reduced, ending on nearby cells.
fascicular oligodendrocytes in the following ways: Where the neural tissue is thin, ependymal cells form
Schwann cells possess a basal lamina and retain some an internal limiting membrane lining the ventricle
cytoplasm within the intracellular domains of the and an external limiting membrane beneath the pia,
myelin lamellae, and connective tissue invests the both formed by thin fused pedicels. Modifications of
myelin sheaths and their surrounding Schwann cells. some of the ependymal cells in the ventricles of the
Satellite oligodendrocytes are closely applied to brain participate in the formation of the choroid
cell bodies of large neurons; their function is not clear. plexus, which is responsible for secreting and main-
taining the chemical composition of the CSF.
Microglial Cells Tanycytes, specialized ependymal cells, extend
processes into the hypothalamus, where they terminate
Microglia are members of the mononuclear phagocyte near blood vessels and neurosecretory cells. It is
system. believed that tanycytes transport CSF to these neu-
rosecretory cells and, possibly under control from the
Scattered throughout the CNS, microglial cells are anterior lobe of the pituitary, may respond to changes
small, dark-staining cells that faintly resemble oligo- in hormone levels in the CSF by discharging secretory
dendrocytes. These cells exhibit scant cytoplasm, an products into capillaries of the median eminence.
oval to triangular nucleus, and irregular short processes.
Spines also adorn the cell body and processes. These
cells function as phagocytes in clearing debris and Schwann Cells
damaged structures in the CNS. Microglial cells also
Schwann cells form both myelinated and unmyelinated
protect the nervous system from viruses, microorgan-
coverings over axons of the PNS.
isms, and tumor formation. When activated, they act as
antigen-presenting cells and secrete cytokines. Unlike Unlike other neuroglial cells, Schwann cells are
the other neuroglial cells, which are derived embry- located in the PNS, where they envelop axons. They can
ologically from the neural tube, microglial cells form either myelinated or unmyelinated coverings over
originate in the bone marrow and are part of the axons. Axons that have myelin wrapped around them
mononuclear phagocytic cell population. are referred to as myelinated nerves.
Schwann cells are flattened cells whose cytoplasm
contains a flattened nucleus, a small Golgi apparatus,
CLINICAL CORRELATIONS and a few mitochondria. Electron microscopy has
Large populations of microglial cells are pre- revealed that myelin is the plasmalemma of the
sent in the brains of patients with acquired Schwann cell organized into a sheath that is wrapped
immunodeficiency syndrome (AIDS) and human several times around the axon. Interruptions occur in
immunodeficiency virus-1 (HIV-1). Although the myelin sheath at regular intervals along the length
HIV-1 does not attack neurons, it does attack of the axon, exposing the axon; these interruptions are
microglial cells, which then produce cytokines called nodes of Ranvier (Fig. 9-13). Each node indi-
that are toxic to neurons. cates an interface between the myelin sheaths of two
different Schwann cells located along the axon.
The outer portion of Schwann cells is covered by a
basal lamina that dips into the nodes of Ranvier, cover-
Ependymal Cells ing the overlapped areas of the myelin sheath lamellae
of adjacent Schwann cells. Thus, each Schwann cell is
Ependymal cells form limiting membranes and also may covered by a basal lamina, as is the axon at the node of
function in the transportation of cerebrospinal fluid. Ranvier. After nerve injury, the regenerating nerve is
guided by the basal lamina to its location.
Ependymal cells (ependymocytes) are low columnar to Areas of the axon covered by concentric lamellae of
cuboidal epithelial cells lining the ventricles of the brain myelin and the single Schwann cell that produced the
and central canal of the spinal cord. They are derived myelin are called internodal segments, which range
from embryonic neuroepithelium of the developing in length from 200 to 1000 µm. Light microscopy has
nervous system. Their cytoplasm contains abundant revealed several cone-shaped, oblique clefts in the
mitochondria and bundles of intermediate filaments. myelin sheath of each internodal segment called clefts
In some regions, these cells are ciliated, a feature (incisures) of Schmidt-Lanterman. These clefts,
Ch009-X2945.qxd 12/8/06 3:29 PM Page 197
Oligodendrocyte
Myelinated nerve fibers
Axon
Node of Ranvier
Schwann cell
Plasmalemma
of Schwann cell
Axon
Figure 9–13 Diagrammatic re-
presentation of the myelin structure
at the nodes of Ranvier of axons in the Myelin sheath
central nervous system and (inset) in
the peripheral nervous system.
viewed with the electron microscope, are demonstrated membrane around the axon. The wrapping may con-
to be Schwann cell cytoplasm trapped within the lamel- tinue for more than 50 turns. During this process, the
lae of myelin. cytoplasm is squeezed back into the body of the
As the membrane spirals around the axon, it pro- Schwann cell, bringing the cytoplasmic surfaces of
duces a series of alternating wide, dense lines with nar- the membranes in contact with each other, thus forming
rower, less dense lines occurring at 12-nm intervals. The the major dense line that spirals through the myelin
wider line (3 nm in width) is known as the major dense sheath. A single Schwann cell can myelinate only one
line. It represents the fused cytoplasmic surfaces of internode of a single axon (and only in the PNS),
the Schwann cell plasma membrane. The narrower whereas oligodendrocytes can myelinate an internode
intraperiod line represents the apposing outer leaflets of several axons (and only in the CNS).
of the Schwann cell plasma membrane. High-resolution Nerves are not myelinated simultaneously during
electron microscopy has revealed small gaps within the development. Indeed, the onset and completion of
intraperiod line between spiraled layers of the myelin myelination vary considerably in different areas of the
sheath called intraperiod gaps. These gaps are nervous system. This variation seems to be correlated
thought to provide access for small molecules to reach with function. For example, motor nerves are nearly
the axon. The region of the intraperiod line that is in completely myelinated at birth, whereas sensory roots
intimate contact with the axon is known as the internal are not myelinated for several months thereafter. Some
mesaxon, whereas its outermost aspect, which is in CNS nerve tracts and commissural axons are not fully
contact with the body of the Schwann cell, is the exter- myelinated until several years after birth.
nal mesaxon (Fig. 9-14; also see Fig. 9-7). Some axons in the PNS are not wrapped with the
The mechanism of myelination, that is, the process many layers of myelin typical of myelinated axons. These
whereby the Schwann cell located in the PNS (or oligo- unmyelinated axons are surrounded by a single layer of
dendrocyte, located in the CNS) concentrically wraps Schwann cell plasma membrane and cytoplasm of the
its membrane around the axon to form the myelin Schwann cell (see Fig. 9-8). Although a single Schwann
sheath, is unclear. It is believed to begin when a cell can myelinate only one axon, several unmyelinated
Schwann cell envelops an axon and somehow wraps its axons may be enveloped by a single Schwann cell.
Ch009-X2945.qxd 12/8/06 3:29 PM Page 198

graph of a myelinated peripheral
nerve. Note the internal (i) and
external (e) mesaxons as well as the
Schwann cell cytoplasm and nucleus.
(From Jennes L, Traurig HH, Conn
PM: Atlas of the Human Brain.
Philadelphia, Lippincott-Raven, 1995.)
potassium ions (K+) is much higher inside the cell than

GENERATION AND CONDUCTION outside the cell, whereas the concentration of sodium
OF NERVE IMPULSES* ions (Na+) and chloride ions (Cl−) is much higher
outside the cells than inside the cell.
Nerve impulses are generated in the spike trigger zone K+ leak channels in the plasmalemma permit a rel-
of the neuron and are conducted along the axon to the atively free flow of potassium ions out of a cell down its
axon terminal. concentration gradient (Fig. 9-15). Although the K+ leak
channel allows sodium ions to enter the cell, the ratio
Nerve impulses are electrical signals that are generated of potassium to sodium is 100:1, so that many more
in the spike trigger zone of a neuron as the result of potassium ions leave the cell than sodium ions enter;
membrane depolarization and are conducted along thus, a small net positive charge accumulates on the
the axon to the axon terminal. Transmission of impulses outside of the plasma membrane. Although mainte-
from the terminals of one neuron to another neuron, a nance of the resting potential depends primarily on K+
muscle cell, or a gland occurs at synapses (see Synapses leak channels, Na+-K+ pumps in the plasma membrane
and the Transmission of the Nerve Impulse). assist by actively pumping Na+ out of the cell and K+
Neurons and other cells are electrically polarized into the cell. For every three sodium ions pumped out,
with a resting potential of about −90 mV (the inside two potassium ions enter the cell, also making a minor
of the cell being less positive than the outside) across contribution to the potential difference between the
the plasma membrane, although in smaller muscle cells two sides of the membrane.
and small nerve fibers, this differential may be as low as In most cells, the potential across the plasma mem-
−40 to −60 mV. This potential arises because of the dif- brane is generally constant. In neurons and muscle
ference between ion concentrations inside and outside cells, however, the membrane potential can undergo
the cell. In mammalian cells, the concentration of controlled changes, making these cells capable of con-
ducting an electrical signal, as follows:
*Although negatively charged proteins within the cytoplasm of the
neuron do not cross the cell membrane, they do affect the behavior 1 Stimulation of a neuron causes opening of voltage-
of the various charged species. However, their role in the generation
and conduction of nerve impulses is not described here. The inter- gated Na+ channels in a small region of the mem-
ested reader is referred to textbooks of physiology or neuroscience for brane, leading to an influx of Na+ into the cell at that
an in-depth explanation of these phenomena. site (Fig. 9-16). Eventually, the overabundance of
Ch009-X2945.qxd 12/8/06 3:29 PM Page 199
Multiple sclerosis (MS), a relatively common disease costeroids is the most common therapy for multiple
affecting myelin, is 1.5 times more common in females sclerosis, although the anti-inflammatory activity of
than in males. It usually occurs between 15 and 45 the therapy is thought to be most beneficial.
years of age, and its principal pathological feature is Radiation therapy can lead to demyelination of
demyelination in the CNS (optic nerve, cerebellum, the brain or spinal cord when these structures are in
and white matter of the cerebrum, spinal cord, and the radiation field during therapy. Toxic agents, such as
cranial and spinal nerves). The disease is distinguished those used in chemotherapy for cancer, may also lead
by episodes of random, multifocal inflammation, to demyelination, resulting in neurological problems.
edema, and subsequent demyelination of axons in the Guillain-Barré Syndrome is an immune disor-
CNS, followed by periods of remission that may last for der that produces inflammation and rapid demyelina-
several months to decades. Each episode may further tion within the peripheral nerves and the motor
jeopardize the patient’s vitality. Any single episode of nerves arising from the ventral roots. This disease is
demyelination may cause deterioration or malignancy associated with recent respiratory and/or gastrointes-
of the affected nerves and may lead to death in a matter tional infection. A symptom of this disease is muscle
of months. Because this demyelination is thought to weakness in the extremities, reaching a high point
result from an autoimmune disease with inflammatory within just a few weeks. Early recognition is followed
features (which may manifest as a possible aftermath by physical therapy and respiratory and autoimmune
of an infectious agent), immunosuppression with corti- globulin treatments.
Na+ inside the cell causes a reversal of the resting that opens as a result of the depolarization of the cell
potential (i.e., the cytoplasmic aspect of the plasma membrane and remains open as long as the mem-
membrane becomes positive relative to its extracyto- brane is depolarized; and an intracytoplasmic gate
plasmic aspect), and the membrane is said to be (inactivation gate) that closes within a few ten-
depolarized. thousandths of a second after the opening of the acti-
2 As a result, the Na+ channels become inactivated for vation gate. Therefore, even though the activation
1 to 2 msec, a condition known as the refractory gate remains open, Na+ can no longer enter or leave
period. During this period the Na+ channels are the cell through these channels.
inactive; that is, they cannot open or close and Na+ 3 During the refractory period, voltage-gated K+
cannot traverse them. The presence of the refractory channels open, permitting an efflux of K+ into the
period is due to the specialized construction of the extracellular fluid that eventually restores the resting
voltage-gated Na+ channels. These channels have two membrane potential; however, there may be a brief
gates: an extracytoplasmic gate (activation gate) period of hyperpolarization.
Extracellular space
+ + + + + +
K K K K K K
Figure 9–15 Schematic diagram
of the establishment of the resting
potential in a typical neuron. Observe
that the potassium ion (K+) leak chan-
nels outnumber the sodium ion (Na+)
and calcium ion (Cl −) channels; conse-
quently, more K+ can leave the cell than
Na+ or Cl− can enter. Because there are
more positive ions outside than inside
the cell, the outside is more positive Cl– Na
+
than the inside, establishing a potential +

K leak channels Cl– channel Na+ channels
difference across the membrane. Ion
channels and ion pumps not directly
responsible for the establishment of
resting membrane potential are not Axoplasm
shown.
Ch009-X2945.qxd 12/8/06 3:29 PM Page 200
Na+ K+
– –
Propagation
+ + + + + + + + – – – – – + + + + + + + + + + + + + + + + + + + + +
– – – – – – – – + + + + + – – – – – – – – – – – – – – – – – – – – –
++ ++
Axon
– – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – –
+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
A
Propagation
+ + + + + +
– – – – +++ – – – – – –
Figure 9–16 Schematic diagram of

– – – – +++ – – – – – – the propagation of an action potential in
an unmyelinated (A) and a myelinated (B)
+ + + + + +
B axon (see text).
4 Once the resting potential is restored, the voltage- represented by gap junctions that permit free
gated K+ channels close, and the refractory period is movement of ions from one cell to another. When
ended with the closing of the activation gate and the this ion movement occurs between neurons, there is
opening of the inactivation gate of the voltage-gated a flow of current. Impulse transmission is much faster
Na+ channel. across electrical synapses than across chemical
synapses.
The cycle of membrane depolarization, hyperpolar-
Chemical synapses are the most common mode of
ization, and return to the resting membrane potential
communication between two nerve cells. The presy-
is called the action potential, an all-or-none response
naptic membrane releases one or more neurotrans-
that can occur at rates of 1000 times per second. The
mitters into the synaptic cleft, a small gap (20 to
membrane depolarization that occurs with the opening
30 nm), located between the presynaptic membrane of
of voltage-gated Na+ channels at one point on an axon
the first cell and the postsynaptic membrane of the
spreads passively for a short distance and triggers
second cell (Fig. 9-17). The neurotransmitter diffuses
the opening of adjacent channels, resulting in the
across the synaptic cleft to gated ion-channel re-
generation of another action potential. In this manner,
ceptors on the postsynaptic membrane. Binding of
the wave of depolarization, or impulse, is con-
the neurotransmitter to these receptors initiates the
ducted along the axon. In vivo, an impulse is con-
opening of ion channels, which permits the passage of
ducted in only one direction, from the site of initial
certain ions, altering the permeability of the postsynap-
depolarization to the axon terminal. The inactivation of
tic membrane and reversing its membrane potential.
the Na+ channels during the refractory periods prevents
Neurotransmitters do not accomplish the reaction
retrograde propagation of the depolarization wave.
events at the postsynaptic membrane; they only activate
the response.
Synapses and the Transmission of When the stimulus at a synapse results in depolar-
the Nerve Impulse ization of the postsynaptic membrane to a threshold
value that initiates an action potential, it is called an
Synapses are the sites of impulse transmission between excitatory postsynaptic potential. A stimulus at the
the presynaptic and postsynaptic cells. synapse that results in maintaining a membrane poten-
tial or increasing its hyperpolarization is called an
Synapses are the sites where nerve impulses are trans-
inhibitory postsynaptic potential.
mitted from a presynaptic cell (a neuron) to a post-
Various types of synaptic contacts between neurons
synaptic cell (another neuron, muscle cell, or cell of a
have been observed. The following synapses are the
gland). Synapses thus permit neurons to communicate
most common (Fig. 9-18; also see Fig. 9-17):
with each other and with effector cells (muscles and
glands). Impulse transmission at synapses can occur 䡲 Axodendritic synapse—between an axon and a
electrically or chemically. dendrite
Although electrical synapses are uncommon in 䡲 Axosomatic synapse—between an axon and a soma
mammals, they are present in the brain stem, retina, 䡲 Axoaxonic synapse—between two axons
and cerebral cortex. Electrical synapses are usually 䡲 Dendrodendritic synapse—between two dendrites
Ch009-X2945.qxd 12/8/06 3:29 PM Page 201
Synaptic vesicles
Presynaptic dense
projection
Synaptic cleft
Postsynaptic density
Spine
apparatus
Shaft Spine
synapse synapse
Figure 9–17 Schematic diagram
of the various types of synapses. Axosomatic Axodendritic
Synaptic Morphology Synapsin-I, a small protein that forms a complex

with the vesicle surface, appears to assist in the
Terminals of axons vary according to the type of synap- clustering of synaptic vesicles held in reserve. When
tic contact. Often the axon forms a bulbous expansion synapsin-I is phosphorylated, these synaptic vesicles
at its terminal end called bouton terminal. Other become free to move to the active zone in preparation
forms of synaptic contacts in axons are derived from for release of the neurotransmitter; dephosphorylation
swellings along the axon called boutons en passage, of synapsin-I reverses the process.
where each bouton may serve as a synaptic site. Synapsin-II and rab3a, another small protein,
The cytoplasm at the presynaptic membrane con- control association of the vesicles with actin microfila-
tains mitochondria, a few elements of SER, and an ments. Docking of the synaptic vesicles with the presy-
abundance of synaptic vesicles assembled around the naptic membrane is under control of two additional
presynaptic membrane (Fig. 9-19). Synaptic vesicles synaptic vesicle proteins: synaptotagmin and syn-
are spherical structures (40 to 60 nm in diameter) filled aptophysin. When an action potential reaches the
with neurotransmitter substance that usually was man- presynaptic membrane, it initiates opening of the
ufactured and packaged near the axon terminal. Peptide voltage-gated calcium ion (Ca2+) channels, permit-
neurotransmitters, however, are manufactured and ting Ca2+ to enter. This Ca2+ influx causes synaptic vesi-
packaged in the cell body and are transported to the cles, under the influence of SNARE (SNAP receptor)
axon terminal via anterograde transport. Enzymes proteins (including synaptobrevin, syntaxin, and soluble
located in the axoplasm protect neurotransmitters from N-ethylmaleimide-sensitive fusion protein attachment
degradation. protein-25 [SNAP-25]) to fuse with the presynaptic
Also located on the cytoplasmic side of the presynap- membrane, emptying neurotransmitter into the synap-
tic membrane are cone-shaped densities that project tic cleft via exocytosis.
from the membrane into the cytoplasm; they appear to Excess membrane is recaptured via clathrin-
be associated with many of the synaptic vesicles, forming mediated endocytosis. Recycling of synaptic vesicles
the active site of the synapse. Those synaptic vesicles involves interactions between synaptotagmin and
associated with the active site are released at stimula- vesicle coat protein AP-2. The endocytic vesicle fuses
tion. Cell adhesion molecules (CAMs) are known to with the smooth endoplasmic reticulum, where new
play an additional role in this location as signaling mole- membrane is continuously recycled. It is interesting
cules at both the presynaptic and postsynaptic aspects of that the target protein for tetanus toxin and Clostridium
the synapse. Other synaptic vesicles, forming a reserve botulinum neurotoxin B is synaptobrevin, the synaptic
pool, adhere to actin microfilaments. vesicle protein. Thus, these toxins selectively block
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A B
Figure 9–18 Electron micrographs

of synapses. The arrow indicates
transmission direction. A, Axodendritic
synapse (×37,600). Presynaptic vesicles
are located to the left B, Axodendritic
synapse (×43,420). Note neurotubules in
dendrite. C, Dendrite in cross section
(×43,420). Note the synapse. D, Axoden-
dritic synapse (×76,000). Note presynaptic
vesicle fusing with the axolemma. E, Axon
terminal with clear synaptic vesicles and
dense-cored vesicles (×31,000). (From
Leeson TS, Leeson CR, Paparo AA:
Text/Atlas of Histology. Philadelphia, WB
Saunders, 1988.)
synaptic vesicle exocytosis without affecting any other increase synaptogenesis, synaptic efficacy, and action-
aspect of nerve function. potential firing.
The postsynaptic membrane, a thickened portion The relative thicknesses and densities of the pre-
of the plasma membrane of the postsynaptic cell, con- synaptic and postsynaptic membranes, coupled with
tains neurotransmitter receptors, and the cytoplasmic the width of the synaptic cleft, generally correlate with
area contains some dense material. Coupling of the neu- the nature of the response. A thick postganglionic
rotransmitter with the receptors in the plasmalemma density and a 30-nm-wide synaptic cleft constitutes
initiates depolarization (an excitatory response) or an asymmetric synapse, which is usually the site of
hyperpolarization (an inhibitory response) of the post- excitatory responses. A thin postsynaptic density and
synaptic membrane. Glial cells have been shown to a 20-nm-wide synaptic cleft constitutes a symmetric
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graph of an axodendritic synapse.
Observe the numerous synaptic vesi-
cles (V) within the axon terminal
synapsing with dendrites and the
synaptic clefts at these sites
(arrows). (From Jennes L, Traurig
HH, Conn PM: Atlas of the Human
Brain. Philadelphia, Lippincott-
Raven, 1995.)
synapse, which is usually the site of inhibitory There are perhaps 100 known neurotransmitters
responses. (and neuromodulators), represented by the following
three groups:
䡲 Small-molecule transmitters
Neurotransmitters 䡲 Neuropeptides
䡲 Gases
Neurotransmitters are signaling molecules that are
released at the presynaptic membranes and activate Small-molecule transmitters are of three major types:
receptors on postsynaptic membranes. 䡲 Acetylcholine (the only one in this group that is not
an amino acid derivative)
Cells of the nervous system communicate mostly by 䡲 The amino acids: glutamate, aspartate, glycine, and γ-
the release of signaling molecules. The released mole- aminobutyric acid (GABA)
cules contact receptor molecules protruding from the 䡲 The biogenic amines: (monoamines) serotonin and
plasmalemma of the target cell, eliciting a response the three catecholamines: dopamine, norepinephrine
from the target cell. These signaling molecules were (noradrenaline), and epinephrine (adrenaline).
called neurotransmitters (Table 9-1). However, such
molecules may act on two types of receptors: (1) those Neuropeptides, many of which are neuromodula-
directly associated with ion channels and (2) those tors, form a large group. They include:
associated with G proteins or receptor kinases, which 䡲 The opioid peptides: enkephalins and endorphins
activate a second messenger. Therefore, signaling 䡲 Gastrointestinal peptides, which are produced by
molecules that act as “first messenger systems” (i.e., cells of the diffuse neuroendocrine system: substance
act on receptors directly associated with ion channels) P, neurotensin, and vasoactive intestinal peptide
retain the name neurotransmitters, and signaling 䡲 Hypothalamic-releasing hormones, such as thyrotropin-
molecules that invoke the “second messenger system” releasing hormone and somatostatin
now are referred to as neuromodulators or neuro- 䡲 Hormones stored in and released from the neurohy-
hormones. Because neurotransmitters act directly, the pophysis (antidiuretic hormone and oxytocin).
entire process is fast, lasting usually less than 1 msec.
Events utilizing neuromodulators are much slower and Gases may act as neuromodulators. The ones that do
may last as long as a few minutes. are nitric oxide (NO) and carbon monoxide (CO).
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TABLE 9–1 Common Neurotransmitters and Functions Elicited by Their Receptor
Neurotransmitter Compound Group Function
Acetylcholine Small molecule transmitter; not Myoneural junctions, all parasympathetic synapses,
derived from amino acids and preganglionic sympathetic synapses
Norepinephrine Small molecule transmitter; biogenic Postganglionic sympathetic synapses (except for
amine; catecholamine eccrine sweat glands)
Glutamate Small molecule transmitter; amino acid Presynaptic sensory and cortex: most common
excitatory neurotransmitter of CNS
γ-Aminobutyric acid Small molecule transmitter; amino acid Most common inhibitory neurotransmitter of CNS
(GABA)
Dopamine Small molecule transmitter; biogenic Basal ganglia of CNS; inhibitory or excitatory,
amine; catecholamine depending on receptor
Serotonin Small molecule transmitter; biogenic amine Inhibits pain; mood control; sleep
Glycine Small molecule transmitter; amino acid Brain stem and spinal cord; inhibitory
Endorphins Neuropeptide; opioid peptide Analgesic; inhibit pain transmission?
Enkephalins Neuropeptide; opioid peptide Analgesic; inhibit pain transmission?
CNS, central nervous system.
Several principles appear to describe the functioning

CLINICAL CORRELATIONS of neurotransmitters. First, a specific neurotransmitter
may elicit different actions under varied circumstances.
Huntington’s chorea is a hereditary condition Second, the nature of the postsynaptic receptors deter-
with an onset in the third or fourth decade of life. mines the effect of a neurotransmitter on postsynaptic
It begins as flicking of the joints that progresses cells. Synaptic communication commonly involves mul-
to severe distortions, dementia, and motor dys- tiple neurotransmitters. Additionally, there is mounting
function. The condition is thought to be related evidence for volume transmission as a method of
to loss of cells producing GABA, an inhibitory communication between brain cells. According to this
neurotransmitter. Without it, outbursts are un- concept, chemical and electrical “neurotransmitters,”
controlled. The dementia associated with this believed to exist in the intercellular fluid–filled spaces
disease is thought to be related to subsequent between brain cells, activate groups or fields of cells that
loss of acetylcholine-secreting cells. contain appropriate receptors rather than individual
Parkinson’s disease, a crippling disease related cells. Whereas synaptic communication is fast-acting,
to the absence of dopamine in certain regions of volume transmission is thought to be slow and may be
the brain, is characterized by muscular rigidity, con- related to such conditions as autonomic function, alert-
stant tremor, bradykinesia (slow movement), and, ness, awareness, changes in brain patterns during sleep,
finally, a mask-like face and difficult voluntary move- sensitivity to pain, and moods.
ment. Because dopamine cannot cross the blood-
brain barrier, therapy is administered as L-dopa
(levodopa), which relieves the motor abnormalities PERIPHERAL NERVOUS SYSTEM
temporarily, although the neurons in the affected The peripheral nervous system includes the peripheral
area continue to die. Efforts to transplant fetal nerves and nerve cell bodies located outside the central
adrenal gland tissue into persons with this disease nervous system (CNS).
have provided only transient relief. The therapeutic
grafting of genetically modified cells capable of Peripheral nerves are bundles of nerve fibers (axons),
secreting dopamine will perhaps allow the establish- located outside the central nervous system and sur-
ment of synaptic connections to cells in the corpus rounded by several investments of connective tissue
striatum of the brain where dopamine is needed. sheaths (Figs. 9-20 through 9-22). These bundles (fasci-
cles) may be observed with the unaided eye; those that
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Sc
Figure 9–20 Light micrograph of a longitudinal section of a

peripheral nerve (×270). Myelin and nodes of Ranvier (arrow) as well
as the lightly stained oval nuclei of Schwann cells (Sc) may be observed.
are myelinated appear white because of the presence of Figure 9–21 Light micrograph of a cross-section of a peripheral
nerve (×132). Observe the axons (A) and the perineurium (P) sur-
myelin. Usually, each bundle of nerve fibers, regardless rounding the fascicle.
of size, has both sensory and motor components.
Connective Tissue Investments

Connective tissue investments of peripheral nerves
include the epineurium, perineurium, and endoneurium. Epineurium
Epineurium is the outermost layer of the three con-

nective tissue investments covering nerves (see Fig. 9- Perineurium
22). The epineurium is composed of dense, irregular,
collagenous connective tissue containing thick elastic
fibers that completely ensheathe the nerve. Collagen
fibers within the sheath are aligned and oriented to Endoneurium
prevent damage by overstretching of the nerve bundle.
The epineurium is thickest where it is continuous with
the dura covering the CNS at the spinal cord or brain,
where the spinal or cranial nerves originate, respec- Schwann
tively. The epineurium becomes progressively thinner cells
as the nerves branch into smaller nerve components,
eventually disappearing.
Perineurium, the middle layer of connective tissue Axon
investments, covers each bundle of nerve fibers (fasci-
cle) within the nerve. The perineurium is composed of
dense connective tissue but is thinner than epineurium.
Its inner surface is lined by several layers of epithelioid Figure 9–22 Structure of a nerve bundle.
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cells joined by zonulae occludentes and surrounded by brane, initiating depolarization, only at the nodes of
a basal lamina that isolates the neural environment. Ranvier, for two reasons:
Between the layers of epithelioid cells are sparse colla- 1 Voltage-gated Na+ channels of the axon plasmalemma
gen fibers oriented longitudinally and intertwined with are clustered mostly at the nodes of Ranvier.
a few elastic fibers. The thickness of the perineurium is 2 The myelin sheath covering the internodes prevents
progressively reduced to a sheet of flattened cells. the outward movement of the excess Na+ in the axo-
Endoneurium, the innermost layer of the three plasm associated with the action potential.
connective tissue investments of a nerve, surrounds indi-
vidual nerve fibers (axons). A loose connective tissue Therefore, the excess positive ions can diffuse only
composed of a thin layer of reticular fibers (produced by through the axoplasm to the next node, triggering depo-
the underlying Schwann cells), scattered fibroblasts, fixed larization there. In this way, the action potential “jumps”
macrophages, capillaries, and perivascular mast cells in from node to node, a process called saltatory conduc-
extracellular fluid, the endoneurium is in contact with the tion (see Fig. 9-16B).
basal lamina of the Schwann cells. Thus, the endo- As noted earlier, unmyelinated fibers lack a thick
neurium is housed in a compartment completely isolated myelin sheath and nodes of Ranvier. These fibers are
from the perineurium and Schwann cells, an important surrounded by a single layer of Schwann cell plasma
factor in regulation of the microenvironment of the nerve membrane and cytoplasm, which provides little insula-
fiber. Near the distal terminus of the axon, the endo- tion. Moreover, voltage-gated Na+ channels are dis-
neurium is reduced to a few reticular fibers surrounding tributed along the entire length of the axon plasma
the basal lamina of the Schwann cells of the axon. membrane. Therefore, impulse propagation in unmyeli-
nated fibers occurs by continuous conduction, which
Functional Classification of Nerves is slower and requires more energy than the saltatory
conduction occurring in myelinated fibers.
Functionally, nerve fibers are classified as sensory As shown in Table 9-2, peripheral nerve fibers are clas-
(afferent) or motor (efferent). sified into three major groups according to their conduc-
tion velocity. In thin unmyelinated fibers, the conduction
Nerve fibers are segregated functionally into sensory velocity ranges from about 0.5 to 2 m/sec, whereas in
(afferent) fibers and motor (efferent) fibers. Sensory heavily myelinated fibers, it ranges from 15 to 120 m/sec.
nerve fibers carry sensory input from the cutaneous The sensory component of the peripheral nervous
areas of the body and from the viscera back to the CNS system is presented in the various chapters related to
for processing. Motor nerve fibers originate in the CNS function.
and carry motor impulses to the effector organs. The
sensory roots and motor roots of the spinal cord unite SOMATIC MOTOR AND
to form mixed peripheral nerves, the spinal nerves,
which carry both sensory and motor fibers. AUTONOMIC NERVOUS SYSTEMS
Conduction Velocity Functionally, the motor component is divided into the

somatic and autonomic nervous systems.
The conduction velocity of peripheral nerve fibers
depends on the extent of their myelination. In myeli- The somatic nervous system provides motor impulses to
nated nerves, ions can cross the axonal plasma mem- the skeletal muscles, whereas the autonomic nervous
TABLE 9–2 Classification of Peripheral Nerve Fibers
Conduction
Fiber Group Diameter (mm) Velocity (m/sec) Function
Type A fibers—heavily 1-20 15-120 High-velocity fibers:

myelinated acute pain, temperature, touch, pressure,
proprioception, somatic efferent fibers
Type B fibers—less 1-3 3-15 Moderate-velocity fibers:

heavily myelinated visceral afferents, preganglionic autonomics
Type C fibers— 0.5-1.5 0.5-2 Slow-velocity fibers:

unmyelinated postganglionic autonomics, chronic pain
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system provides motor impulses to the smooth muscles leave the brain or spinal cord and travel to the skeletal
of the viscera, cardiac muscle of the heart, and secre- muscle via the cranial nerves or spinal nerves (Fig.
tory cells of the exocrine and endocrine glands, thus 9-23). They synapse with the skeletal muscle at the
helping to maintain homeostasis. motor end plate (see Chapter 8).
Motor Component of the Somatic Autonomic Nervous System

Nervous System
Autonomic nerves provide motor innervation to smooth
Motor innervation to skeletal muscles is provided by muscle and cardiac muscle and supply secretomotor
somatic nerves. innervation to glands.
Skeletal muscles receive motor nerve impulses con- The autonomic (involuntary, visceral) nervous system
ducted to them by spinal and selected cranial nerves of is generally defined as a motor system; although agree-
the somatic nervous system. The cell bodies of these ment on this point is not universal, it is regarded as a
nerve fibers originate in the CNS. The cranial nerves motor system in this discussion. The autonomic nervous
containing somatic efferent components are cranial system controls the viscera of the body by supplying the
nerves III, IV, VI, and XII (excluding those nerves sup- general visceral efferent (visceral motor) compo-
plying muscles of branchiomeric origin). Most of the 31 nent to smooth muscle, cardiac muscle, and glands.
pairs of spinal nerves contain somatic efferent compo- In contrast to the somatic system, in which one
nents to skeletal muscles. neuron originating in the CNS acts directly on the effec-
Cell bodies of neurons of the somatic nervous system tor organ, the autonomic nervous system possesses two
originate in motor nuclei of the cranial nerves embed- neurons between the CNS and the effector organ.
ded within the brain or in the ventral horn of the spinal Cell bodies of the first neurons in the chain lie in the
cord. These neurons are multipolar, and their axons CNS and their axons are usually myelinated. These pre-
Somatic reflex Visceral reflex
Interneuron
Dorsal horn
Dorsal root Dorsal root
Ventral Dorsal
Spinal root
nerve root
ganglion
Ventral Lateral horn

horn
Sympathetic
chain ganglion
Spinal
nerve
Prevertebral
ganglion
Gut
Visceral afferent fibers

Visceral preganglionic
Somatic afferent fibers
efferent fibers
Somatic efferent fibers Visceral postganglionic
Figure 9–23 Comparison of soma-
tic and visceral reflexes. efferent fibers
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ganglionic fibers (axons) seek an autonomic gan- The sympathetic nervous system originates in the spinal
glion located outside the CNS, where they synapse on cord from segments of the thoracic spinal cord and
multipolar cell bodies of postganglionic neurons. upper lumbar spinal cord (T1 to L2). Thus, the sym-
Postganglionic fibers, which are usually unmyelinated pathetic nervous system is sometimes called the
although they always are enveloped by Schwann cells, thoracolumbar outflow (see Fig. 9-24). Cell bodies of
exit the ganglion to terminate on the effector organ preganglionic neurons are small, spindle-shaped cells
(smooth muscle, cardiac muscle, gland). that originate in the lateral horn of the spinal cord; their
Also unlike the somatic system, the autonomic axons exit the cord via the ventral roots to join the spinal
system has postganglionic synapses that branch out, and nerve. After a short distance, the fibers leave the
the neurotransmitter diffuses out for some distance to peripheral nerve, via white rami communicantes, to
the effector cells, thus contributing to more prolonged enter one of the paravertebral chain ganglia.
and widespread effects than in the somatic system. Typically, the preganglionic neuron either synapses
Smooth muscle cells stimulated by the neurotransmit- on a cell body of one of the multipolar postganglionic
ter activate adjacent smooth muscle cells to contract by neurons residing in the ganglion associated with that
relaying the information via gap junctions. spinal cord segment or ascends or descends in the sym-
The autonomic nervous system is subdivided into pathetic trunk to synapse on a cell in another of the
two functionally different divisions (Fig. 9-24): chain ganglia. However, certain preganglionic fibers do
not synapse in the chain ganglia; instead, they pass
䡲 In general, the sympathetic nervous system pre- through to enter the abdominal cavity as splanchnic
pares the body for action by increasing respiration, nerves. Here they seek collateral ganglia located along
blood pressure, heart rate, and blood flow to the the abdominal aorta for synapsing on cell bodies of post-
skeletal muscles, dilating pupils of the eyes and gen- ganglionic fibers residing there.
erally slowing down visceral function. Axons of postganglionic neurons housed in the chain
䡲 The parasympathetic nervous system tends to be ganglia exit the ganglia, via gray rami communicantes,
functionally antagonistic to the sympathetic system in to reenter the peripheral nerve for distribution to effec-
that it decreases respiration, blood pressure, and tor organs in the periphery (i.e., sweat glands, blood
heart rate, reduces blood flow to skeletal muscles, vessels, dilator pupillae muscles, cardiac muscle, bronchial
constricts the pupils, and generally increases the tree, salivary glands, and arrector muscles of hair).
actions and functions of the visceral system. Axons of postganglionic neurons housed in the
collateral ganglia exit the ganglia and accompany the
Thus, the parasympathetic nervous system brings
myriad blood vessels to the viscera, where they synapse
about homeostasis, whereas the sympathetic nervous
on the effector organs (i.e., blood vessels and the
system prepares the body for “fight or flight” (see later).
smooth muscles and glands of the viscera).
The sympathetic nervous system is broadly con-
sidered to function in vasoconstriction, whereas the
parasympathetic nervous system is broadly considered Parasympathetic Nervous System
to be secretomotor in function. Because the visceral
components of the body receive innervation from both The effect of the parasympathetic nervous system is to
prepare the body to “rest or digest.”
divisions of the autonomic nervous system, these two
systems are balanced in health.
The parasympathetic nervous system originates in the
Acetylcholine is the neurotransmitter at all
brain and the sacral segments of the spinal cord (S2 to
synapses between preganglionic and postganglionic
S4); thus, the parasympathetic system is called the
fibers and between parasympathetic postganglionic
craniosacral outflow (see Fig. 9-24).
endings and effector organs. Norepinephrine is the
Cell bodies of preganglionic parasympathetic
neurotransmitter at synapses between postganglionic
neurons originating in the brain lie in the visceromo-
sympathetic fibers and effector organs. Generally, pre-
tor nuclei of the four cranial nerves that carry visceral
ganglionic fibers of the sympathetic system are short but
motor components (cranial nerves III, VII, IX, and X).
postganglionic fibers are long. In contrast, preganglionic
Axons of preganglionic parasympathetic fibers of
fibers of the parasympathetic system are long, whereas
cranial nerves III, VII, and IX seek parasympathetic
postganglionic fibers are short.
(terminal) ganglia located outside the brain case,
where they synapse on cell bodies of postganglionic
parasympathetic neurons housed in the ganglia. Axons
Sympathetic Nervous System of these nerves are usually delivered by cranial nerve V
to the effector organs they serve, including salivary
The effect of the sympathetic nervous system is to
glands and mucous glands, whereas cranial nerve III
prepare the body for “flight or fight.”
delivers postganglionic parasympathetic fibers to the
Ch009-X2945.qxd 12/8/06 3:29 PM Page 209
Sympathetic division Parasympathetic division

Lacrimal gland Ciliary body
Ciliary ganglion
Parotid gland
Pterygopalatine ganglion
Sublingual gland
Otic ganglion
Submandibular
gland Submandibular ganglion
Larynx
Trachea
Lungs III
VII
Cervical Heart IX
ganglia
X
1 1
2 2
3 3
Cervical 4 4 Cervical
5 Liver 5
6 6
7 7
8 8
1 Pancreas 1
2 2
3 3
4 4
5 Celiac 5
6 ganglion Stomach 6
Thoracic Thoracic
7 7
8 8
9
Large and 9
small
10 10
intestine
11
Adrenal 11
12 12
1 Large 1
2 intestine 2
Lumbar and rectum Lumbar
3 3
4 4
5 Kidney 5
1 1
2 2
Sacral Bladder and
3 3 Sacral
genitalia
4 4
5 5
Pelvic nerve
C Superior C
mesenteric
ganglion
Preganglionic cholinergic fibers
Inferior
mesenteric Postganglionic cholinergic fibers
ganglion
Postganglionic adrenergic fibers
Figure 9–24 The autonomic nervous system. Left, Sympathetic division. Right, Parasympathetic division.
Ch009-X2945.qxd 12/8/06 3:29 PM Page 210
ciliary muscle and the sphincter pupillae muscles of By definition, nerve cell bodies of autonomic ganglia are
the eye. motor in function because they cause smooth or cardiac
Axons of preganglionic parasympathetic fibers in muscle contraction or glandular secretion. In the sympa-
cranial nerve X travel to the thorax and abdomen before thetic system, preganglionic sympathetic fibers synapse
synapsing in the terminal ganglia within the respective on postganglionic sympathetic cell bodies in the sympa-
viscera. thetic ganglia located in either the sympathetic chain
Axons of postganglionic parasympathetic nerves ganglia, adjacent to the spinal cord, or the collateral
synapse on the glands, smooth muscles, and cardiac ganglia, along the abdominal aorta in the abdomen.
muscle. Postganglionic sympathetic nerves originating in these
Cell bodies of preganglionic parasympathetic nerves ganglia are then distributed, for the most part, by periph-
originating in segments of the sacral spinal cord are eral nerves that they join after exiting the ganglia. They
located in the lateral segment of the ventral horn and then terminate in the effector organs that they innervate.
leave via the ventral root with the sacral nerves. From In the parasympathetic system, preganglionic para-
here, the axons project to terminal ganglia (Meissner’s sympathetic fibers originate in one of two places: in
and Auerbach’s plexuses) in the walls of the lower gas- certain cranial nerves or, as previously described, in
trointestinal tract, where they synapse on cell bodies of certain segments of the sacral spinal cord. These fibers
postganglionic parasympathetic neurons. synapse on postganglionic cell bodies (Fig. 9-25) located
Axons of postganglionic neurons synapse on the in terminal ganglia. Preganglionic parasympathetic
effector organs in the viscera of the lower abdominal fibers originating in the nuclei (term for a cluster of nerve
wall and the pelvis. cell bodies located in the CNS) of the cranial nerves con-
ducting parasympathetic fibers synapse in one of the four
terminal ganglia located in the head (except those of
GANGLIA cranial nerve X). Terminal ganglia associated with cranial
Ganglia are aggregations of cell bodies of neurons nerve X and for preganglionic fibers arising from the
located outside the CNS. There are two types of ganglia: sacral spinal cord are located in the walls of the viscera.
sensory and autonomic. Postganglionic parasympathetic nerves originating in
the terminal ganglia within the head exit the ganglia and
Sensory Ganglia usually join the trigeminal nerve (cranial nerve V) to be
distributed to the effector organs. Those postganglionic
Sensory ganglia house cell bodies of sensory neurons. parasympathetic nerves originating in the ganglia
located in the walls of the viscera pass directly to the
Sensory ganglia are associated with cranial nerves V, VII, effector organs located within the viscera.
IX, and X and with each of the spinal nerves originating
from the spinal cord. A sensory ganglion of a cranial
nerve appears as a swelling of the nerve either inside the CENTRAL NERVOUS SYSTEM
cranial vault or at its exit. Ganglia are usually identified The CNS, composed of the brain and the spinal cord,
with specific names that relate to the nerves. Sensory consists of white matter and gray matter without inter-
ganglia of the spinal nerves are called dorsal root vening connective tissue elements; therefore, the CNS
ganglia. Sensory ganglia house unipolar (pseudounipo- has the consistency of a semifirm gel.
lar) cell bodies of the sensory nerves enveloped by White matter is composed mostly of myelinated
cuboidal capsule cells. These capsule cells are then nerve fibers along with some unmyelinated fibers and
surrounded by a connective tissue capsule composed of neuroglial cells; its white color results from the abun-
satellite cells and collagen. The endoneurium of each dance of myelin surrounding the axons.
axon becomes continuous with the connective tissue Gray matter consists of aggregations of neuronal
surrounding the ganglia. Peripheral processes of the cell bodies, dendrites, and unmyelinated portions of
neurons possess specialized receptors at their terminals axons as well as neuroglial cells; the absence of myelin
to transduce various types of stimuli from the internal causes these regions to appear gray in live tissue.
and external environments. Central processes pass from Axons, dendrites, and neuroglial processes form a
the ganglion unsynapsed to the brain within the cranial tangled network of neural tissue called the neuropil
nerves or to the spinal cord within the spinal nerves, (Fig. 9-26). In certain regions, aggregations of neuron
where they terminate on other neurons for processing. cell bodies embedded in white matter are called nuclei,
whereas their counterparts in the peripheral nervous
Autonomic Ganglia system are called ganglia.
Gray matter in the brain is located at the periphery
Autonomic ganglia house cell bodies of postganglionic
(cortex) of the cerebrum and cerebellum and forms the
autonomic nerves.
deeper basal ganglia, whereas the white matter lies deep to
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graph of the ciliary ganglion. At, axon
terminal; Ax, axon; Den, dendrite;
GIPr, gastric inhibitory peptide
receptor; LF, lipofuscin granules;
Nu, nucleus; rER, rough endoplas-
mic reticulum; Sat, satellite cells.
(From May PJ, Warren S: Ultra-
structure of the macaque ciliary
ganglion. J Neurocytol 22:1073-
1095, 1993.)
the cortex and surrounds the basal ganglia. The reverse is is the arachnoid, and the innermost or intimate layer
true in the spinal cord; white matter is located in the of the meninges is the pia mater (Fig. 9-27).
periphery of the spinal cord, whereas gray matter lies deep
in the spinal cord, where it forms an H shape in cross Dura Mater
section. A small central canal, lined by ependymal cells
and representing the lumen of the original neural tube, The dura mater is the dense outermost layer of the
lies in the center of the crossbar of the H. The upper verti- meninges.
cal bars of the H represent the dorsal horns of the spinal
cord, which receive central processes of the sensory The dura mater covering the brain is a dense, collage-
neurons whose cell bodies lie in the dorsal root gan- nous connective tissue composed of two layers that are
glion. Cell bodies of interneurons are also located in the closely apposed in the adult. Periosteal dura mater,
dorsal horns. Cell bodies of interneurons (internuncial the outer layer, is composed of osteoprogenitor cells,
neurons or intercalated neurons) originate in the CNS fibroblasts, and organized bundles of collagen fibers
and are entirely confined there, where they form networks that are loosely attached to the inner surface of the
of communication for integration between sensory and skull, except at the sutures and base of the skull, where
motor neurons. Interneurons constitute the vast majority the attachment is firm. As the name implies, periosteal
of the neurons of the body. The lower vertical bars of the H dura mater serves as the periosteum of the inner surface
represent the ventral horns of the spinal cord, which of the skull, and as such it is well vascularized.
house cell bodies of large multipolar motor neurons whose The inner layer of the dura, meningeal dura
axons exit the spinal cord via the ventral roots. mater, is composed of fibroblasts displaying dark-
staining cytoplasm, elongated processes, ovoid nuclei,
and sheet-like layers of fine collagen fibers. This layer
Meninges
also contains small blood vessels.
The three connective tissue coverings of the brain and A layer of cells internal to the meningeal dura
spinal cord are the meninges. The outermost layer of mater, called the border cell layer, is composed of
the meninges is the dura mater, the intermediate layer flattened fibroblasts exhibiting long processes that are
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Figure 9–26 Electron micrograph of axodendritic synapses (arrow). (From Jennes L, Traurig HH, Conn PM: Atlas of the Human Brain.
Philadelphia, Lippincott-Raven, 1995.)
Scalp
Skull
Dura mater
Subdural
space
Arachnoid
membrane
Vein
Artery
Subarachnoid
space
Pia mater
Figure 9–27 The skull and the layers of
Brain the meninges covering the brain.
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occasionally attached to one another by desmosomes Pia Mater

and gap junctions. Collagen fibers are lacking in this
layer, but in their place an extracellular, amorphous, Pia mater, the innermost highly vascular layer of the
flocculent material (thought to be a proteoglycan) sur- meninges, is in close contact with the brain.
rounds the fibroblasts and extends into the interface
between this layer and the meningeal dura. The pia mater is the innermost layer of the meninges
Spinal dura mater does not adhere to the walls of and is intimately associated with the brain tissue, fol-
the vertebral canal; rather, it forms a continuous tube lowing closely all of its contours. The pia mater does not
from the foramen magnum to the second segment of quite come into contact with the neural tissue, however,
the sacrum and is pierced by the spinal nerves. The because a thin layer of neuroglial processes is always
epidural space, the space between the dura and the interposed between them.
bony walls of the vertebral canal, is filled with epidural The pia mater is composed of a thin layer of flat-
fat and a venous plexus. tened, modified fibroblasts that resemble arachnoid tra-
becular cells. Blood vessels, abundant in this layer, are
surrounded by pial cells interspersed with macro-
Arachnoid phages, mast cells, and lymphocytes. Fine collagenous
The arachnoid is the intermediate layer of the meninges.
and elastic fibers lie between the pia and neural tissue.
The arachnoid layer of the meninges is avascular,

although blood vessels course through it. This intermedi- CLINICAL CORRELATIONS
ate layer of the meninges consists of fibroblasts, collagen,
Meningiomas are slow growing tumors of the
and some elastic fibers. The fibroblasts form gap junc-
meninges that are usually benign and produce
tions and desmosomes with one another. The arachnoid is
clinical effects by compressing the brain and
composed of two regions. The first is a flat, sheet-like
increasing intracranial pressure. Meningitis is
membrane in contact with the dura mater. The second is
an inflammation of the meninges resulting from
a deeper, gossamer-like region composed of loosely
bacterial or viral infection in the CSF.
arranged arachnoid trabecular cells (modified fibro-
Viral meningitis is not as severe a condition as
blasts), along with a few collagen fibers, which form tra-
bacterial meningitis, which is contagious and can
beculae that contact the underlying pia mater. These
be quite a severe condition leading to brain damage,
arachnoid trabeculae span the subarachnoid space, the
hearing loss, learning disability, and death, if
space between the sheet-like portion of the arachnoid and
untreated. Presently, in the United States, all
the pia. The arachnoid trabecular cells have long
children 4 years of age or younger are vaccinated
processes that attach to one another via desmosomes and
for the most prevalent form of this disease. Major
communicate with one another by gap junctions.
symptoms of bacterial meningitis include fever,
The interface between the dura and arachnoid,
headache, stiff neck, and alteration of conscious-
the subdural space, is considered a “potential space”
ness. Diagnosis is based on spinal fluid culture
because it appears only as the aftermath of injury result-
to determine the bacterial species involved, fol-
ing in subdural hemorrhage, when blood forces these
lowed by treating with a specific antibiotic. Bac-
two layers apart.
terial meningitis can be spread by respiratory and
Blood vessels from the dura pierce the arachnoid on
throat secretions (e.g., coughing, kissing).
their way to the vascular pia mater. However, these
vessels are isolated both from the arachnoid and from
the subarachnoid space by a close investment of arach-
noid-derived, modified fibroblasts. In certain regions, The pia mater is completely separated from the
the arachnoid extends through the dura to form arach- underlying neural tissue by neuroglial cells. Blood
noid villi, which protrude into the spaces connected to vessels penetrate the neural tissues and are covered by
the lumina of the dural venous sinuses. These special- pia mater until they form the continuous capillaries
ized regions of the arachnoid function in transporting characteristic of the CNS. End-feet of astrocytes,
CSF from the subarachnoid space into the venous pedicels, rather than pia mater, cover capillaries within
system. In later life, the villi enlarge and become sites the neural tissue.
for calcium deposits.
The interface between the arachnoid mater and pia Blood-Brain Barrier
mater is difficult to distinguish; therefore, the two layers
Endothelial cells of CNS capillaries prevent the free
are often called the pia-arachnoid, with both surfaces
passage of selective blood-borne substances into the
being covered by a thin layer of squamous epithelioid
neural tissue.
cells composed of modified fibroblasts.
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A highly selective barrier, known as the blood-brain Choroid Plexus

barrier, exists between specific blood-borne substances
and the neural tissue of the CNS. This barrier is estab- The choroid plexus, composed of folds of pia mater
lished by the endothelial cells lining the continuous within the ventricles of the brain, produces CSF.
capillaries that course through the CNS. These
endothelial cells form fasciae occludentes with one Folds of pia mater housing an abundance of fenestrated
another, retarding the flow of materials between cells. capillaries and invested by the simple cuboidal
Additionally, these endothelial cells have relatively few (ependymal) lining extend into the third, fourth, and
pinocytotic vesicles, and vesicular traffic is almost com- lateral ventricles of the brain, forming the choroid
pletely restricted to receptor-mediated transport. plexus (Fig. 9-28). The choroid plexus produces
Macromolecules injected into the vascular system cerebrospinal fluid (CSF), which fills the ventricles
cannot enter the intercellular spaces of the CNS; con- of the brain and central canal of the spinal cord. The
versely, macromolecules injected into the intercellular CSF bathes the CNS as it circulates through the sub-
spaces of the CNS cannot enter the capillary lumen. arachnoid space. Although more than half of the CSF
Certain substances, however, such as oxygen, water, and is produced by the choroid plexus, there is evidence that
carbon dioxide, and other small, lipid-soluble materials, parenchyma in several other regions of the brain
including some drugs, can easily penetrate the blood- produce a substantial amount of CSF, which diffuses
brain barrier. Molecules such as glucose, amino acids, through the ependymal lining to enter the ventricles.
certain vitamins, and nucleosides are transferred across
the blood-brain barrier by specific carrier proteins, Cerebrospinal Fluid
many via facilitated diffusion. Ions are also transported
Cerebrospinal fluid bathes, nourishes, and protects the
across the blood-brain barrier through ion channels
brain and spinal cord.
via active transport. The energy requirement for this
process is satisfied by the presence of large numbers of CSF is produced by the choroid plexus at the rate of
mitochondria within the endothelial cell cytoplasm. about 14 to 36 mL/hour, replacing its total volume about
Capillaries of the CNS are invested by well-defined four to five times daily. CSF circulates through the ven-
basal laminae, which in turn are almost completely sur- tricles of the brain, the subarachnoid space, the perivas-
rounded by the end-feet of numerous astrocytes, col- cular space, and the central canal of the spinal cord.
lectively called the perivascular glia limitans. It is CSF is low in protein but rich in sodium, potassium, and
believed that these astrocytes help convey metabolites
from blood vessels to neurons. Additionally, astrocytes
remove excess K+ and neurotransmitters from the
neuron’s environment, thus maintaining the neuro-
chemical balance of the CNS extracellular milieu.
Ce
Because the blood-brain barrier is very selective, C
antibiotics, some therapeutic drugs, and certain
neurotransmitters (e.g., dopamine) cannot pass
across it. Perfusion of a hypertonic solution of
mannitol transiently opens the tight junctions of
the capillary endothelial cells for administration
of therapeutic drugs. Therapeutic drugs can also
be bound to antibodies developed against trans-
ferrin receptors in the endothelial cells of the
capillaries, permitting their transport across the
blood-brain barrier and into the CNS.
In some diseases of the CNS (e.g., stroke,
infection, tumors), the integrity of the blood-
brain barrier is compromised, resulting in the
accumulation of toxins and extraneous metabo-
lites in the extracellular environment. Figure 9–28 Light micrograph of the choroid plexus (×270).
Observe capillaries (C) and the simple cuboidal epithelium of the
choroid plexus (Ce).
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chloride ions. It is clear and has a low density. Consist-

ing of about 90% water and ions, it may also contain a TABLE 9–3 Comparison of Serum and
few desquamated cells and occasional lymphocytes. Cerebrospinal Fluid (CSF)
CSF is important to the metabolic activity of the
CNS because brain metabolites diffuse into the CSF as Constituent Serum CSF
it passes through the subarachnoid space. It also serves
as a liquid cushion for protection of the CNS. CSF is White blood cells (cells/mL) 0 0-5
able to flow by diffusion and is reabsorbed through the Protein (g/L) 60-80 Negligible
thin cells of the arachnoid villi in the superior sagittal
venous sinus from where the CSF is returned to the Glucose (mMol/L) 4.0-5.5 2.1-4.0
bloodstream.
Na+ (mMol/L) 135-150 135-150
K+ (mMol/L) 4.0-5.1 2.8-3.2
Cl− (mMol/L) 100-105 115-130
Because CSF is constantly being produced by
the choroid plexus, any decrease in absorption Ca2+ (mMol/L) 2.1-2.5 1.0-1.4
of the fluid by the arachnoid villi or blockage
Mg2+ (mMol/L) 0.7-1.0 0.8-1.3
within the ventricles of the brain causes swelling
in the brain tissue. This condition, called hydro- pH 7.4 7.3
cephalus, leads to enlargement of the head in
the fetus and neonate, impairment of mental and
muscular functions, and death if left untreated.
2 The external granular layer contains mostly
granule (stellate) cells and neuroglial cells.
The chemical stability of the CSF is maintained by 3 The external pyramidal layer contains neuroglial
the blood-CSF barrier, which is composed of zonulae cells and large pyramidal cells, which become
occludentes between the cells of the simple cuboidal increasingly larger from the external to the internal
epithelium. These tight junctions impede the move- border of this layer.
ment of substances between cells, compelling the sub- 4 The internal granular layer is a thin layer charac-
stances to take the transcellular route. The production terized by closely arranged, small granule cells (stel-
of CSF thus depends on facilitated and active transport late cells), pyramidal cells, and neuroglia. This layer
across the simple cuboidal epithelium, resulting in dif- has the greatest cell density of the cerebral cortex.
ferences in composition between CSF and plasma 5 The internal pyramidal layer contains the largest
(Table 9-3). pyramidal cells and neuroglia. This layer has the
lowest cell density of the cerebral cortex.
Cerebral Cortex 6 The multiform layer consists of cells of various
shapes (Martinotti cells), and neuroglia.
The cerebral cortex is responsible for learning, memory,
sensory integration, information analysis, and initiation Cerebellar Cortex
of motor responses.
The cerebellar cortex is responsible for balance,
Gray matter at the periphery of the cerebral hemi- equilibrium, muscle tone, and muscle coordination.
spheres is folded into many gyri and sulci called the
cerebral cortex. This portion of the brain is responsible The layer of gray matter located in the periphery of the
for learning, memory, information analysis, initiation of cerebellum is called the cerebellar cortex (Fig. 9-29).
motor response, and integration of sensory signals. This portion of the brain is responsible for maintaining
The cerebral cortex is divided into six layers com- balance and equilibrium, muscle tone, and coordination
posed of neurons that exhibit a morphology unique to of skeletal muscles. Histologically, the cerebellar cortex
the particular layer. The most superficial layer lies just is divided into three layers:
deep to the pia mater; the sixth, or deepest, layer of the 1 The molecular layer lies directly below the pia
cortex is bordered by white matter of the cerebrum. mater and contains superficially located stellate cells,
The six layers and their components are as follows: dendrites of Purkinje cells, basket cells, and un-
1 The molecular layer is composed mostly of nerve myelinated axons from the granular layer.
terminals originating in other areas of the brain, hor- 2 The Purkinje cell layer contains the large, flask-
izontal cells, and neuroglia. shaped Purkinje cells, which are present only in the
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PM PC
D
ML
PC
Figure 9–30 Higher-magnification light micrograph of the gran-

ular layer of the cerebellum illustrating Purkinje cells (x540). The
multi-polar Purkinji cells (PC) display a nucleus (N) and a dentritic
tree (D).
NERVE REGENERATION
GL
Nerve cells, unlike neuroglial cells, cannot proliferate
but can regenerate their axons, located in the PNS.
When a traumatic event destroys neurons, they are not

replaced because neurons cannot proliferate (although
some suggest that proliferation of certain neurons may
take place even within the CNS); therefore, the damage
to the CNS is permanent. However, if a peripheral
nerve fiber is injured or transected, the neuron attempts
Figure 9–29 Light micrograph of the cerebellum showing its to repair the damage, regenerate the process, and
layers: the pia mater (PM), molecular layer (ML), and granular layer restore function by initiating a series of structural and
(GL) (×132). Especially note the prominent Purkinje cells (PC). metabolic events, collectively called the axon reaction.
Axon Reaction
cerebellum (Fig. 9-30; also see Figs. 9-4 and 9-29). The reactions to the trauma are characteristically local-
Their arborized dendrites project into the molecular ized in three regions of the neuron: (1) at the site of
layer, and their myelinated axons project into the damage (local changes); (2) distal to the site of damage
white matter. Each Purkinje cell receives hundreds (anterograde changes); and (3) proximal to the site of
of thousands of excitatory and inhibitory synapses damage (retrograde changes). Some of the changes
that it must integrate to form the proper response. occur simultaneously, whereas others may occur weeks
The Purkinje cell is the only cell of the cerebellar or months apart. The following description of nerve
cortex that sends information to the outside, and it regeneration assumes that the cut ends remain near
is always an inhibitory output using GABA as the each other; otherwise, regeneration is unsuccessful
neurotransmitter. (Fig. 9-31).
3 The granular layer (the deepest layer) consists of
small granule cells and glomeruli (cerebellar Local Reaction
islands). Glomeruli are regions of the cerebellar
Local reaction to injury involves repair and removal of
cortex where synapses are taking place between
debris by neuroglial cells.
axons entering the cerebellum and the granule cells.
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A Normal neuron Normal

Injury muscle
B 2 weeks after injury
Fewer Nissl bodies Degenerating fiber

and myelin sheath
Peripheral nucleus Macrophage
C 3 weeks after injury

Atrophied muscle
Proliferating
Schwann cells
Axon penetrating
Schwann cells
D 3 months after injury

Muscle
Successful nerve regeneration
regeneration
Unsuccessful nerve regeneration
E Months after injury

Disorganized Atrophied
Figure 9–31 Schematic diagram axon growth muscle
of nerve regeneration. A, Normal
neuron. Appearance 2 weeks (B), 3
weeks (C), and 3 months (D) after
injury. Appearance several months
after injury of neuron with unsuccess- Cord of
Schwann cells
ful nerve regeneration is shown in E.
In local reaction, the severed ends of the axon retract Anterograde Reaction
away from each other, and the cut membrane of each
stump fuses to cover the open end, preventing loss In the anterograde reaction process, that portion of the
of axoplasm. Each severed end begins to expand as axon distal to an injury undergoes degeneration and is
material delivered by axoplasmic flow accumulates. phagocytosed.
Macrophages and fibroblasts infiltrate the damaged
area, secrete cytokines and growth factors, and up- The axon undergoes anterograde changes as follows:
regulate the expression of their receptors. Macrophages 1 The axon terminal becomes hypertrophied and
invade the basal lamina and, assisted to a certain limited degenerates within a week; as a result, contact with
extent by Schwann cells, phagocytose the debris. the postsynaptic membrane is terminated. Schwann
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cells proliferate and phagocytose the remnants of the cells atrophy and degenerate or other cells targeting
axon terminal, and the newly formed Schwann cells that particular neuron also atrophy and degenerate.
occupy the synaptic space. This process, called transneuronal degeneration, may
2 The distal portion of the axon undergoes waller- thus be anterograde or retrograde but occurs only
ian degeneration (orthograde degeneration), infrequently.
whereby, distal to the lesion, the axon and the myelin
disintegrate, Schwann cells dedifferentiate, and Regeneration in the Central
myelin synthesis is discontinued. Moreover, macro- Nervous System
phages and, to a certain extent, Schwann cells phago-
cytose the disintegrated remnants. Regeneration in the CNS is much less likely than in the
3 Schwann cells proliferate, forming a column of PNS because connective tissue sheaths are absent in the
Schwann cells (Schwann tubes) enclosed by the CNS. Injured cells within the CNS are phagocytosed
original basal lamina of the endoneurium. by special macrophages, known as microglia, and the
space liberated by the phagocytosis is occupied by pro-
Retrograde Reaction and Regeneration liferation of glial cells, which form a cell mass called a
glial scar. It is believed that the glial cell masses hinder
In retrograde reaction and regeneration process, the the process of repair. Thus, generally, neuronal damage
proximal portion of the injured axon undergoes within the CNS appears to be irreparable.
degeneration followed by sprouting of a new axon Although neurons do not divide, there is evidence
whose growth is directed by Schwann cells. that there are neural stem cells within the adult mam-
malian and human brain that, when provided the proper
The portion of the axon proximal to the damage under- stimulus, could be activated to replace lost or injured
goes the following changes: neurons. Some of these cells have the capacity to
1 The perikaryon of the damaged neuron becomes produce glial cells and others to differentiate into
hypertrophied, its Nissl bodies disperse, and its neurons. These neural stem cells exhibit multi-potential
nucleus is displaced. These events, called chroma- ability to differentiate into the cells of the tissue into
tolysis, may last several months. Meanwhile, the which they were introduced.
soma is actively producing free ribosomes and syn- It has been shown recently that reducing additional
thesizing proteins and various macromolecules, cell damage or death within 1 hour of injury increases
including ribonucleic acid (RNA). During this time, the survivability of neurons in the vicinity of the lesion.
the proximal axon stump and surrounding myelin This information—coupled with results of recent inves-
sheath degenerate as far proximally as the nearest tigations concerning growth factors, applications of
collateral axon. embryonic neural stem cells, reducing neuron growth
2 Several “sprouts” of axons emerge from the proximal inhibitors, applying axon grafts and grafting axons
axon stump, enter the endoneurium, and are guided directly into the gray matter of the spinal cord—is pro-
by the Schwann cells to their target cell. For regen- viding promising results for the future in spinal cord
eration to occur, the Schwann cells, macrophages, therapy.
and fibroblasts as well as the basal lamina must be
present. These cells manufacture growth factors and Neuronal Plasticity
cytokines and up-regulate the expression for the
Plasticity is evident during development because those
receptors of these signaling molecules.
neurons that are present in excess and/or not making
3 The sprout is guided by the Schwann cells that re-
correct connections must be destroyed. However, it has
differentiate and either begin to manufacture myelin
been shown in adult mammals that after injury neuronal
around the growing axon or, in nonmyelinated axons,
circuits may be reestablished from the growth of neu-
form a Schwann cell sheath. The sprout that reaches
ronal processes located at some distance away from the
the target cell first forms a synapse, whereas the other
lesion; these neuronal circuits are able to provide at
sprouts degenerate. The process of regeneration pro-
least some functional recovery. Regeneration of this sort
ceeds at about 3 to 4 mm/day.
relies on growth factors called neurotrophins pro-
duced by neurons, glial cells, Schwann cells, and certain
Transneuronal Degeneration
target cells. Evidence for neuronal plasticity in humans
The nerve cell has a trophic influence on the cells may be observed in stroke victims as well as in victims
it contacts. If the neuron dies, sometimes its target of other neurological injuries.
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10 䡲䡲䡲
Blood and Hemopoiesis
Blood is a bright to dark red, viscous, slightly alkaline with an anticoagulant such as heparin. Upon centrifu-
fluid (pH, 7.4) that accounts for approximately 7% of gation, the formed elements settle to the bottom of the
the total body weight. The total volume of blood of tube as a red precipitate (44%) covered by a thin
an average adult is about 5 L, and it circulates through- translucent layer, the buffy coat (1%), and the fluid
out the body within the confines of the circulatory plasma remains on top as the supernatant (55%). The
system. Blood is a specialized connective tissue com- red precipitate is composed of red blood cells, and
posed of formed elements—red blood cells (RBCs; the total red blood cell volume is known as the hema-
erythrocytes), white blood cells (WBCs; leuko- tocrit; the buffy coat consists of white blood cells and
cytes), and platelets—suspended in a fluid component platelets.
(the extracellular matrix), known as plasma (Figs. 10-1 The finite life span of blood cells requires their
and 10-2). constant renewal to maintain a steady circulating
Because blood circulates throughout the body, it is population. This process of blood cell formation from
an ideal vehicle for the transport of materials. The established blood cell precursors is called hemopoiesis
primary functions of blood include conveying nutrients (also referred to as hematopoiesis).
from the gastrointestinal system to all of the cells of the
body and subsequently delivering the waste products of
these cells to specific organs for elimination. Numerous
other metabolites, cellular products (e.g., hormones and BLOOD
other signaling molecules), and electrolytes are also
ferried by the bloodstream to their final destinations. Blood is composed of a fluid component (plasma) and
Oxygen (O2) is carried by hemoglobin within erythro- formed elements consisting of the various types of blood
cytes from the lungs for distribution to the cells of the cells as well as platelets.
organism, and carbon dioxide (CO2) is conveyed both
by hemoglobin and by the fluid component of plasma Light microscopic examination of circulating blood cells
(as bicarbonate ion, HCO3−, and in its free form) for is performed by evenly smearing a drop of blood on a
elimination by the lungs. glass slide, air-drying the preparation, and staining it
Blood also helps to regulate body temperature and with mixtures of dyes specifically designed to demon-
to maintain the acid-base and osmotic balance of the strate distinctive characteristics of the cells. The current
body fluids. Finally, blood acts as a pathway for migra- methods are derived from the technique developed in
tion of white blood cells between various connective the late 19th century by Romanovsky, who used a
tissue compartments of the body. mixture of methylene blue and eosin. Most laboratories
The fluid state of blood necessitates the presence now use either the Wright or Giemsa modifications
of a protective mechanism, coagulation, to stop its of the original procedure, and identification of blood
flow in case of damage to the vascular tree. The process cells is based on the colors produced by these stains.
of coagulation is mediated by platelets and blood- Methylene blue stains acidic cellular components blue,
borne factors that transform blood from a sol to a gel and eosin stains alkaline components pink. Still other
state. components are colored a reddish blue by binding to
When blood is removed from the body and placed azures, substances formed when methylene blue is
in a test tube, clotting occurs unless the tube is coated oxidized.
219
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220 䡲䡲䡲 Chapter 10 䡲 Blood and Hemopoiesis
into the clot. The remaining fluid, which no longer

has those components dissolved or suspended in it,
differs from plasma, is straw-colored, and is known as
serum.
The major component of plasma is water, constitut-
ing about 90% of its volume. Proteins constitute 9%,
and inorganic salts, ions, nitrogenous compounds, nutri-
ents, and gases constitute the remaining 1%. The types,
origins, and functions of the blood proteins are listed in
Table 10-1.
The fluid component of blood leaves the capillaries
and small venules to enter the connective tissue spaces
as extracellular fluid, which has a composition of
electrolytes and small molecules similar to that in
plasma. The concentration of proteins in extracellular
fluid is much lower than that in plasma, however,
because it is difficult even for small proteins, such as
albumin, to traverse the endothelial lining of a capil-
lary. In fact, albumin is chiefly responsible for the
establishment of blood’s colloid osmotic pressure,
the force that maintains normal blood and interstitial
fluid volumes.
Formed Elements
Red blood cells, white blood cells, and platelets
Figure 10–1 Light micrograph of circulating blood (×270). Note constitute the formed elements of blood.
the abundance of erythrocytes as well as the three leukocytes. Also
observe the presence of numerous platelets that appear as small dots
interspersed among the erythrocytes. Erythrocytes
Erythrocytes (red blood cells), the smallest and most
Neutrophil Lymphocyte Eosinophil Monocyte numerous cells of blood, have no nuclei and are
responsible for the transport of oxygen and carbon
dioxide to and from the tissues of the body.
Each erythrocyte resembles a biconcave-shaped disk

7.5 µm in diameter, 2.0 µm thick at its widest region,
and less than 1 µm thick at its center (Figs. 10-3 and
10-4). This shape provides the cell with a large surface
area relative to its volume, thus enhancing its capability
for gaseous exchange. Although erythrocyte precursor
cells within the bone marrow possess nuclei, during
development and maturation the precursor cells or ery-
Erythrocytes Platelets Basophil throcytes expel not only their nuclei but also all of their
(red blood cells) organelles before entering the circulation. Thus, mature
erythrocytes have no nuclei. When stained with Giemsa
Figure 10–2 Cells and platelets of circulating blood. or Wright stain, erythrocytes display a salmon-pink
color.
Plasma Although erythrocytes possess no organelles, they do
have soluble enzymes in their cytosol. Within the ery-
Plasma is a yellowish fluid in which cells, platelets, throcyte, the enzyme carbonic anhydrase facilitates
organic compounds, and electrolytes are suspended the formation of carbonic acid from CO2 and water. This
and/or dissolved. acid dissociates to form bicarbonate (HCO3−) and
hydrogen (H+). It is as bicarbonate that most of the CO2
During coagulation, some of the organic and inorganic is ferried to the lungs for exhalation. The ability of bicar-
components leave the plasma to become integrated bonate to cross the erythrocyte cell membrane is medi-
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Chapter 10 䡲 Blood and Hemopoiesis ■ ■ ■ 221
TABLE 10–1 Proteins of Plasma
Protein Size Source Function
Albumin 60,000-69,000 Da Liver Maintains colloid osmotic pressure and transports

certain insoluble metabolites
Globulins
α- and β-Globulins 80,000-1 × 106 Da Liver Transport metal ions, protein-bound lipids, and
lipid-soluble vitamins
γ-Globulin Plasma cells Antibodies of immune defense
Clotting proteins
(e.g., prothrombin, Varied Liver Formation of fibrin threads
fibrinogen,
accelerator globulin)
Complement proteins
C1 through C9 Varied Liver Destruction of microorganisms and initiation of
inflammation
Plasma lipoproteins
Chylomicrons 100-500 µm Intestinal Transport of triglycerides to liver
epithelial cells
Very-low-density 25-70 nm Liver Transport of triglycerides from liver to body cells
lipoprotein (VLDL)
Low-density lipoprotein 3 × 106 Da Liver Transport of cholesterol from liver to body cells
(LDL)
ated by the integral membrane protein band 3, a Hemoglobin

coupled anion transporter that exchanges intracellular
bicarbonate for extracellular chloride; this exchange is Hemoglobin is a large protein composed of four
known as the chloride shift. Additional enzymes polypeptide chains, each of which is covalently bound to
include those of the glycolytic pathway (Embden- a heme group.
Meyerhoff pathway) as well as enzymes that are respon-
sible for the pentose monophosphate shunt (hexose Red blood cells are packed with hemoglobin, a large
monophosphate shunt) for the production of the high- tetrameric protein (68,000 Da) composed of four
energy molecule reduced nicotinamide adenine dinu- polypeptide chains, each of which is covalently bound
cleotide phosphate (NADPH), a reducing agent. The to an iron-containing heme; this molecule is bound
glycolytic pathway does not require the presence of within a hydrophobic depression, the heme pocket, of
oxygen and is the chief method whereby the erythro- the globin chain which protects the iron from being
cyte produces adenosine triphosphate (ATP), necessary oxidized while permitting the binding of oxygen to
for its energy requirement. it. It is hemoglobin that provides the unstained cell
Males have more erythrocytes per unit volume of with its pale yellow color. The globin moiety of hemo-
blood than do females (5 × 106 versus 4.5 × 106 per globin releases CO2, and, in regions of high oxygen
mm3), and members of both sexes living at higher alti- concentration, such as in the lungs, O2 binds to the
tudes have correspondingly more red blood cells than iron of each heme. When oxygen is bound to the heme,
residents living at lower altitudes. the hemoglobin molecule is in the relaxed state [(R−)
Human erythrocytes have an average life span of Hb], the globin moieties of the molecule are less con-
120 days; when they reach that age, they display on strained and can move with respect to each other, and
their surface a group of oligosaccharides. Red blood the O2 can easily be released. When O2 is released, its
cells bearing these sugar groups are destroyed by place becomes occupied by 2,3-diphosphoglycerate and
macrophages of the spleen, bone marrow, and liver. the hemoglobin becomes known as deoxyhemoglobin,
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E E
E
E
Figure 10–3 Light micrograph of cells and platelets of circulat-

ing blood (×1325). Each light micrograph in this series displays ery-
throcytes (E), platelets (arrows), and a single white blood cell. A,
Lymphocyte; B, monocyte; C, neutrophil; D, eosinophil; E, basophil.
or taut hemoglobin [(T −) Hb]. The number of ionic carrying CO2 is called carbaminohemoglobin (or
and H bonds between the globin chains of (T −) Hb carbamylhemoglobin). Hypoxic tissues release 2,3-
is greater than that of (R−) Hb, and the movement diphosphoglyceride, a carbohydrate that facilitates
of the globin chains with respect to each other is the release of oxygen from the erythrocyte. Hemo-
reduced. However, in oxygen-poor regions, as in globin also binds nitric oxide (NO), a neurotrans-
tissues, hemoglobin releases O2 and binds CO2. This mitter substance that causes dilation of blood vessels,
property of hemoglobin makes it ideal for the con- permitting red blood cells to release more oxygen
veyance of respiratory gases. Hemoglobin carrying and pick up more CO2 within the tissues of the
O2 is known as oxyhemoglobin, and hemoglobin body.
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α-chains and two γ-chains, is replaced shortly after birth

by adult hemoglobin (HbA). There are two types of
normal adult hemoglobin, HbA1 (α2β2) and the much
rarer form, HbA2 (α2δ2). In the adult, approximately
96% of the hemoglobin is HbA1, 2% is HbA2, and the
remaining 2% is HbF.
Several hereditary diseases result from defects in
the genes encoding the hemoglobin polypeptide
chains. Diseases referred to as thalassemia are
marked by decreased synthesis of one or more
hemoglobin chains. In β-thalassemia, synthesis of
the β-chains is impaired. In the homozygous form
of this disease, which is most prevalent among
persons of Mediterranean descent, HbA is
missing and high levels of HbF persist after birth.
Sickle cell anemia is the result of a point
mutation at a single locus of the β-chain (valine is
incorporated into the sequence instead of gluta-
mate), forming the abnormal hemoglobin HbS.
When the oxygen tension is reduced (e.g., during
strenuous exercise), HbS changes shape, produc-
ing abnormally shaped (crescent-shaped) eryth-
Figure 10–4 Scanning electron micrograph of circulating red rocytes that are less pliant, more fragile, and
blood cells displaying their biconcave disk shape (×5850). (From
Leeson TS, Leeson CR, Paparo AA: Text/Atlas of Histology. Philadel- more prone to hemolysis than normal cells. Sickle
phia, WB Saunders, 1988.) cell anemia is prevalent in the black population,
especially in those whose ancestors lived in
regions of Africa where malaria is endemic. In the
United States, about 1 of 600 newborn African-
American babies is stricken with this condition.
Carbon monoxide (CO) has a much greater affin-
ity than O2 for the heme portion of hemoglobin,
and when CO binds to the iron of the heme, the Erythrocyte Cell Membrane
hemoglobin molecule is transformed to its (R−)
Hb form and will increase its affinity to oxygen The cell membrane of the erythrocyte and the
so that it cannot be released to the tissues even underlying cytoskeleton are highly pliable and can
in hypoxic regions. People who are trapped in withstand great shear forces.
areas of poor ventilation with a running gasoline-
powered engine or in a building on fire fre- The red blood cell plasma membrane, a typical lipid
quently succumb to CO poisoning. Many such bilayer, is composed of about 50% protein, 40% lipids,
victims, if fair-skinned, instead of being cyanotic and 10% carbohydrates. Most of the proteins are trans-
(with a bluish pallor) present with healthy- membrane proteins, principally glycophorin A (as well
looking, cherry-red skin because of the color of as lesser quantities of glycophorins B, C, and D), ion
the CO-hemoglobin complex (carbon monoxy- channels (calcium-dependent potassium channels and
hemoglobin). Na+-K+ adenosine triphosphatase), and the anion
transporter band 3 protein, which transports Cl− and
HCO3−; it also acts as an anchoring site for ankyrin,
band 4.1 protein, hemoglobin, and glycolytic enzymes
On the basis of the amino acid sequences, there are (Fig. 10-5). Additionally, the red blood cell membrane
four normal, human polypeptide chains of hemoglobin, also possesses the peripheral proteins band 4.1 protein,
designated α, β, γ, and δ. The principal hemoglobin of spectrin, ankyrin, and actin. Band 4.1 protein acts
the fetus, fetal hemoglobin (HbF), composed of two as an anchoring site for spectrin, band 3 protein, and
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Glycophorin C Ankyrin Membrane

Band 3
Actin
Band 4.2
a chain Band 4.1
Spectrin Figure 10–5 The cytoskeleton and

integral proteins of the erythrocyte plas-
malemma. Spectrin forms a hexagonal
b chain Actin latticework that is anchored to the ery-
throcyte plasma membrane by band
4.1 and band 3 proteins as well as by
Band 4.9 ankyrin.
glycophorins. Thus, ankyrin, band 3 protein, and band

4.1 protein anchor the cytoskeleton, a hexagonal lattice TABLE 10–2 ABO Blood Group System
composed chiefly of spectrin tetramers, actin, and
adducin, to the cytoplasmic aspect of the red blood cell Blood Antigens
plasmalemma (see Chapter 2). This subplasmalemmal Group Present Miscellaneous
cytoskeleton helps to maintain the biconcave disk shape
of the erythrocyte. A Antigen A
During its 120-day life, each erythrocyte negotiates B Antigen B
the entire circulatory system at least 100,000 times and
therefore must pass through innumerable capillaries AB Antigens A and B Universal acceptor
whose lumen is smaller than the cell’s diameter. To nav-
O Neither antigen Universal donor
igate through such small-bore vessels, the erythrocyte
A nor B
undergoes deformations of its shape and becomes
subject to tremendous shear forces. It is the erythrocyte
cell membrane and the underlying cytoskeleton that
contribute to the ability of the red blood cell to main-
tain its structural and functional integrity.
The extracellular surface of the red blood cell plas-
malemma has specific inherited carbohydrate chains
that act as antigens and determine the blood group of
CLINICAL CORRELATIONS an individual for the purposes of blood transfusion. The
most notable of these are the A and B antigens, which
Defects in the cytoskeletal components of eryth- determine the four primary blood groups, A, B, AB,
rocytes result in various conditions marked by and O (Table 10-2). People who lack either the A or B
abnormally shaped cells. Hereditary spherocy- antigen, or both, have antibodies against the missing
tosis, for instance, is caused by synthesis of an antigen in their blood; if they undergo transfusion with
abnormal spectrin that exhibits defective binding blood containing the missing antigen, the donor ery-
to band 4.1 protein. Red blood cells of patients throcytes are attacked by the recipient’s serum anti-
with this condition are more fragile and transport bodies and are eventually lysed.
less oxygen compared with normal erythrocytes. Another important blood group, the Rh group, is
Moreover, these spherocytes are preferentially so-named because it was first identified in rhesus
destroyed in the spleen, leading to anemia. monkeys. This complex group comprises more than
two dozen antigens, although many are relatively rare.
Three of the Rh antigens (C, D, and E) are so common
Deficiency of glycophorin C is responsible for in the human population that the erythrocytes of 85%
elliptocytic red blood cells without the resultant of Americans have one of these antigens on their
hemolytic anemia. These cells are unstable and fragile surface, and these individuals are thus said to be Rh-
and are less capable of deformation than normal positive (Rh+). Individuals lacking these antigens are
erythrocytes. RH-negative (RH −).
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Neutrophils
Neutrophils compose most of the white blood cell
When an Rh− pregnant woman delivers her first population; they are avid phagocytes, destroying
Rh+ baby, enough of the baby’s blood is likely to bacteria that invade connective tissue spaces.
enter her circulation to induce the formation of
anti-Rh antibodies. During a subsequent preg- Polymorphonuclear leukocytes (polys, neutro-
nancy with an Rh+ fetus, these antibodies attack phils) are the most numerous of the white blood cells,
the erythrocytes of the fetus, causing erythro- constituting 60% to 70% of the total leukocyte popula-
blastosis fetalis, a condition that may be fatal to tion. In blood smears, neutrophils are 9 to 12 µm in
the newborn. Prenatal and postnatal transfusions diameter and have a multilobed nucleus (see Figs. 10-
to the fetus are necessary to prevent brain damage 2 and 10-3). The lobes, connected to each other
and death of the newborn unless the mother has by slender chromatin threads, increase in number with
been treated with anti-Rh agglutinins—Rh0(D) the age of the cell. In females, the nucleus presents a
immune globulin (RhoGAM)—before or shortly characteristic small appendage, the “drumstick,” which
after the birth of the first Rh+ baby. contains the condensed, inactive second X chromo-
some. It is also called the Barr body or sex chro-
mosome but is not always evident in every cell.
Neutrophils are among the first cells to appear in acute
Leukocytes bacterial infections. The neutrophil plasmalemma pos-
sesses complement receptors as well as Fc receptors
Leukocytes are white blood cells that are classified into for IgG.
two major categories: granulocytes and agranulocytes.
NEUTROPHIL GRANULES
The number of leukocytes is much smaller than that of
red blood cells; in fact, in a healthy adult there are only Neutrophils possess specific, azurophilic, and tertiary
6500 to 10,000 white blood cells per mm3 of blood. granules.
Unlike erythrocytes, leukocytes do not function within
the bloodstream but use it as a means of traveling from Three types of granules are present in the cytoplasm of
one region of the body to another. When leukocytes neutrophils:
reach their destination, they leave the bloodstream by 䡲 Small, specific granules (0.1 µm in diameter)
migrating between the endothelial cells of the blood 䡲 Larger azurophilic granules (0.5 µm in diameter)
vessels (diapedesis), enter the connective tissue 䡲 Tertiary granules.
spaces, and perform their function. Within the blood-
stream as well as in smears, leukocytes are round; in Specific granules contain various enzymes and
connective tissue, they are pleomorphic. They generally pharmacological agents that aid the neutrophil in per-
defend the body against foreign substances. forming its antimicrobial functions (see Table 10-3). In
White blood cells are classified into two groups electron micrographs these granules appear somewhat
(Table 10-3): oblong (Fig. 10-6).
Azurophilic granules, as already indicated, are
䡲 Granulocytes, which have specific granules in their lysosomes, containing acid hydrolases, myeloperoxi-
cytoplasm dase, the antibacterial agent lysozyme, bactericidal
䡲 Agranulocytes, which lack specific granules. permeability-increasing (BPI) protein, cathepsin G,
Both granulocytes and agranulocytes possess non- elastase, and nonspecific collagenase.
specific (azurophilic) granules, now known to be Tertiary granules contain gelatinase and cathepsins
lysosomes. as well as glycoproteins that are inserted into the
There are three types of granulocytes, differenti- plasmalemma.
ated according to the color of their specific granules
after application of Romanovsky-type stains: NEUTROPHIL FUNCTIONS
䡲 Neutrophils Neutrophils phagocytose and destroy bacteria by using
䡲 Eosinophils the contents of their various granules.
䡲 Basophils.
Neutrophils interact with chemotactic agents to
There are two types of agranulocytes: migrate to sites invaded by microorganisms. They
䡲 Lymphocytes accomplish this by entering postcapillary venules in the
䡲 Monocytes. region of inflammation and adhering to the various
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TABLE 10–3 Leukocytes
GRANULOCYTES AGRANULOCYTES
Features Neutrophils Eosinophils Basophils Lymphocytes Monocytes

3
Number/mm 3500-7000 150-400 50-100 1500-2500 200-800
% of WBCs 60-70 2-4 <1 20-25 3-8
Diameter (µm)
Section 8-9 9-11 7-8 7-8 10-12
Smear 9-12 10-14 8-10 8-10 12-15
Nucleus Three to four Two lobes (sausage S-shaped Round Kidney-shaped

lobes shaped)
Specific 0.1 µm, light 1-1.5 µm, 0.5 µm, None None
granules pink* dark pink* blue/black*
Contents of Type IV Aryl sulfatase, Histamine, None None

specific collagenase, histaminase, heparin,
granules phospholipase β-glucuronidase, eosinophil
A2, lactoferrin, acid phosphatase, chemotactic
lysozyme, phospholipase, factor,
phagocytin, major basic neutrophil
alkaline protein, chemotactic
phosphatase, eosinophil factor,
vitamin B12- cationic protein, peroxidase,
binding neurotoxin, neutral
protein ribonuclease, proteases,
cathepsin, chondroitin
peroxidase sulfate
Surface Fc receptors, IgE receptors, IgE receptors T cells: T-cell Class II HLA,
markers platelet- eosinophil receptors, CD Fc receptors
activating chemotactic molecules, IL
factor factor receptor receptors
receptor, B cells: surface
leukotriene immunoglobulins
B4 receptor,
leukocyte
cell adhesion
molecule-1
Life span <1 week <2 weeks 1-2 years (in Few months to Few days in
murines) several years blood, several
months in
connective
tissue
Function Phagocytosis and Phagocytosis of Similar to T cells: cell- Differentiate

destruction antigen-antibody mast cells to mediated into
of bacteria complex; mediate immune response macrophage:
destruction of inflammatory B cells: humorally phagocytosis,
parasites responses mediated presentation
immune response of antigens
*Using Romanovsky-type stains (or their modifications).

CD, cluster of differentiation; HLA, human leukocyte antigen; IgE, immunoglobulin E; IL, interleukin; WBC, white blood cell.
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N N
Figure 10–6 Electron micrograph of a

human neutrophil. Note the three lobes of the
nucleus (N), the presence of granules (arrows)
throughout the cytoplasm, and the centrally
located centriole (C). Although it appears as if
there are three distinct nuclei in this image,
they are merely lobes of the same nucleus, and
the connections are outside the present field of
view. (From Zucker-Franklin D, et al [eds]:
Atlas of Blood Cells. Vol 1. Milan, Edi Ermes,
1981.)
selectin molecules of endothelial cells of these vessels the contents of tertiary granules into the extracellu-
by use of their selectin receptors. The interaction lar matrix.
between the neutrophil’s selectin receptors and the 2 Gelatinase degrades the basal lamina, facilitating
selectins of the endothelial cells causes the neutro- neutrophil migration. Glycoproteins that become
phils to roll slowly along the vessel’s endothelial inserted in the cell membrane aid the process of
lining. As the neutrophils are slowing their migra- phagocytosis.
tions, interleukin-1 (IL-1) and tumor necrosis 3 The contents of the specific granules are also released
factor (TNF) induce the endothelial cells to express into the extracellular matrix, where they attack
intercellular adhesion molecule type 1 (ICAM-1), to the invading microorganisms and aid neutrophil
which the integrin molecules of neutrophils avidly migration.
bind. 4 Microorganisms, phagocytosed by neutrophils, be-
When binding occurs, the neutrophils stop migrat- come enclosed in phagosomes (Fig. 10-7A and B).
ing in preparation for their passage through the Enzymes and pharmacological agents of the
endothelium of the postcapillary venule to enter the azurophilic granules are usually released into the
connective tissue compartment. Once there, they lumina of these intracellular vesicles, where they
destroy the microorganisms by phagocytosis and by destroy the ingested microorganisms. Because of
the release of hydrolytic enzymes (and respiratory their phagocytic functions, neutrophils are also
burst). In addition, by manufacturing and releasing known as microphages to distinguish them from the
leukotrienes, neutrophils assist in the initiation of the larger phagocytic cells, the macrophages.
inflammatory process. The sequence of events is: 5 Bacteria are killed not only by the action of
enzymes but also by the formation of reactive
1 The binding of neutrophil chemotactic agents to the oxygen compounds within the phagosomes of
neutrophil’s plasmalemma facilitates the release of neutrophils. These are superoxide (O2−), formed
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Neutrophil
C3b receptor
C3b complements
Endocytosis
Bacterium
Fc region of
antibody
A Fc receptor B
Lysozyme, lactoferrin,
PLA2 released from
specific granule
O2
–
O2 H2O2 Cationic
HOCl H2O2 HOCl proteins
MPO
Azurophilic granule
releasing its contents
C into endolysosome D
Figure 10–7 Bacterial phagocytosis and destruction by a neutrophil. These actions are dependent on the ability of the neutrophil to rec-
ognize the bacterium via the presence of complement and/or antibody attached to the microorganism. H2O2, hydrogen peroxide; HOCl,
hypochlorous acid; MPO, myeloperoxidase, O2−, superoxide, PLA2, phospholipase A2.
by the action of NADPH oxidase on O2 in a res-

piratory burst; hydrogen peroxide (H2O2), formed CLINICAL CORRELATIONS
by the action of superoxide dismutase on super-
oxide; and hypochlorous acid (HOCl), formed Children with hereditary deficiency of
by the interaction of myeloperoxidase (MPO) and NADPH oxidase are subject to persistent bac-
chloride ions with hydrogen peroxide (see Fig. 10-7C terial infections because their neutrophils cannot
and D). form a respiratory burst response to the bacter-
6 Frequently, the contents of the azurophilic granules ial challenge. Their neutrophils cannot generate
are released into the extracellular matrix, causing superoxide, hydrogen peroxide, or hypochlorous
tissue damage, but usually catalase and glutathione acid during phagocytosis of bacteria.
peroxidase limit the tissue injury by degrading
hydrogen peroxide.
7 Once neutrophils perform their function of killing
microorganisms, they also die, resulting in the Eosinophils
formation of pus, the accumulation of dead leuko-
cytes, bacteria, and extracellular fluid. Eosinophils phagocytose antigen-antibody complexes
8 Not only do neutrophils destroy bacteria, they also and kill parasitic invaders.
synthesize leukotrienes from arachidonic acids
in their cell membranes. These newly formed Eosinophils constitute less than 4% of the total white
leukotrienes aid the initiation of the inflammatory blood cell population. They are round cells in suspen-
process. sion and in blood smears, but they may be pleomorphic
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during their migration through connective tissue. Their which are highly efficacious agents in combating para-
cell membrane has receptors for immunoglobulin G sites. The externum also contains the enzymes listed in
(IgG), IgE, and complement. Eosinophils are 10 to Table 10-3.
14 µm in diameter (in blood smears) and have a The nonspecific azurophilic granules are lysosomes
sausage-shaped, bilobed nucleus in which the two lobes (0.5 µm in diameter) containing hydrolytic enzymes
are connected by a thin chromatin strand and sur- similar to those found in neutrophils. These function
rounding nuclear envelope (see Figs. 10-2 and 10-3). both in the destruction of parasitic worms and in the
Electron micrographs display a small, centrally located hydrolysis of antigen-antibody complexes internalized
Golgi apparatus, a limited amount of rough endoplas- by eosinophils.
mic reticulum (RER), and only a few mitochondria,
usually in the vicinity of the centrioles near the cyto- EOSINOPHIL FUNCTIONS
center. Eosinophils are produced in the bone marrow,
and it is interleukin-5 (IL-5) that causes proliferation Eosinophils help to eliminate antibody-antigen
of their precursors and their differentiation into mature complexes and to destroy parasitic worms.
cells.
Eosinophils are associated with these functions:
䡲 Binding of histamine, leukotrienes, and eosinophil
EOSINOPHIL GRANULES
chemotactic factor (released by mast cells, basophils,
The specific granules of eosinophils possess an externum and neutrophils) to eosinophil plasmalemma recep-
and an internum. tors, which results in the migration of eosinophils to
the site of allergic reaction, inflammatory reaction, or
Eosinophils possess specific granules and azurophilic parasitic worm invasion
granules. Specific granules are oblong (1.0 to 1.5 µm in 䡲 Degranulation of their major basic protein or
length, <1.0 µm in width) and stain deep pink with eosinophil cationic protein on the surface of parasitic
Giemsa and Wright stains. Electron micrographs show worms, killing them by forming pores in their pelli-
that specific granules have a crystal-like, electron-dense cles, thus facilitating access of agents such as super-
center, the internum, surrounded by a less electron- oxides and hydrogen peroxide to the parasite
dense externum (Fig. 10-8). The internum contains 䡲 Release of substances that inactivate the pharmaco-
major basic protein, eosinophilic cationic protein, logical initiators of the inflammatory response, such
and eosinophil-derived neurotoxin, the first two of as histamine and leukotriene C
Figure 10–8 Electron micrograph of a human

eosinophil. Note the electron-dense internum
(arrows) of the eosinophilic granules and the two
lobes of the nucleus (N). (From Zucker-Franklin D:
Eosinophil function and disorders. Adv Intern Med
19:1-25, 1974.)
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䡲 Engulfing of antigen-antibody complexes, which pass ticular class of immunoglobulin, IgE. The Fc portions
into the endosomal compartment for eventual of the IgE molecules become attached to the FceRi of
degradation. basophils and mast cells without any apparent effect.
However, the next time the same antigens enter the
body, they bind to the IgE molecules on the surface of
CLINICAL CORRELATIONS these cells. Although mast cells and basophils appear to
have similar functions, they are different cells and have
Connective tissue cells in the vicinity of antigen- different origins.
antibody complexes release the pharmacological Although the following sequence of steps occurs in
agents histamine and IL-5, causing increased for- both mast cells and basophils, the basophil is used here
mation and release of eosinophils from the bone for descriptive purposes:
marrow. In contrast, elevation of blood
corticosteroid levels depresses the number of 1 Binding of antigens to the IgE molecules on the sur-
eosinophils in circulation. face of a basophil causes the cell to release the contents
of its specific granules into the extracellular space.
2 In addition, the enzyme phospholipase A generates
arachidonic acid residues from the plasma membrane
Basophils which then are fed into the cyclooxigenase or the
lipoxigenase pathway to produce chemical factors that
Basophils are similar to mast cells in function even
mediate the inflammatory response. These factors are
though they have different origins.
platelet activating factor, leukotriene B4, prostaglandin
D2, thromboxane A2, leukotriene C4, leukotriene
Basophils constitute less than 1% of the total leukocyte
D4, leukotriene E4 (formerly called slow-reacting
population. They are round cells in suspension but may
substance of anaphylaxis, or SRS-A), adenosine,
be pleomorphic during migration through connective
bradykinin, superoxide, TNF factor α, IL4, IL5, IL6,
tissue. They are 8 to 10 µm in diameter (in blood
and granulocyte-monocyte colony-stimulating factor.
smears) and have an S-shaped nucleus, which is com-
3 The release of histamine causes vasodilation, smooth
monly masked by the large specific granules present in
muscle contraction (in the bronchial tree), and leak-
the cytoplasm (see Figs. 10-2 and 10-3). In electron
iness of blood vessels.
micrographs, the small Golgi apparatus, a few mito-
4 Leukotrienes have similar effects, but these actions
chondria, extensive RER, and occasional glycogen
are slower and more persistent than those associated
deposits are clearly evident. Basophils have several
with histamine. In addition, leukotrienes activate
surface receptors on their plasmalemma, including
immunoglobulin E (IgE) receptors (FceRI). leukocytes, causing them to migrate to the site of
antigenic challenge.
BASOPHIL GRANULES
Basophils possess specific and azurophilic granules. CLINICAL CORRELATIONS

The specific granules of basophils stain dark blue to In certain hyperallergic individuals, a second
black with Giemsa and Wright stains. They are approx- exposure to the same allergen may result in an
imately 0.5 µm in diameter and frequently press against intense generalized response. A large number of
the periphery of the cell, creating the basophil’s basophils (and mast cells) degranulate, resulting
characteristic “roughened” perimeter, as seen by light in widespread vasodilation and sweeping reduc-
microscopy. The granules contain heparin, histamine, tion in blood volume (because of vessel leaki-
eosinophil chemotactic factor, neutrophil chemotactic ness). Thus, the person goes into circulatory
factor, neutral proteases, chondroitin sulfate, and per- shock. The smooth muscles of the bronchial tree
oxidase (see Table 10-3). The nonspecific azurophilic constrict, causing respiratory insufficiency. The
granules are lysosomes, which contain enzymes similar combined effect is a life-threatening condition
to those of neutrophils. known as anaphylactic shock.
BASOPHIL FUNCTIONS
Basophils function as initiators of the inflammatory

Monocytes
process
Monocytes, the largest of the circulating blood cells,
enter the connective tissue spaces, where they are
In response to the presence of some antigens in certain
known as macrophages.
individuals, plasma cells manufacture and release a par-
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Monocytes are the largest of the circulating blood cells Lymphocytes

(12 to 15 µm in diameter in blood smears) and consti-
tute 3% to 8% of the leukocyte population. They have Lymphocytes are agranulocytes and form the second
a large, acentric, kidney-shaped nucleus that frequently largest population of white blood cells.
has a “moth-eaten,” soap-bubble” appearance and
whose lobe-like extensions seem to overlap one another. Lymphocytes constitute 20% to 25% of the total circu-
The chromatin network is coarse but not overly dense, lating leukocyte population. They are round cells in
and typically two nucleoli are present, although they are blood smears, but they may be pleomorphic as they
not always evident in smears. The cytoplasm is bluish migrate through connective tissue. Lymphocytes are
gray and has numerous azurophilic granules (lysosomes) somewhat larger than erythrocytes, 8 to 10 µm in diam-
and occasional vacuole-like spaces (see Figs. 10-2 and eter (in blood smears), and have a slightly indented,
10-3). round nucleus that occupies most of the cell. The
Electron micrographs display both heterochromatin nucleus is dense, rich in heterochromatin, and is acen-
and euchromatin in the nucleus as well as two nucleoli. trically located. The peripherally situated cytoplasm
The Golgi apparatus is usually near the indentation of stains a light blue and contains a few azurophilic gran-
the kidney-shaped nucleus. The cytoplasm contains ules. On the basis of size, lymphocytes may be described
deposits of glycogen granules, a few profiles of RER, as small (8 to 10 µm in diameter), medium (12 to
some mitochondria, free ribosomes, and numerous lyso- 15 µm), or large (15 to 18 µm), although the latter two
somes. The periphery of the cell displays microtubules, are much less numerous (see Figs. 10-2 and 10-3).
microfilaments, pinocytotic vesicles, and filopodia. Electron micrographs of lymphocytes display a scant
Monocytes stay in circulation for only a few days; amount of peripheral cytoplasm housing a few mito-
they then migrate through the endothelium of venules chondria, a small Golgi apparatus, and a few profiles of
and capillaries into the connective tissue, where they RER. A small number of lysosomes, representing
differentiate into macrophages. Macrophages are dis- azurophilic granules 0.5 µm in diameter, and an abun-
cussed in greater detail in Chapter 12; an introduction dant supply of ribosomes also are evident (Fig. 10-9).
to their properties and functions follows here. Lymphocytes are discussed in greater detail in
Chapter 12; an introduction to their properties and
functions follows here.
FUNCTION OF MACROPHAGES Lymphocytes are subdivided into three functional
categories:
Macrophages phagocytose unwanted particular
matter, produce cytokines that are required for the 䡲 B lymphocytes (B cells)
inflammatory and immune responses, and present 䡲 T lymphocytes (T cells)
epitopes to T lymphocytes. 䡲 Null cells.
Macrophages are avid phagocytes and, as members of Although morphologically they are indistinguishable
the mononuclear phagocyte system, they phagocy- from each other, they can be recognized immunocyto-
tose and destroy dead and defunct cells (such as senes- chemically by the differences in their surface markers
cent erythrocytes) as well as antigens and foreign (see Table 10-3). Approximately 80% of the circulating
particulate matter (such as bacteria). The destruction lymphocytes are T cells, about 15% are B cells, and the
occurs within the phagosomes through both enzymatic remainder are null cells. Their life spans also differ
digestion and the formation of superoxide, hydrogen widely: some T cells may live for years, whereas some
peroxide, and hypochlorous acid. B cells may die in a few months.
Macrophages produce cytokines that activate the
inflammatory response as well as the proliferation and FUNCTIONS OF B AND T CELLS
maturation of other cells.
Certain macrophages, known as antigen-present- In general, B cells are responsible for the humorally
ing cells, phagocytose antigens and present their most mediated immune system, whereas T cells are
antigenic portions, the epitopes, in conjunction with responsible for the cellularly mediated immune system.
the integral proteins, class II human leukocyte
antigen (class II HLA; also known as major histo- Lymphocytes have no function in the bloodstream, but
compatibility complex antigens [MHC II]), to in the connective tissue these cells are responsible for
immunocompetent cells. the proper functioning of the immune system. To be
In response to large foreign particulate matter, immunologically competent, they migrate to specific
macrophages fuse with one another, forming foreign- body compartments to mature and to express specific
body giant cells that are large enough to phagocytose surface markers and receptors. B cells enter as yet
the foreign particle. unidentified regions of the bone marrow, whereas T
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Figure 10–9 Electron micrograph of a lympho-

cyte (×14,173). Arrows point to the rough endoplas-
mic reticulum. G, Golgi apparatus; nu, nucleus.
(From Hopkins CR: Structure and Function of Cells.
cells migrate to the cortex of the thymus. Once they foreign or virally altered cells. In addition, certain T
have become immunologically competent, lymphocytes cells are responsible for the initiation and development
leave their respective sites of maturation, enter the lym- (T helper cells) or for the suppression (regulatory T
phoid system, and undergo mitosis, forming a group cells, formerly known as T suppressor cells) of most
of identical cells, known as a clone. All members of a humorally and cellularly mediated immune responses.
particular clone can recognize and respond to the same They accomplish this by releasing signaling molecules
antigen. known as cytokines (lymphokines) that elicit specific
After stimulation by a specific antigen, both B responses from other cells of the immune system (see
and T cells proliferate and differentiate into two Chapter 12).
subpopulations:
䡲 Memory cells do not participate in the immune FUNCTIONS OF NULL CELLS
response but remain as part of the clone with an Null cells are composed of two distinct populations:
“immunological memory,” ready to undergo cell
division and mount a response against a subsequent 䡲 Circulating stem cells, which give rise to all of the
exposure to a particular antigen or foreign substance. formed elements of blood
䡲 Effector cells are classified as B cells and T cells 䡲 Natural killer (NK) cells, which can kill some
(and their subtypes). foreign and virally altered cells without the influence
of the thymus or T cells.
Effector cells are immunocompetent lymphocytes
that can perform lymphocyte immune functions; that is, Platelets
eliminating antigens. B cells are responsible for the
humorally mediated immune system; that is, they Platelets (thromboplastids) are small, disk-shaped, non-
differentiate into plasma cells, which produce anti- nucleated cell fragments derived from megakaryocytes
bodies against antigens. T cells are responsible for the in the bone marrow.
cellularly mediated immune system. Some T cells
differentiate into cytotoxic T cells (CTLs; T killer Platelets are about 2 to 4 µm in diameter in blood smears
cells), which make physical contact with and kill (see Figs. 10-2 and 10-3). In light micrographs, they
Ch010-X2945.qxd 15/8/06 4:24 PM Page 233
display a peripheral clear region, the hyalomere, and a Platelet Function

central darker region, the granulomere. The platelet
plasmalemma has numerous receptor molecules as well Platelets function in limiting hemorrhage to the
as a relatively thick (15 to 20 nm) glycocalyx. There are endothelial lining of the blood vessel in case of injury.
between 250,000 and 400,000 platelets per mm3 of
blood, each with a life span of less than 14 days. If the endothelial lining of a blood vessel is disrupted
and platelets come in contact with the subendothelial
Platelet Tubules and Granules collagen, they become activated, release the contents
of their granules, adhere to the damaged region of the
Platelets possess three types of granules (alpha, delta, vessel wall (platelet adhesion), and adhere to each
lambda) as well as two tubular systems (dense and other (platelet aggregation). Interactions of tissue
surface opening). factors, plasma-borne factors, and platelet-derived
factors form a blood clot (Figs. 10-12 and 10-13).
Electron micrographs of platelets display 10 to 15 Although the mechanism of platelet aggregation, adhe-
microtubules arranged parallel to each other and sion, and blood clotting is beyond the scope of histol-
forming a ring within the hyalomere. The microtubules ogy, some of its salient features are as follows:
assist platelets in maintaining their diskoid morphology.
Associated with this bundle of microtubules are actin 1 Normally the intact endothelium produces prosta-
and myosin monomers, which can rapidly assemble to cyclins and NO, which inhibit platelet aggregation.
form a contractile apparatus. In addition, two tubular It also blocks coagulation by the presence of
systems are present in the hyalomere, the surface- thrombomodulin and heparin-like molecule
opening (connecting) and the dense tubular on its luminal plasmalemma. These two membrane-
systems (Figs. 10-10 and 10-11). The surface-opening associated molecules inactivate specific coagulation
system is coiled, forming a labyrinthine complex within factors.
the platelet. Because this system communicates with 2 Injured endothelial cells cease the production and
the outside, the luminal aspect of this tubular system is expression of the inhibitors of coagulation and
a continuation of the outer surface of the platelet, thus platelet aggregation and they release von Wille-
increasing the platelet surface area by a factor of seven brand factor and tissue thromboplastin. They
or eight. also release endothelin, a powerful vasoconstrictor
The ultrastructure of the granulomere displays the that reduces the loss of blood.
presence of a small number of mitochondria, glycogen 3 Platelets avidly adhere to subendothelial collagen,
deposits, peroxisomes, and three types of granules: alpha especially in the presence of von Willebrand factor,
granules (a-granules), delta granules (d-granules), release the contents of their granules, and adhere to
and lambda granules (l-granules) (lysosomes). The one another. These three events are collectively
tubules and granules, as well as their contents and func- called platelet activation.
tions, are listed in Table 10-4. The granulomere also 4 The release of some of their granular contents,
houses a system of enzymes that permits platelets to especially adenosine diphosphate (ADP) and
catabolize glycogen, consume oxygen, and generate ATP. thrombospondin, makes platelets “sticky,” causing
Microtubules Microtubules
Plasma membrane
Dense tubular Delta granules

system
Surface-opening tubule
Mitochondrion
Dense tubular system
Alpha
Figure 10–10 Platelet ultra- granules
structure. Note that the periphery of
the platelet is occupied by actin fila- Glycogen
ments that encircle the platelet and Lysosomes (lambda granules)
maintain the discoid morphology of
this structure.
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Pi
Fe
Th
Mi
Er
Nu Figure 10–11 Electron micro-

Go graph of a platelet and two erythro-
Pi cytes in the gastric mucosa capillary
(×22,100). Th, platelet; Bm, basal
lamina; Er, erythrocyte; Fe, fenestra;
Go, Golgi apparatus; Mi, mitochon-
drion; Nu, nucleus of the capillary; Pi,
Pi pinocytotic vesicles; Th, platelet.
(From Rhodin JAG: An Atlas of
Bm Ultrastructure. Philadelphia, WB
Saunders, 1963.)
circulating platelets to adhere to the collagen-bound platelet aggregation. In the presence of calcium
platelets and to degranulate. (Ca2+), it also converts fibrinogen to fibrin.
5 Arachidonic acid, formed in the activated platelet 8 The fibrin monomers thus produced polymerize
plasmalemma, is converted to thromboxane A2, a and form a reticulum of clot, entangling additional
potent vasoconstrictor and platelet activator. platelets, erythrocytes, and leukocytes into a stable,
6 The aggregated platelets act as a plug, blocking gelatinous blood clot (thrombus). The erythro-
hemorrhage. In addition, they express platelet cytes facilitate platelet activation, whereas neu-
factor 3 on their plasmalemma, providing the nec- trophils and endothelial cells limit both platelet
essary phospholipid surface for the proper assembly activation and thrombus size.
of the coagulation factors (especially of thrombin). 9 Approximately 1 hour after clot formation, actin and
7 As part of the complex cascade of reactions involv- myosin monomers form thin and thick filaments,
ing the various coagulation factors, tissue throm- which interact by utilizing ATP as their energy
boplastin and platelet thromboplastin both act on source. As a result, the clot contracts to about half its
circulating prothrombin, converting it into previous size, pulling the cut edges of the damaged
thrombin. Thrombin is an enzyme that facilitates vessel closer together and minimizing blood loss.
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Thrombin
Prothrombin Prothrombin
Fibrinogen
Platelets
Tissue Platelet
thromboplastin thromboplastin
Platelet
Thrombospondin binding
Fibrin
ADP
Exposed
Aggregation collagen
Injured
cell
A B
Figure 10–12 Clot formation. A, Injury to the endothelial lining releases various clotting factors and ceases the release of inhibitors of
clotting. B, The increase in the size of the clot plugs the defect in the vessel wall and stops the loss of blood. (Modified from Fawcett DW:
Bloom and Fawcett’s A Textbook of Histology, 12th ed. New York, Chapman and Hall, 1994.)
Figure 10–13 This close-up

view of a clot forming in human
blood shows beautifully how the
different blood components are
crammed into the plasma. (The
scanning electron micrographs have
been colored to emphasize the
different structures.) Red blood
cells are entangled with the fibrin
(yellow) that makes up the scaffold-
ing of the clot. The platelets (blue),
which initiate clotting, are fragments
of larger cells (megakaryocytes).
(© 2000 by Dennis Kunkel, Ph.D.)
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TABLE 10–4 Platelet Tubules and Granules
Structure (Size) Location Contents Function
Surface-opening Hyalomere Expedites rapid uptake and release of

tubule system molecules from activated platelets
Dense tubular Hyalomere Probably sequesters calcium ions to prevent

system platelet “stickiness”
α-Granules Granulomere Fibrinogen, platelet-derived Contained factors facilitate vessel repair,

(300-500 nm) growth factor, platelet platelet aggregation, and coagulation of
thromboplastin, thrombo- blood
spondin, coagulation factors
δ-Granules (dense Granulomere Calcium, ADP, ATP, serotonin, Contained factors facilitate platelet
bodies) histamine, pyrophosphatase aggregation and adhesion, as well as
(250-300 nm) vasoconstriction
λ-Granules Granulomere Hydrolytic enzymes Contained enzymes aid clot resorption

(lysosomes)
(200-250 nm)
ADP, adenosine diphosphate; ATP, adenosine triphosphate.
10 When the vessel is repaired, the endothelial cells accumulation of large quantities of fat and the absence
release plasminogen activators, which convert of hemopoiesis in the shafts of these bones.
circulating plasminogen to plasmin, the enzyme The vascular supply of bone marrow is derived from
that initiates lysis of the thrombus. The hydrolytic the nutrient arteries that pierce the diaphysis via the
enzymes of λ-granules assist in this process. nutrient foramina, tunnels leading from the outside
surface of bone into the medullary cavity. These arter-
ies enter the marrow cavity and give rise to a number
BONE MARROW of small, peripherally located vessels that provide
numerous branches both centrally, to the marrow, and
Bone marrow, a gelatinous, vascular connective tissue peripherally, to the cortical bone. Vessels entering the
located in the marrow cavity, is richly endowed with cortical bone are distributed through the haversian and
cells that are responsible for hemopoiesis. Volkmann canals to serve the compact bone.
The centrally directed branches deliver their blood
The medullary cavity of long bones and the interstices to the extensive network of large sinusoids (45 to
between trabeculae of spongy bones house the soft, 80 µm in diameter). The sinusoids drain into a central
gelatinous, highly vascular, and cellular tissue known longitudinal vein, which is drained by veins leaving
as marrow. Bone marrow is isolated from bone by the bone via the nutrient canal.
the endosteum (composed of osteoprogenitor cells, It is interesting that the veins are smaller than the
osteoblasts, and occasional osteoclasts). Bone marrow arteries, thus establishing high hydrostatic pressure
constitutes almost 5% of the total body weight. It is within the sinusoids, thus preventing their collapse. The
responsible for the formation of blood cells (hemo- veins, arteries, and sinusoids form the vascular com-
poiesis) and their delivery into the circulatory system, partment, and the intervening spaces are filled with
and it performs this function from the fifth month of pleomorphic islands of hemopoietic cells that merge
prenatal life until the person dies. Bone marrow also with each other, forming the hemopoietic compart-
provides a microenvironment for much of the matura- ment (Fig. 10-14).
tion process of B lymphocytes and for the initial matu- The sinusoids are lined by endothelial cells and are
ration of T lymphocytes. surrounded by slender threads of reticular fibers and a
The marrow of the newborn is called red marrow large number of adventitial reticular cells. Processes
because of the great number of erythrocytes being pro- of adventitial reticular cells touch the sparse basement
duced there. By age 20 years, however, the diaphyses of membrane of the endothelial cells, covering a large
long bones house only yellow marrow because of the portion of the sinusoidal surface. Additional processes of
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In a patient with a thromboembolism, the most
common type of embolism, clots break free and
circulate in the bloodstream until they reach a
vessel whose lumen is too small to accommodate
them. If a clot is large enough to occlude the
bifurcation of the pulmonary artery (saddle
embolus), it can result in sudden, unexpected
death. If a clot obstructs branches of the coro-
nary artery, a myocardial infarct may occur.
Several types of coagulation disorders that
result in excessive bleeding are known. The disor-
der may be acquired (as in vitamin K deficiency)
or hereditary (as in hemophilia) or may be caused
by low levels of blood platelets (thrombocytope-
nia). Vitamin K is required by the liver as a cofac-
tor in the synthesis of the clotting factors VII,
IX, and X and prothrombin. Absence of or
reduced levels of these factors result in partial or
complete dysfunction of the clotting process.
The most common type of hemophilia is due
to factor VIII deficiency (classic hemophilia), a
recessive hereditary trait transmitted by mothers
to their male children. Because the trait is carried
on the X chromosomes, girls are not affected
unless both parents have deficient X chromo- Figure 10–14 Light micrograph of human bone marrow dis-
somes. Affected persons are likely to bleed after playing two megakaryocytes (arrows) (×270). Observe that marrow
has a much greater population of nucleated cells than does periph-
trauma, usually involving damage to larger vessels. eral blood. Also note the presence of epithelial reticular cells that
In patients with thrombocytopenia, the resemble adipocytes. The decalcified bone with osteocytes located in
blood level of platelets is decreased. The condi- lacunae is evident at the top of the photomicrograph.
tion becomes serious when the platelet level
is below 50,000/mm3. Although bleeding is
common in these patients, the bleeding is gener- processes of macrophages penetrate the spaces between
alized and occurs from small vessels, resulting in endothelial cells to enter the sinusoidal lumina.
purplish splotches on the skin. This condition is As adventitial reticular cells accumulate fat in their
believed to be an autoimmune disease, in which cytoplasm, they begin to resemble adipose cells. The
antibodies are formed to one’s own platelets and volume occupied by these very large cells reduces the
these antibodies destroy the platelets. hemopoietic compartment in size, transforming the red
marrow to yellow marrow.
these cells are directed away from the sinusoids and are In certain leukemias or in severe bleeding,
in contact with similar processes of other adventitial adventitial reticular cells may lose their lipids and
reticular cells, forming a three-dimensional network sur- decrease in size, transforming yellow marrow to
rounding discrete hemopoietic cords (islands). red marrow, thus making more space available
The islands of hemopoietic cells are composed of for hemopoiesis.
blood cells in various stages of maturation as well as
macrophages, which not only destroy the extruded
nuclei of erythrocyte precursors, malformed cells, and
excess cytoplasm but also regulate hemopoietic cell Prenatal Hemopoiesis
differentiation and maturation, as well as transmit iron
Prenatally, hemopoiesis is subdivided into four phases:
to developing erythroblasts to be utilized in the synthe-
mesoblastic, hepatic, splenic, and myeloid.
sis of the heme portion of hemoglobin. Frequently,
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Blood cell formation begins 2 weeks after conception

(mesoblastic phase) in the mesoderm of the yolk sac,
where mesenchymal cells aggregate into clusters known
as blood islands. The peripheral cells of these islands
form the vessel wall, and the remaining cells become
erythroblasts, which differentiate into nucleated
erythrocytes.
The mesoblastic phase begins to be replaced by the
hepatic phase by the 6th week of gestation. The ery-
throcytes still have nuclei, and leukocytes appear by the
8th week of gestation. The splenic phase begins during
the second trimester, and both hepatic and splenic
phases continue until the end of gestation.
Hemopoiesis begins in the bone marrow (myeloid
phase) by the end of the second trimester. As the skele-
tal system continues to develop, the bone marrow
assumes an increasing role in blood cell formation.
Although postnatally the liver and the spleen are not
active in hemopoiesis, they can revert to forming new
blood cells if the need arises.
Postnatal Hemopoiesis
Postnatal hemopoiesis occurs almost exclusively in bone
marrow. Figure 10–15 Light micrograph of a human bone marrow
smear (×270).
Because all blood cells have a finite life span, they must
be replaced continuously. This replacement is accom-
plished by hemopoiesis, starting from a common popu- colony-forming unit-lymphocyte (CFU-Ly) cells
lation of stem cells within the bone marrow (Fig. 10-15). and colony-forming unit-granulocyte, erythrocyte,
On a daily basis, more than 1011 blood cells are produced monocyte, megakaryocyte (CFU-GEMM) cells,
in the marrow to replace cells that leave the blood- previously known as colony-forming unit-spleen [CFU-
stream, die, or are destroyed. During hemopoiesis, stem S] cells. These two populations of MHSCs are respon-
cells undergo multiple cell divisions and differentiate sible for the formation of various progenitor cells.
through several intermediate stages, eventually giving CFU-GEMM cells are predecessors of the myeloid
rise to the mature blood cells discussed earlier. Table cell lines (erythrocytes, granulocytes, monocytes, and
10-5 outlines the numerous intermediate cells in the platelets); CFU-Ly cells are predecessors of the lym-
formation of each type of mature blood cell. The entire phoid cell lines (T cells and B cells). Both PHSCs and
process is regulated by various growth factors and MHSCs resemble lymphocytes and constitute a small
cytokines that act at different steps to control the type fraction of the null-cell population of circulating blood.
of cells formed and their rate of formation. Stem cells are commonly in the G0 stage of the cell
cycle but can be driven into the G1 stage by various
Stem Cells, Progenitor Cells, and growth factors and cytokines. Early stem cells may be
Precursor Cells recognized because they express the specific marker
molecules CD34, p170 pump, and c-kit on their plasma
The least differentiated of the cells responsible for the membranes. Homeobox genes may be active in the
formation of the formed elements of blood are stem differentiation of the early stages of hemopoietic cells,
cells; stem cells give rise to progenitor cells whose specifically Hox1 in the myeloid (but not erythroid) cell
progeny are the precursor cells. lines and certain members of the Hox2 group in the ery-
throid (but not myeloid) cell lines.
All blood cells arise from pluripotential hemopoietic Progenitor cells also resemble small lymphocytes
stem cells (PHSCs), which account for about 0.1% of but are unipotential (i.e., committed to forming a
the nucleated cell population of bone marrow. They are single cell line, such as eosinophils). Their mitotic activ-
usually amitotic but may undergo bursts of cell division, ity and differentiation are controlled by specific hemo-
giving rise to more PHSCs as well as to two types of poietic factors. These cells have only limited capacity
multipotential hemopoietic stem cells (MHSCs): for self-renewal.
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TABLE 10–5 Cells of Hemopoiesis
PHSC
Stem cells
CFU-GEMM CFU-Ly
Progenitor BFU-E CFU-Meg CFU-Eosinophil CFU-Basophil CFU-GM

cells
CFU-E CFU-G CFU-M

CFU-LyT CFU-LyB
Proerythroblast Megakaryoblast Myeloblast Myeloblast Myeloblast Promocyte
T B
Basophilic Promyelocyte Promyelocyte Promyelocyte lymphocyte lymphocyte
erythroblast
T B
lymphoblast lymphoblast
Polychromatophilic
erythroblast
Precursor Eo. myelocyte Ba. myelocyte Neutro.

cells myelocyte
Orthochromatophilic Eo. Ba. Neutro.

erythroblast metamyelocyte metamyelocyte metamyelocyte
Reticulocyte Eo. stab Ba. stab Neutro. stab
Mature Erythrocyte Megakaryocyte Eosinophil Basophil Neutrophil Monocyte T B

cells lymphocyte lymphocyte
Ba., basophil; BFU, burst-forming unit (E, erythrocyte); CFU, colony-forming unit (E, erythrocyte); G, granulocyte; GEMM, granulocyte,
erythrocyte, monocyte, megakaryocyte; GM, granulocyte-monocyte; Ly, lymphocyte; LyB, B cell; LyT, T cell; M, monocyte; Meg, megakary-
oblast); Eo., eosinophil; Neutro., neutrophil; PHSC, pluripotential hemopoietic stem cell.
Modified from Gartner LP, Hiatt JL, Strum J: Histology. Baltimore, Williams & Wilkins, 1988.
Precursor cells arise from progenitor cells and are shown that all blood cells are derived from a single
incapable of self-renewal. They have specific morpho- pluripotential stem cell. More frequently, however,
logical characteristics that permit them to be recognized isolated individual cells give rise to only erythrocytes or
as the first cell of a particular cell line. Precursor cells eosinophils or another type of blood cell. Because these
undergo cell division and differentiation, eventually experiments used the spleen as the site of hemopoiesis,
giving rise to a clone of mature cells. As cell maturation the individual lymphocyte-like cells were originally
and differentiation proceed, succeeding cells become called colony-forming units-spleen (CFU-S), but have
smaller, their nucleoli disappear, their chromatin been renamed to describe their function to CFU-
network becomes denser, and the morphological char- GEMM. Careful observations have shown that, as
acteristics of their cytoplasm approximate those of the stated previously, there are two types of multipotential
mature cells (Fig. 10-16). cells (CFU-GEMM and CFU-Ly) that give rise to the
Researchers studying hemopoiesis have isolated myeloid series of cells and lymphocytes, respectively.
individual lymphocyte-like cells that, under proper con- Newer research has demonstrated that each precursor
ditions, occasionally give rise to groups (colonies) of cell has a unipotential CFU as its predecessor (see Table
cells composed of granulocytes, erythrocytes, mono- 10-5). Precursor cells undergo a series of cell divisions
cytes, lymphocytes, and platelets. Thus, it has been and differentiations to yield the mature cell.
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ERYTHROCYTIC
Proerythroblast Basophilic Polychromatophilic Orthochromatophilic Reticulocyte Erythrocyte

erythroblast erythroblast erythroblast
EOSINOPHILIC
Eosinophilic Eosinophilic Eosinophilic stab cell Eosinophil

myelocyte metamyelocyte
NEUTROPHILIC
Neutrophilic Neutrophilic Neutrophilic stab cell Neutrophil

Myeloblast myelocyte metamyelocyte
Promyelocyte
BASOPHILIC
Basophilic Basophilic Basophilic stab cell Basophil

myelocyte metamyelocyte
Figure 10–16 Precursor cells in the formation of erythrocytes and granulocytes. The myeloblast and promyelocyte intermediaries in the
formation of eosinophils, neutrophils, and basophils are indistinguishable for the three cell types.
Patients who require bone marrow transplants after expressed only by these cells, permit the use of small
therapeutic procedures (such as irradiation or volumes of bone marrow enriched in PHSCs. These
chemotherapy) must be matched for the major histo- procedures are being investigated clinically, involving
compatibility complex of the donor. Unless an identi- patients with various types of malignancies.
cal twin is available for the transplantation, grafting Perhaps in the relatively near future, people with
failure is common. This can be circumvented by hereditary blood cell disorders (e.g., sickle cell
freezing the patient’s own bone marrow in liquid anemia) may be treated by the use of genetically
nitrogen and reintroducing it (as in an autologous engineered stem cells. PHSCs isolated from the
transplant) in the patient after treatment with irra- patient may be transfected with the normal gene
diation or chemotherapy. Because the number of (e.g., for hemoglobin) and reintroduced as an autol-
stem cells per unit volume of bone marrow is rela- ogous transplant. These genetically engineered cells
tively small, large volumes of marrow have to be har- bearing the normal gene would proliferate, and their
vested from the patient. Newer procedures that progeny would produce normal blood cells. Although
permit the isolation of pluripotential hemopoietic the patient would still be producing some defective
stem cells (PHSCs) by the use of monoclonal anti- cells, it is hoped that enough normal cells would be
bodies against the CD34 molecule, which is produced to minimize the hereditary defect.
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Hemopoietic Growth Factors (Colony- nized by receptors of the macrophage plasma mem-
Stimulating Factors) brane. These phagocytic cells engulf and destroy the
apoptotic cells.
Hemopoiesis is regulated by a number of cytokines and It has been suggested that there are factors respon-
growth factors, such as interleukins, colony-stimulating sible for the release of mature (and almost mature)
factors, macrophage inhibiting protein-a, and steel blood cells from the marrow. These proposed factors
factor. have not yet been characterized completely, but they
include interleukins, CSF, and steel factor.
Hemopoiesis is regulated by numerous growth factors
produced by various cell types. Each factor acts on
specific stem cells, progenitor cells, and precursor cells,
generally inducing rapid mitosis, differentiation, or both CLINICAL CORRELATIONS
(Table 10-6). Some of these growth factors also promote
the functioning of mature blood cells. Most hemopoi- Pathologically increased secretion of erythropoi-
etic growth factors are glycoproteins. etin can cause secondary polycythemia, an
Three routes are used to deliver growth factors to increase in the total number of red blood cells in
their target cells: (1) transport via the bloodstream (as the blood, increasing its viscosity, reducing its
endocrine hormones), (2) secretion by stromal cells flow rate, and thus impeding circulation. The
of the bone marrow near the hemopoietic cells (as increased secretion is usually caused by tumors
paracrine hormones), and (3) direct cell-to-cell contact of erythropoietin-secreting cells. Patients may
(as surface signaling molecules). have an erythrocyte count of 10 million red blood
Certain growth factors—principally, steel factor cells/mm3.
(also known as stem cell factor), granulocyte-
macrophage colony-stimulating factor (GM-CSF)
and two interleukins (IL-3 and IL-7)—stimulate
proliferation of pluripotential and multipotential stem Erythropoiesis
cells, thus maintaining their populations. Additional
cytokines, such as granulocyte colony-stimulating Erythropoiesis, the formation of red blood cells, is under
factor (G-CSF), monocyte colony-stimulating factor the control of several cytokines, namely steel factor, IL-3,
(M-CSF), IL-2, IL-5, IL-6, IL-11, IL-12, macrophage IL-9, GM-CSF, and erythropoietin.
inhibitory protein-α (MIP-α), and erythropoietin, are
believed to be responsible for the mobilization and dif- The process of erythropoiesis, red blood cell formation,
ferentiation of these cells into unipotential progenitor generates 2.5 × 1011 erythrocytes every day. In order to
cells. produce such a tremendous number of cells, two types
Colony-stimulating factors (CSFs) are also of unipotential progenitor cells arise from the CFU-
responsible for the stimulation of cell division and GEMM: the burst-forming units-erythrocyte (BFU-
for the differentiation of unipotential cells of the E) and colony-forming units-erythrocyte (CFU-E).
granulocytic and monocytic series. Erythropoietin If the circulating red blood cell level is low, the
activates cells of the erythrocytic series, whereas kidney produces a high concentration of erythropoi-
thrombopoietin stimulates platelet production. Steel etin, which, in the presence of IL-3, IL-9, steel factor,
factor (stem cell factor), which, as discussed previ- and GM-CSF, induces CFU-GEMM to differentiate
ously, acts on pluripotential, multipotential, and unipo- into BFU-E. These cells undergo a “burst” of mitotic
tential stem cells, is produced by stromal cells of the activity, forming a large number of CFU-E. Interest-
bone marrow and is inserted into their cell membranes. ingly, this transformation requires the loss of IL-3
Stem cells must come in contact with these stromal cells receptors.
before they can become mitotically active. It is believed CFU-E require a low concentration of erythropoi-
that hemopoiesis cannot occur without the presence of etin not only to survive but also to form the first recog-
cells that express stem cell factors, which is why post- nizable erythrocyte precursor, the proerythroblast
natal blood cell formation is restricted to the bone (Fig. 10-17; also see Fig. 10-16). The proerythroblasts
marrow (and liver and spleen, if necessary). and their progeny (Figs. 10-18 and 10-19) form spher-
Hemopoietic cells are programmed to die by under- ical clusters around macrophages (nurse cells) which
going apoptosis unless they come into contact with phagocytose extruded nuclei and excess or deformed
growth factors. Such dying cells display clumping of erythrocytes. Nurse cells may also provide growth
the chromatin in their shrunken nuclei and a dense, factors to assist erythropoiesis. The properties of the
granular-appearing cytoplasm. On their cell surface, cells in the erythropoietic series are presented in Table
they express specific macromolecules that are recog- 10-7.
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TABLE 10–6 Hemopoietic Growth Factors
Factors Principal Action Site of Origin
Stem cell factor Promotes hemopoiesis Stromal cells of bone marrow
GM-CSF Promotes CFU-GM mitosis and differentiation; facilitates T cells; endothelial cells
granulocyte activity
G-CSF Promotes CFU-G mitosis and differentiation; facilitates Macrophages; endothelial cells
neutrophil activity
M-CSF Promotes CFU-M mitosis and differentiation Macrophages; endothelial cells
IL-1 In conjunction with IL-3 and IL-6, it promotes proliferation of Monocytes; macrophages,
PHSC, CFU-GEMM, CFU-S, and CFU-Ly; suppresses endothelial cells
erythroid precursors
IL-2 Stimulates activated T- and B-cell mitosis; induces differentiation Activated T cells
of NK cells
IL-3 In conjunction with IL-1 and IL-6, it promotes proliferation of Activated T and B cells
PHSC, CFU-GEMM, CFU-S, and CFU-Ly as well as all
unipotential precursors (except for LyB and LyT)
IL-4 Stimulates T- and B-cell activation and development of mast Activated T cells
cells and basophils
IL-5 Promotes CFU-Eo mitosis and activates eosinophils T cells
IL-6 In conjunction with IL-1 and IL-3, it promotes proliferation of Monocytes and fibroblasts
PHSC, CFU-GEMM, CFU-S, and CFU-Ly; also facilitates
CTL and B-cell differentiation
IL-7 Promotes differentiation of CFU-LyB; enhances differentiation Stromal cells, adventitial

of NK cells reticular cells?
IL-8 Induces neutrophil migration and degranulation Leukocytes, endothelial cells,

and smooth muscle cells
IL-9 Induces mast cell activation and proliferation; modulates IgE T helper cells
production; promotes T helper cell proliferation
IL-10 Inhibits cytokine production by macrophages, T cells, and NK Macrophages and T cells
cells; facilitates CTL differentiation and proliferation of B
cells and mast cells
IL-12 Stimulates NK cells; enhances TCL and NK cell function Macrophages
γ-Interferons Activate B cells and monocytes; enhance CTL differentiation; T cells and NK cells
augment the expression of class II HLA
Erythropoietin CFU-E differentiation; BFU-E mitosis Endothelial cells of the

peritubular capillary network
of kidney; hepatocytes
Thrombopoietin Proliferation and differentiation of CFU-meg and megakaryoblasts Not known
BFU-E, burst-forming unit-erythrocyte; CTL, cytotoxic T cell; CFU, colony-forming unit (E, erthrocyte; Eo., eosinophil; G, granulocyte;
GEMM, granulocyte, erythrocyte, monocyte, megakaryocyte; GM, granulocyte-monocyte; Meg, megakaryoblast; Ly, lymphocyte; LyB, B cell;
LyT, T cell; S, spleen); CSF, colony-stimulating factor (G, granulocyte; GM, granulocyte-monocyte; M, monocyte); Meg, megakaryocyte; IL,
interleukin; Neut., neutrophil; NK, natural killer; PHSC, pluripotential hemopoietic stem cell.
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Granulocytopoiesis
Granulocytopoiesis, the formation of the granulocytes
L (neutrophils, eosinophils, and basophils), is under the
O influence of several cytokines, namely G-CSF and GM-
CSF, as well as IL-1, IL-5, IL-6, TNF-a, and IL-5.
Although the granulocytic series usually is discussed

under a single heading, as it is here, the three types of
E granulocytes are actually derived from their own unipo-
tential (or bipotential, as with neutrophils) stem cells
(see Table 10-5). Each of these stem cells is a descen-
P dant of the pluripotential stem cell CFU-GEMM. Thus,
CFU-Eo, of the eosinophil lineage, and CFU-Ba, of the
basophil lineage, each undergo cell division, giving rise
to the precursor cell, or myeloblast. Neutrophils orig-
inate from the bipotential stem cell, CFU-GM, whose
mitosis produces two unipotential stem cells, CFU-G
E
(of the neutrophil line) and CFU-M, responsible for the
monocyte lineage. Similar to CFU-Ba and CFU-Eo,
CFU-G divides to give rise to myeloblasts.
The proliferation and differentiation of these stem cells
B are under the influence of G-CSF, GM-CSF, and IL-5.
Therefore, these three factors facilitate the development
of neutrophils, basophils, and eosinophils. In turn, IL-1,
IL-6, and TNF-α are cofactors necessary for the synthesis
and release of G-CSF and GM-CSF. In addition, IL-5 may
also play a role in the activation of eosinophils.
Myeloblasts (Fig. 10-20; also see Fig. 10-16) are pre-
cursors of all three types of granulocytes, and they cannot be
differentiated from one another. It is not known whether a
Figure 10–17 Light micrograph of bone marrow displaying all single myeloblast can produce all three types of granulo-
of the stages of red blood cell formation except for reticulocytes cytes or whether there is a specific myeloblast for each type
(×1325). B, basophilic erythroblast; E, erythrocyte; L, polychro- of granulocyte. Myeloblasts undergo mitosis, giving rise to
matophilic erythroblast; O, orthochromatophilic erythroblast; P,
proerythroblast.
promyelocytes, which in turn divide to form myelocytes. It
is at the myelocyte step that specific granules are present
and the three granulocyte lines may be recognized. Each
day, the average adult produces approximately 800,000
neutrophils, 170,000 eosinophils, and 60,000 basophils.
Table 10-8 details the neutrophil lineage. The
CLINICAL CORRELATIONS eosinophil and basophil lineages appear to be identical
to the neutrophil lineage except for the differences in
Iron-deficiency anemia, the most common their specific granules.
form of anemia resulting from nutritional defi- Newly formed neutrophils leave the hemopoietic cords
ciency, affects about 10% of the U.S. population. by piercing the endothelial cells lining the sinusoids rather
Although the cause may be low dietary intake of than by migrating between them. Once neutrophils enter
iron, that is usually not the case in the United the circulatory system, they marginate; that is, they
States; instead, it is caused by either malabsorp- adhere to the endothelial cells of the blood vessels and
tion or chronic blood loss. The erythrocytes of an remain there until they are needed. The process of
iron-deficient person are smaller than usual; the margination requires the sequential expression of various
patient presents with a whitish pallor, and the transmembrane adhesion molecules and integrins by the
nails appear spoon-shaped with accentuated neutrophils as well as of specific surface receptor mole-
longitudinal ridges. The patient complains of cules by the endothelial cells, the description of which is
generalized weakness, constant tiredness, and beyond the scope of this textbook. Because of the process
lack of energy. of margination, there are always many more neutrophils in
the circulatory system than in the circulating blood.
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Figure 10–18 Electron micrograph of a pro-

erythroblast, displaying its nucleolus (nuc) as well as
the perinuclear cytoplasm (×14,000). Note that the
nucleoplasm is relatively smooth in appearance and
that the cytoplasm is rich in mitochondria and free
ribosomes, indicating that the cell is active in protein
synthesis. (From Hopkins CR: Structure and Func-
tion of Cells. Philadelphia, WB Saunders, 1978.)
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Figure 10–19 Electron micrograph of an

orthochromatophilic erythroblast (×21,300). Observe
that the nucleus possesses a large amount of
heterochromatin (H). (From Hopkins CR: Structure
and Function of Cells. Philadelphia, WB Saunders,
1978.)
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TABLE 10–7 Cells of the Erythropoietic Series
Nucleus* and Electron

Cell Size (mm) Mitosis Nucleoli Cytoplasm* Micrographs
Proerythroblast 14-19 Round, burgundy-red; 3-5 Gray-blue, Scant RER; many

chromatin network: peripheral polysomes, few
fine; mitosis clumping mitochondria; ferritin
Basophilic Same as above, but 1-2? Similar to above, Similar to above, but
erythroblast chromatin network but slight some hemoglobin is
is coarser; mitosis pinkish present
background
Polychromatophilic 12-15 Round and densely None Yellowish-pink Similar to above, but
erythroblast staining; very in bluish more hemoglobin is
coarse chromatin background present
network; mitosis
Orthochromatophilic 8-12 Small, round, dense; None Pink in a slight Few mitochondria and
erythroblast excentric or is being bluish polysomes; much
extruded; no mitosis background hemoglobin
Reticulocyte 7-8 None None Like mature Clusters of ribosomes;

RBC, but cell is filled with
when stained hemoglobin
with cresyl
blue; display
bluish
reticulum in
pink cytoplasm
Erythrocyte 7.5 None None Pink cytoplasm Only hemoglobin
*Colors as they appear using Romanovsky-type stains (or their modifications).

RBC, red blood cell; RER, rough endoplasmic reticulum.
in diameter) that have a kidney-shaped, acentrically

CLINICAL CORRELATIONS located nucleus. The cytoplasm of promonocytes is
bluish and houses numerous azurophilic granules.
Acute myeloblastic leukemia results from Electron micrographs of promonocytes disclose a
uncontrolled mitosis of a transformed stem cell well-developed Golgi apparatus, abundant RER, and
whose progeny do not differentiate into mature numerous mitochondria. The azurophilic granules are
cells. The cells involved may be the CFU-GM, lysosomes, about 0.5 µm in diameter. Every day, the
CFU-Eo, or CFU-Ba, whose differentiation average adult forms more than 1010 monocytes, most of
stops at the myeloblast stage. The disease affects which enter the circulation. Within a day or two, the
young adults between 15 and 40 years of age and newly formed monocytes enter the connective tissue
is treated by intensive chemotherapy and, more spaces of the body and differentiate into macrophages.
recently, by bone marrow transplantation.
Platelet Formation
The formation of platelets is under the control of
Monocytopoiesis thrombopoietin, which induces the development and
proliferation of giant cells known as megakaryoblasts.
Monocytes share their bipotential cells with neu-
trophils. CFU-GM undergoes mitosis and gives rise to The unipotential platelet progenitor, CFU-Meg, gives
CFU-G and CFU-M (monoblasts). The progeny of rise to a very large cell, the megakaryoblast (25 to
CFU-M are promonocytes, large cells (16 to 18 µm 40 µm in diameter), whose single nucleus has several
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P
NM
NM
Figure 10–20 Light micrographs of granulocytopoiesis displaying the various intermediary cell types (×1234). A, Myeloblast (M) and neu-
trophilic metamyelocyte (NM). B, Promyelocyte (P). C, Neutrophilic myelocyte (arrow). D, Neutrophilic metamyelocyte (NM), promyelocyte
(P), and neutrophilic stab cell (arrowhead).
lobes. These cells undergo endomitosis, whereby the Lymphopoiesis

cell does not divide; instead, it becomes larger and
the nucleus becomes polyploid, as much as 64 N. The Pluripotential hemopoietic stem cells give rise to the
bluish cytoplasm accumulates azurophilic granules. myeloid series of cells via CFU-GEMM cells as well as to
These cells are stimulated to differentiate and prolifer- the lymphoid series of cells via CFU-Ly cells.
ate by thrombopoietin.
Megakaryoblasts differentiate into megakaryocytes The multipotential stem cell CFU-Ly divides in the
(see Fig. 10-14), which are large cells (40 to 100 µm bone marrow to form the two unipotential progenitor
in diameter), each with a single lobulated nucleus. cells, CFU-LyB and CFU-LyT, neither of which is
Electron micrographs of megakaryocytes display a well- immunocompetent.
developed Golgi apparatus, numerous mitochondria, In birds, the CFU-LyB cell migrates to a diverticu-
abundant RER, and many lysosomes (Fig. 10-21). lum attached to the gut, known as the bursa of Fabri-
Megakaryocytes are located next to sinusoids, into cius (thus B cell). Here the CFU-LyB cell divides
which they protrude their cytoplasmic processes. These several times, giving rise to immunocompetent B
cytoplasmic processes fragment along complex, narrow lymphocytes expressing specific surface markers,
invaginations of the plasmalemma, known as demarca- including antibodies. A similar event occurs in
tion channels, into clusters of proplatelets. Shortly mammals, but in the absence of a bursa this develop-
after the proplatelets are released, they disperse into ment of immunocompetence occurs in a bursa-equiva-
individual platelets. Each megakaryocyte can form lent location in the bone marrow.
several thousand platelets. The remaining cytoplasm CFU-LyT cells undergo mitosis, forming immunoin-
and nucleus of the megakaryocyte degenerate and are competent T cells, which travel to the cortex of the
phagocytosed by macrophages. thymus, where they proliferate, mature, and begin to
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TABLE 10–8 Cells of the Neutrophilic Series
Nucleus* and Electron

Cell Size (mm) Mitosis Nucleoli Cytoplasm* Granules Micrographs
Myeloblast 12-14 Round, reddish- 2-3 Blue clumps in None RER, small Golgi,
blue; chromatin a pale blue many
network: fine; background; mitochondria
mitosis cytoplasmic and polysomes
blebs at cell
periphery
Promyelocyte 16-24 Round to oval, 1-2 Bluish cytoplasm; Azurophilic RER, large Golgi,
reddish blue; no cytoplasmic granules many
chromatin blebs at cell mitochondria,
network: coarse; periphery numerous
mitosis lysosomes
(0.5 µm in
diameter)
Neutrophilic 10-12 Flattened, acentric; 0-1 Pale blue Azurophilic RER, large Golgi,
myelocyte chromatin cytoplasm and numerous
network: coarse; specific mitochondria,
mitosis granules lysosomes
(0.5 µm) and
specific granules
(0.1 µm)
Neutrophilic 10-12 Kidney-shaped, None Pale blue Azurophilic Organelle

metamyelocyte dense; chromatin cytoplasm and population is
network: coarse; specific reduced, but
no mitosis granules granules are
as above
Neutrophilic 9-12 Horseshoe-shaped; None Pale blue Azurophilic Same as above

band (stab; chromatin cytoplasm and
juvenile) network: very specific
coarse; no mitosis granules
Neutrophil 9-12 Multilobed; None Pale bluish-pink Azurophilic Same as above

chromatin and
network: very specific
coarse; no mitosis granules
*Colors as appear using Romanovsky-type stains (or their modifications).

RER, rough endoplasmic reticulum.
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Figure 10–21 Electron micrograph of a mega-

karyocyte displaying segmentation in the formation
of platelets (×3166). Although this cell possesses a
single nucleus, it is lobulated, which gives the
appearance that the cell possesses several nuclei.
(From Hopkins CR: Structure and Function of Cells.
express cell surface markers. As these surface markers Both B lymphocytes and T lymphocytes proceed to
appear on the T-cell plasmalemma (such as T-cell lymphoid organs (such as the spleen and lymph nodes),
receptors and clusters of differentiation markers), the where they form clones of immunocompetent T and
cells become immunocompetent T lymphocytes. Most B cells in well-defined regions of the organs. The
of these newly formed T cells are destroyed in the lymphocytic series is discussed in more detail in
thymus and are phagocytosed by resident macrophages. Chapter 12.
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11 䡲䡲䡲
Circulatory System
The circulatory system is composed of two separate but General Structure of Blood Vessels
related components: the cardiovascular system and the
lymphatic vascular system. The function of the cardio- Arteries generally have thicker walls and are smaller in
vascular system is to carry blood in both directions diameter than their venous counterparts.
between the heart and the tissues. The function of the
lymphatic vascular system is to collect lymph, the Most blood vessels have several features that are struc-
excess extracellular tissue fluid, and to deliver it back to turally similar, although dissimilarities exist and are the
the cardiovascular system. Thus, the lymphatic system bases for classifying the vessels into different identifi-
provides one-way transport, whereas the cardiovascular able groups. For example, the walls of high-pressure
system provides two-way circulation. vessels (e.g., subclavian arteries) are thicker than ves-
sels conducting blood at low pressure (e.g., subclavian
veins). However, arterial diameters continue to
CARDIOVASCULAR SYSTEM decrease at each branching, whereas vein diameters
increase at each convergence, thus altering the respec-
The cardiovascular system is composed of two circuits:
tive layers of the walls of the vessels. Therefore, the
the pulmonary circuit to the lungs and the systemic
descriptions used as distinguishing characteristics for a
circuit to the tissues of the body.
particular type of artery or vein are not always absolute.
Indeed, the walls of the capillaries and venules are com-
The cardiovascular system comprises the heart, a mus- pletely modified and less complex compared with those
cular organ that pumps the blood into two separated of larger vessels. Generally, arteries have thicker walls
circuits: the pulmonary circuit, which carries blood to and are smaller in diameter than are the corresponding
and from the lungs, and the systemic circuit, which veins. Moreover, in histological sections, arteries are
distributes blood to and from all of the organs and round and usually have no blood in their lumina.
tissues of the body. These circuits consist of:
Vessel Tunics
䡲 Arteries—a series of vessels that transport blood
away from the heart by branching into vessels of Walls of blood vessels are composed of three layers: the
smaller and smaller diameter, eventually branching tunica intima, the tunica media, and the tunica
into capillaries to supply all regions of the body with adventitia.
blood
䡲 Capillaries—thin-walled vessels with the smallest Three separate concentric layers of tissue, or tunics,
diameter, form capillary beds, where gases, nutrients, make up the wall of the typical blood vessel (Fig. 11-1).
metabolic wastes, hormones, and signaling sub- The innermost layer, the tunica intima, is composed
stances are interchanged or passed between the of a single layer of flattened, squamous endothelial cells,
blood and the tissues of the body to sustain normal which form a tube lining the lumen of the vessel, and
metabolic activities the underlying subendothelial connective tissue. The
䡲 Veins—vessels that drain capillary beds and form intermediate layer, the tunica media, is composed
larger and larger vessels returning blood to the mostly of smooth muscle cells oriented concentrically
heart around the lumen. The outermost layer, the tunica
251
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252 䡲䡲䡲 Chapter 11 䡲 Circulatory System
Vasa vasorum Regulation of Arterial Blood Pressure later), as well

as enzymes that inactivate bradykinin, serotonin,
prostaglandins, thrombin, and norepinephrine; more-
External elastic lamina Nerve over, they also bind lipoprotein lipase, the enzyme that
Adventitia degrades lipoproteins.
A subendothelial layer lies immediately beneath
the endothelial cells. It is composed of loose connective
tissue and a few scattered smooth muscle cells, both
Smooth muscle arranged longitudinally. Beneath the subendothelial
Internal elastic layer is an internal elastic lamina that is especially well
lamina
developed in muscular arteries. Separating the tunica
Subendothelial intima from the tunica media, the internal elastic lamina
connective tissue
is composed of elastin, which is a fenestrated sheet that
Variable basal lamina
of endothelium
permits the diffusion of substances into the deeper
Lumen
regions of the arterial wall to nourish the cells there.
Endothelium of tunica intima
Tunica intima
Tunica Media
Tunica media The tunica media, usually the thickest layer of the vessel
wall, is composed of helically disposed layers of smooth
Tunica adventitia muscle.
Figure 11–1 A typical artery. The tunica media is the thickest layer of the blood
vessel. The concentric cell layers forming the tunica
media comprise mostly helically arranged smooth
muscle cells. Interspersed within the layers of smooth
adventitia, is composed mainly of fibroelastic connec- muscle are some elastic fibers, type III collagen, and
tive tissue arranged longitudinally. proteoglycans. The fibrous elements form lamellae
The tunica intima houses in its outermost layer the within the ground substance secreted by smooth muscle
internal elastic lamina, a thin band of elastic fibers cells. Larger muscular arteries have an external elastic
that is well developed in medium-sized arteries. The lamina, which is more delicate than the internal elastic
outermost layer of the tunica media houses another lamina and separates the tunica media from the overly-
band of elastic fibers, the external elastic lamina, ing tunica adventitia. Capillaries and postcapillary
although it is not distinguishable in all arteries. The venules do not have a tunica media; in these small
deeper cells of the tunica media and tunica adventitia vessels, pericytes replace the tunica media (see
are nourished by the vasa vasorum. Capillaries section).
Tunica Intima Tunica Adventitia
The tunica intima is composed of a simple squamous The tunica adventitia, the outermost layer of the blood
epithelium and the subendothelial connective tissue. vessel wall, blends into the surrounding connective
tissue.
The endothelial cells (simple squamous epithelium)
lining the lumen of the blood vessel rest on a basal Covering the vessels on their outside surface is the
lamina. These flattened cells are elongated into a sheet tunica adventitia, composed mostly of fibroblasts,
such that their long axis is more or less parallel to the type I collagen fibers, and longitudinally oriented elastic
long axis of the vessel, which permits each endothelial fibers. This layer becomes continuous with the connec-
cell to nearly surround the lumen of a small-caliber tive tissue elements surrounding the vessel.
vessel. In larger-bore vessels, several to many individual
endothelial cells are required to line the circumference Vasa Vasorum
of the lumen. Endothelial cells not only provide an
exceptionally smooth surface but also function in secret- Vasa vasorum furnish the muscular walls of the larger
ing types II, IV, and V collagens, lamin, endothelin, blood vessels with a blood supply.
nitric oxide, and von Willebrand factor. Moreover,
they possess membrane-bound enzymes, such as The thickness and muscularity of larger vessels—the
angiotensin-converting enzyme (ACE), which tunica media and tunica adventitia—prevent the cells
cleaves angiotensin I to generate angiotensin II (see composing the tunics from being nourished by diffusion
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Chapter 11 䡲 Circulatory System ■ ■ ■ 253
from the lumen of the vessel. These cells are nourished sends branches to the body wall and viscera. The
by the vasa vasorum, small arteries that enter the abdominal aorta terminates by bifurcating into the right
vessel walls and branch profusely to serve the cells and left common iliac arteries in the pelvis.
located primarily in the tunica media and tunica adven- Three major arterial trunks—the right brachioce-
titia. Compared with arteries, veins have more cells that phalic artery, the left common carotid artery, and the
cannot be supplied with oxygen and nutrients by diffu- left subclavian artery—arise from the arch of the aorta
sion, because venous blood contains less oxygen and to supply the superior extremities and the head and
nutrients than arterial blood. For this reason, the vasa neck. It is interesting to note that the right common
vasorum are more prevalent in the walls of veins than carotid artery arises from the right brachiocephalic
arteries. trunk, whereas the left common carotid artery arises
directly from the aortic arch. Branching of all of these
Nerve Supply to Blood Vessels arteries into large numbers of smaller and smaller arter-
ies continues until the vessel walls contain a single layer
Sympathetic nerves supply vasomotor innervation to the of endothelial cells. The resulting vessels, called capil-
smooth muscles of the tunica media. laries, are the smallest functional vascular elements of
the cardiovascular system.
A network of vasomotor nerves of the sympathetic
component of the autonomic nervous system supplies Classification of Arteries
smooth muscle cells of blood vessels. These unmyeli-
nated, postganglionic sympathetic nerves are responsi- Arteries are of three types: elastic arteries (conducting
ble for vasoconstriction of the vessel walls. Because arteries), muscular arteries (distributing arteries), and
the nerves seldom enter the tunica media of the vessel, arterioles.
they do not synapse directly on the smooth muscle cells.
Instead, they release the neurotransmitter norepi- Arteries are classified into three major types based on
nephrine, which diffuses into the media and acts on their relative size, morphological characteristics, or
smooth muscle cells nearby. These impulses are propa- both (Table 11-1). From largest to smallest, they are
gated throughout all of the smooth muscle cells via their as follows:
gap junctions, thereby orchestrating contractions of the
䡲 Elastic (conducting) arteries
entire smooth muscle cell layer and thus reducing the
䡲 Muscular (distributing) arteries
diameter of the vessel lumen.
䡲 Arterioles
Arteries are more heavily endowed with vasomotor
nerves than are veins, but veins also receive vasomotor Because the vessels decrease in diameter in a con-
nerve endings in the tunica adventitia. The arteries tinuous fashion, there are gradual changes in morpho-
supplying skeletal muscles also receive cholinergic logical characteristics as they morph from one type to
(parasympathetic) nerves to bring about vasodilation. another. Therefore, some vessels having characteristics
of two categories cannot be assigned to a specific cate-
Arteries gory with certainty.
Arteries are blood vessels that carry blood away from Elastic Arteries
the heart.
Concentric layers of elastic membranes, known as
Arteries are efferent vessels that transport blood away fenestrated membranes, occupy much of the tunica
from the heart to the capillary beds. The two major media.
arteries that arise from the right and left ventricles
of the heart are the pulmonary trunk and the aorta, The aorta and the branches originating from the aortic
respectively. arch (the common carotid artery and the subclavian
The pulmonary trunk branches, shortly after exiting artery), the common iliac arteries, and the pulmonary
the heart, into right and left pulmonary arteries that trunk are elastic (conducting) arteries (Fig. 11-2). The
enter the lungs for distribution. (Chapter 15 describes walls of these vessels may be yellow in the fresh state
the branching and blood supply to the lungs.) The right because of the abundance of elastin.
and left coronary arteries, which supply the heart The tunica intima of the elastic arteries is com-
muscle, arise from the aorta as it exits the left ventricle. posed of an endothelium that is supported by a narrow
The aorta, upon leaving the heart, courses in an layer of underlying connective tissue containing a few
obliquely posterior arch to descend in the thoracic fibroblasts, occasional smooth muscle cells, and colla-
cavity, where it sends branches to the body wall and the gen fibers. Thin laminae of elastic fibers, the internal
viscera; it then enters the abdominal cavity, where it elastic laminae, are also present.
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TABLE 11–1 Characteristics of Various Types of Arteries
Artery Tunica Intima Tunica Media Tunica Adventitia
Elastic artery Endothelium with Weibel-Palade 40 to 70 fenestrated elastic Thin layer of fibroelastic
(conducting) bodies, basal lamina, membranes; smooth muscle connective tissue, vasa
(e.g., aorta) subendothelial layer, incomplete cells interspersed between vasorum, lymphatic
internal elastic lamina elastic membranes; thin vessels, nerve fibers
external elastic lamina; vasa
vasorum in outer half
Muscular artery Endothelium with Weibel-Palade Up to 40 layers of smooth Thin layer of fibroelastic
(distributing) bodies, basal lamina, muscle cells; thick external connective tissue; vasa
(e.g., femoral subendothelial layer, thick elastic lamina vasorum not very
artery) internal elastic lamina prominent; lymphatic
vessels, nerve fibers
Arteriole Endothelium with Weibel-Palade One or two layers of smooth Loose connective tissue,
bodies; basal lamina, muscle cells nerve fibers
subendothelial layer not very
prominent; some elastic fibers
instead of a defined internal
elastic lamina
Metarteriole Endothelium, basal lamina Smooth muscle cells form Sparse, loose connective
precapillary sphincter tissue
The endothelial cells of the elastic arteries are 10 to The tunica media of the elastic arteries consists of
15 µm wide and 25 to 50 µm long; their long axes are many fenestrated lamellae of elastin, known as fenes-
oriented parallel to the longitudinal axis of the vessel. trated membranes, alternating with circularly ori-
These cells are connected to each other mostly by ented layers of smooth muscle cells. The number of
occluding junctions. Their plasma membranes contain lamellae of elastin increases with age; there are approx-
small vesicles thought to be related to transport of imately 40 in newborns and 70 in adults. These fenes-
water, macromolecules, and electrolytes. Occasional trated membranes also increase in thickness because of
blunt processes may extend from the plasma membrane the continued deposition of elastin, which constitutes
through the internal elastic lamina to form gap junctions much of the tunica media; smooth muscles cells are less
with smooth muscle cells located in the tunica media. abundant in elastic arteries than in some of the muscu-
The endothelial cells contain Weibel-Palade bodies, lar arteries. The extracellular matrix, secreted by the
membrane-bound inclusions 0.1 µm in diameter and smooth muscle cells, is composed mostly of chondroitin
3 µm long, that have a dense matrix housing tubular ele- sulfate, collagen, and reticular and elastin fibers. An
ments containing the glycoprotein von Willebrand external elastic lamina is also present in the tunica
factor. This factor, which facilitates the coagulation of media.
platelets during clot formation, is manufactured by most The tunica adventitia of elastic arteries is relatively
endothelial cells but is stored only in arteries. thin and is composed of loose fibroelastic connective
tissue housing some fibroblasts. Vasa vasorum also are
abundant throughout the adventitia. Capillary beds
arise from the vasa vasorum and extend to the tissues of
CLINICAL CORRELATIONS the tunica media, where they supply the connective
tissue and smooth muscle cells with oxygen and nutri-
Patients with von Willebrand disease, an ents. Fenestrations in the elastic laminae permit some
inherited disorder that results in impaired adhe- diffusion of oxygen and nutrients to the cells in the
sion of platelets, have prolonged coagulation tunica media from the blood flowing through the
times and excessive bleeding at an injury site. lumen, although most of the nourishment is derived
from branches of the vasa vasorum.
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iEL TA
TM
TM
FM
xEL
Figure 11–3 Light micrograph of a muscular artery (×132). Note

the tunica adventitia (TA) and the internal (iEL) and external (xEL)
elastic laminae within the thick tunica media (TM).
TA
endothelium conforms. Occasionally the internal ela-

stic lamina is duplicated; this is called bifid internal
elastic lamina. As in elastic arteries, the endothelium
has processes that pass through fenestrations within the
Figure 11–2 Light micrograph of an elastic artery (×132).
Observe the fenestrated membranes (FM), tunica media (TM), and internal elastic lamina and make gap junctions with
tunica adventitia (TA). smooth muscle cells of the tunica media that are near
the interface with the tunica intima. It is believed that
these gap junctions may couple metabolically the
Muscular Arteries endothelium and the smooth muscle cells.
The tunica media of the muscular arteries is com-
Muscular arteries are characterized by a thick tunica posed predominantly of smooth muscle cells, although
media that is composed mostly of smooth muscle cells. these cells are considerably smaller than those located
in the walls of the viscera. The orientation of most of
Muscular (distributing) arteries include most vessels the smooth muscle cells is circular where the tunica
arising from the aorta, except for the major trunks media interfaces with the tunica intima; however, a few
orginating from the arch of the aorta and the terminal bundles of smooth muscle fibers are arranged longitu-
bifurcation of the abdominal aorta, which are identified dinally in the tunica adventitia. Small muscular arteries
as elastic arteries. Indeed, most of the named arteries, have three or four layers of smooth muscle cells,
even those with a diameter of only 0.1 mm, are classi- whereas larger muscular arteries may have as many as
fied as muscular arteries (e.g., brachial, ulnar, renal). 40 layers of circularly arranged smooth muscle cells.
The identifying characteristic of muscular arteries is a The number of cell layers decreases as the diameter of
relatively thick tunica media composed mostly of the artery diminishes.
smooth muscle cells (Fig. 11-3). Each smooth muscle cell is enveloped by an exter-
The tunica intima in the muscular arteries is nal lamina (similar to a basal lamina), although
thinner than that in the elastic arteries, but the suben- muscle cell processes extend through intervals in the
dothelial layer contains a few smooth muscle cells; also, basal lamina to form gap junctions with other muscle
in contrast with that of elastic arteries, the internal cells, ensuring coordinated contractions within the
elastic lamina of the muscular arteries is prominent tunica media. Interspersed within the layers of smooth
and displays an undulating surface to which the muscle cells are elastic fibers, type III collagen fibers,
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and chondroitin sulfate, all secreted by the smooth

muscle cells. Type III collagen fibers (30 nm in diame-
ter) are located in bundles within the intercellular
spaces.
An external elastic lamina is identifiable in histo-
A
logical sections of larger muscular arteries as several
layers of thin elastic sheets; in electron micrographs, L
these sheets display fenestrations.
The tunica adventitia of the muscular arteries con- TM
sists of elastic fibers, collagen fibers (60 to 100 nm in
diameter), and ground substance composed mostly of N
dermatan sulfate and heparan sulfate. This extracellular
matrix is produced by fibroblasts in the adventitia. The
collagen and elastic fibers are oriented longitudinally
and blend into the surrounding connective tissues.
Located at the outer regions of the adventitia are vasa
vasorum and unmyelinated nerve endings. Neurotrans-
mitters released at the nerve endings diffuse through RBC
fenestrations in the external elastic lamina into the
tunica media to depolarize some of the superficial L
smooth muscle cells. Depolarization is propagated to all
of the muscle cells of the tunica media via gap junctions.
Ve
Aneurysm, a sac-like dilation of the wall of an TM
artery (or less often of a vein), results from weak-
ness in the vessel wall and is usually age related.
The aneurysm occurs in regions of the vessel wall
where, frequently as a result of atherosclerosis,
Marfan syndrome, syphilis, and Ehlers-Danlos
Figure 11–4 Light micrograph of an arteriole and a venule con-
syndrome, elastic fibers are displaced by collagen taining blood cells (×540). The arteriole (A) is well defined with a thick
fibers. The abdominal aorta is the most common tunica media (TM). Nuclei of endothelial cells (N) bulge into the
vessel with this type of aneurysm. When discov- lumen (L). The venule (Ve) is poorly defined with a large poorly
ered, the ballooned area can be repaired but if it defined lumen containing red blood cells (RBC). The tunica media of
is not discovered and it ruptures, there is rapid the venule is not as robust as that in the arteriole.
massive blood loss that may result in death of the
individual.
oles but present in larger arterioles (Fig. 11-5). In small

arterioles, the tunica media is composed of a single
Arterioles smooth muscle cell layer that completely encircles the
endothelial cells (Fig. 11-6). In larger arterioles, the
Arteries with a diameter of less than 0.1 mm are tunica media consists of two to three layers of smooth
considered to be arterioles. muscle cells. Arterioles do not have an external elastic
lamina. The tunica adventitia of arterioles is scant and
Arterioles are the terminal arterial vessels that regulate is represented by fibroelastic connective tissue housing
blood flow into the capillary beds. In histological sec- a few fibroblasts.
tions, the width of the wall of an arteriole is approxi- Arteries that supply blood to capillary beds are called
mately equal to the diameter of its lumen (Fig. 11-4). metarterioles. They differ structurally from arterioles
The endothelium of the tunica intima is supported by in that the smooth muscle layer is not continuous;
a thin subendothelial connective tissue layer consisting rather, the individual muscle cells are spaced apart, and
of type III collagen and a few elastic fibers embedded each encircles the endothelium of a capillary arising
in ground substance. A thin, fenestrated internal from the metarteriole. It is believed that this arrange-
elastic lamina is absent in small and terminal arteri- ment permits these smooth muscle cells to function as
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a sphincter upon contraction, thus controlling blood

flow into the capillary bed.
Vessel walls that are weakened from embryolog-
ical defects or damaged from diseases such as
atherosclerosis, syphilis, and connective tissue
disorders (e.g., Marfan syndrome and Ehler-
Danlos syndrome) may balloon out at the
affected site, forming an aneurysm. Further
weakening may cause the aneurysm to rupture,
a grave condition that may lead to death.
Specialized Sensory Structures

in Arteries
Specialized sensory structures in the arteries include the
carotid sinus, the carotid body, and aortic bodies.
Figure 11–5 Electron micrograph of an arteriole. (From
Yamazaki K, Allen TD: Ultrastructural morphometric study of effer-
ent nerve terminals on murine bone marrow stromal cells, and the Three types of specialized sensory structures are located
recognition of a novel anatomical unit: The “neuro-reticular complex.” in the major arteries of the body: carotid sinuses,
Am J Anat 187:261-276, 1990.) carotid bodies, and aortic bodies. Nerve endings in
these structures monitor blood pressure and blood com-
position, providing essential inputs to the brain for con-
trolling heartbeat, respiration, and blood pressure.
Carotid Sinus
The carotid sinus is a baroreceptor located in the region
of the internal carotid artery just distal to the
bifurcation of the common carotid artery.
The carotid sinus is a baroreceptor; that is, it perceives

changes in blood pressure. This structure is a special-
ization within the wall of the internal carotid artery just
above the bifurcation of the common carotid artery. At
this site, the adventitia of this vessel is relatively thicker
and heavily endowed with sensory nerve endings from
the glossopharyngeal nerve (cranial nerve IX). The
tunica media at this site is relatively thinner, thus per-
mitting it to be distended during increases in blood
pressure; this distention stimulates the nerve endings.
The afferent impulses, received at the vasomotor center
in the brain, trigger adjustments in vasoconstriction,
Figure 11–6 Scanning electron micrograph of an arteriole illus-
trating its compact layer of smooth muscle and its attendant nerve resulting in maintenance of proper blood pressure.
fibers (×4200). (From Fujiwara T, Uehara Y: The cytoarchitecture of Additional small baroreceptors are located in the aorta
the wall and innervation pattern of the microvessels in the rat and in some of the larger vessels.
mammary gland: A scanning electron microscopic observation. Am J
Anat 170:39-54, 1984.) Carotid Body
The carotid body functions as a chemoreceptor,
monitoring changes in oxygen and carbon dioxide levels
as well as hydrogen ion concentration
Ch011-X2945.qxd 15/8/06 2:46 PM Page 258
Located at the bifurcation of the common carotid artery ized burst of blood that first enters into the elastic
is a small, oval structure known as the carotid body. The arteries, then moves into the muscular arteries and
carotid body possesses specialized chemoreceptor arterioles, and finally moves into capillaries, which
nerve endings responsible for monitoring changes in serve the tissues. The vasomotor center in the brain
oxygen and carbon dioxide levels as well as blood H+ responds to the continual monitoring of blood pressure
concentration. The carotid body, 3 to 5 mm in diame- by controlling vasomotor tone, the constant state of
ter, is composed of multiple clusters of pale-staining contraction of the vessel walls, which is modulated via
cells embedded in connective tissue. Two types of vasoconstriction and vasodilation. Vasoconstriction
parenchymal cells are clearly distinguishable in elec- is accomplished via vasomotor nerves of the sym-
tron micrographs: glomus (type I) cells and sheath pathetic nervous system, whereas vasodilation is
(type II) cells. a function of the parasympathetic system. During
Glomus cells have a large nucleus and the usual vasodilation, acetylcholine from the nerve terminals
array of organelles. They are distinguished by the pres- in the vessel walls initiates release of nitric oxide
ence of dense-cored vesicles, 60 to 200 nm in diameter, (NO) from the endothelium to diffuse into the smooth
that resemble vesicles located in the chromaffin cells muscle cells, which activates the cyclic guanosine
of the suprarenal medulla. Cell processes also contain monophosphate (cGMP) system, resulting in relax-
longitudinally oriented microtubules, dense-cored vesi- ation of the muscle cells, thus dilating the vessel
cles, and a few small electron-lucent vesicles. These lumen.
processes contact other glomus cells and capillary Smooth muscle cells of the arteries have receptors
endothelial cells. for substances besides the neurotransmitter norepi-
Sheath cells are more complex and have long nephrine. When the blood pressure is low, the kid-
processes that almost completely ensheath the neys secrete the enzyme renin, which cleaves
processes of the glomus cells. The nuclei of these cells angiotensinogen circulating in the blood, forming
are irregular and contain more heterochromatin com- angiotensin I. This mild vasoconstrictor is conver-
pared with the nuclei of glomus cells; moreover, sheath ted to angiotensin II by ACE, which is located on
cells contain no dense-cored vesicles. As nerve termi- the luminal plasmalemmae of capillary endothelia
nals enter clusters of glomus cells, they lose their (especially capillaries of the lungs). Angiotensin II is a
Schwann cells and become covered by the sheath cells potent vasoconstrictor that initiates smooth muscle
in much the same way as glial cells ensheath fibers in contraction, thereby reducing vessel lumen diameter,
the central nervous system. resulting in increased blood pressure. Severe hemor-
Carotid bodies contain catecholamines (as do the rhage induces pituitary secretion of antidiuretic
cells of the suprarenal medulla and paraganglia), but hormone (ADH), or vasopressin, another powerful
whether they produce hormones is unclear. The glos- vasoconstrictor.
sopharyngeal and vagus nerves supply the carotid body The structure of elastic arteries permits distention
with numerous afferent fibers. In some of the synapses, of their walls during systole (heart contraction), fol-
the glomus cells appear to function as presynaptic cell lowed by recoil of their walls during diastole (heart
bodies, but the specific relationships are as yet not relaxation), which assists in delivering a more constant
understood. blood pressure and flow of blood. Muscular arteries
branching from the elastic arteries distribute blood to
the body and are subject to constant changes in diam-
Aortic Bodies eter resulting from vasoconstriction and vasodilation.
Aortic bodies are located on the arch of the aorta To assist in accommodating for these events, the tunica
between the right subclavian and the right common adventitia blends loosely into the surrounding con-
carotid artery and between the left common carotid nective tissue, thus preventing restraint on the vessel
artery and the left subclavian artery. Their structure and during contractions and expansions for changes in
function are similar to those of carotid bodies. blood pressure.
Artery location also dictates the thickness of the
various tunics. For example, the thickness of the tunica
Regulation of Arterial media in the arteries of the leg is greater than that found
Blood Pressure in the arteries of the upper extremity. This is in response
to the continued pressure resulting from gravitational
Arterial blood pressure is regulated by the vasomotor forces. Moreover, the coronary arteries, serving the
center in the brain. heart, are high-pressure arteries and, as such, have a
thick tunica media. Conversely, arteries in the pul-
The heart, which serves as the cardiovascular pump, monary circulation are under low pressure; thus, the
rests between each stroke, thus developing a pressur- tunica media in these vessels is thinner.
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Normal and Pathological Vascular Changes The smooth muscle cell layer in the tunica media
The largest arteries continue to grow until about age of a healthy person undergoes renewal, but when the
25 years, although there is progressive thickening of endothelium is injured, platelets that accumulate at
their walls and an increase in the number of elastic the site release platelet-derived growth factor
laminae. In the muscular arteries, from middle age (PDGF), stimulating proliferation of smooth muscle
on, deposits of collagen and proteoglycans increase cells. As a consequence, these cells begin to be
in the walls, thus reducing their flexibility. The coro- packed with cholesterol-rich lipids, which stimulate
nary vessels are the first to display the effects of the muscle cells to manufacture additional collagen
aging, with the intima displaying the greatest age- and proteoglycans, resulting in a cycle whereby the
related changes. These natural changes are not tunica intima becomes thickened. This further
unlike the regressive changes observed in arte- damage to the endothelium leads to necrosis, which
riosclerosis (hardening of the arteries). attracts more platelets, and finally clotting, forming
a thrombus that may occlude the vessel at that site
Arteriosclerosis or get into the general circulation and occlude a more
Small arteries and arterioles, especially those of the dangerous vessel (e.g., a coronary vessel or a cerebral
kidneys, are prone to the most common type of arte- vessel).
riosclerosis, displaying a hyaline or concentric thick- The pathogenesis of cardiovascular heart diseases
ening which is often associated with hypertension is still unclear, although current research theories
and/or diabetes. point to the role of cholesterol, lipoproteins, and
certain mitogens. A correlation between blood cho-
Atherosclerosis lesterol levels and heart disease is established, but
The largest of the arteries—including the coronary recently learned is that C-reactive protein (CRP),
arteries, carotid arteries, and the major arteries of synthesized by the liver, can be used as a marker for
the brain among others—are susceptible to athero- inflammation. Furthermore, CRP appears to be a far
sclerosis, a disease that is the forerunner of heart more accurate indicator of the risk for cardiovascu-
attack and stroke. Atherosclerosis is distinguished by lar disease. Statins, which have been used exten-
infiltrations of soft, noncellular lipid material into sively for reducing cholesterol levels in the blood
the intima walls; these infiltrations can reduce the and thereby reducing the risk of heart disease, have
luminal diameter appreciably even by age 25. It is been shown to reduce CRP levels also. This fact is
not clear whether these conditions are physiological important because the response to inflammation is
or a manifestation of a disease process. The fibrous as critical in heart disease as are high levels of cho-
plaques that form in the intima of older persons, lesterol. Thus there is a commonality between inflam-
however, are pathological. mation and cardiovascular disease.
Capillaries layer of squamous endothelial cells rolled into a tube,

with the long axis of these cells lying in the same direc-
Arising from the terminal ends of the arterioles are tion as the blood flow. These endothelial cells are flat-
capillaries (Fig. 11-7), which form, by branching and tened, with the attenuated ends tapering to a thickness
anastomosing, a capillary bed (network) between the to 0.2 µm or less, although an elliptical nucleus bulges
arterioles and the venules. Electron micrographs have out into the lumen of the capillary. The cytoplasm con-
revealed three types of capillaries: (1) continuous (Fig. tains a Golgi complex, a few mitochondria, some rough
11-8), (2) fenestrated, and (3) sinusoidal (also see Fig. endoplasmic reticulum (RER), and free ribosomes (Fig.
11-12). The differences among them are discussed later. 11-9; also see Fig. 11-8). Intermediate filaments (9 to
11 nm in diameter), located around the perinuclear
General Structure of Capillaries zone, vary in filament composition. For example, some
cells contain filaments composed of desmin, others
Capillaries, composed of a single layer of endothelial contain filaments composed of vimentin, and some
cells, are the smallest blood vessels. endothelial cells contain both kinds of filaments. These
filaments provide structural support to the endothelial
Capillaries are the smallest of the vascular channels, on cells, but the significance of their variation is unclear.
the average approximately 50 µm in length with a diam- The large number of pinocytotic vesicles associated
eter of 8 to 10 µm. Capillaries are formed by a single with the entire plasmalemma is an identifying charac-
Ch011-X2945.qxd 15/8/06 2:46 PM Page 260
Ca
RBC
Figure 11–7 Light micrograph of a capillary in the monkey cerebellum (×270) A capillary (Ca) is present in the field of view, and red blood
cells (RBC) are evident in its lumen (L). Note the nucleus (arrow) of an endothelial cell bulging into the lumen.
teristic of capillaries. These vesicles may be in singular

array, two single vesicles may be fused together, or
several vesicles may be fused, forming a transient
channel. Where the endothelial cells are the thinnest, a
single vesicle may span from the adluminal plas-
malemma across the cytoplasm to the abluminal plas-
malemma of the endothelial cell.
The endothelial cells of capillaries are rolled into a
tube, giving the lumen a diameter that ranges from 8 to
10 mm but remains constant throughout the entire
length of a capillary. This diameter is sufficient to
permit individual cells of the blood to pass without
being hindered. Although not all of the capillary beds
are open at any one time, increased demand initiates
the opening of more beds, thus increasing blood flow to
meet physiological needs. The external surfaces of the
endothelial cells are surrounded by a basal lamina
secreted by the endothelial cells (see Fig. 11-9). When
viewed in cross section, the endothelial walls making up
small capillaries are formed by one endothelial cell,
whereas portions of two or three endothelial cells con-
tribute to forming the endothelial wall of larger capil-
Figure 11–8 Electron micrograph of a continuous capillary in laries. At these cellular junctions, the endothelial cells
the rat submandibular gland (×13,000). The pericyte shares the
endothelial cell’s basal lamina. (From Sato A, Miyoshi S: Morphomet-
tend to overlap, forming a marginal fold that projects
ric study of the microvasculature of the main excretory duct subep- into the lumen. Endothelial cells are joined together by
ithelia of the rat parotid, submandibular, and sublingual salivary fasciae occludentes, or tight junctions.
glands. Anat Rec 226:288-294, 1990.) Pericytes are located along the outside of the capil-
laries and small venules, and appear to be surrounding
them (Figs. 11-10 and 11-11). These cells have long
Ch011-X2945.qxd 15/8/06 2:46 PM Page 261

graph of a testicular capillary. CL,
capillary lumen; MC, myoid cell; E,
nucleus of endothelial cell. Arrows
represent the basal lamina. (From
Meyerhofer A, Hikim APS, Bartke
A, Russell LD: Changes in the tes-
ticular microvasculature during
photoperiod-related seasonal transi-
tion from reproductive quiescence
to reproductive activity in the adult
golden hamster. Anat Rec 224:495-
507, 1989.)
Figure 11–10 Scanning elec-

tron micrograph of a capillary dis-
playing pericytes on its surface
(×5000). (From Fujiwara T, Uehara,
Y: The cytoarchitecture of the wall
and innervation pattern of the micro-
vessels in the rat mammary gland: A
scanning electron microscopic obser-
vation. Am J Anat 170:39-54, 1984.)
primary processes that are located along the long axis of ies. Further, as discussed in Chapter 6, after injury peri-
the capillary and from which secondary processes arise cytes may undergo differentiation to become smooth
to wrap around the capillary, forming a few gap junc- muscle cells and endothelial cells in the walls of arteri-
tions with the endothelial cells. Pericytes share the oles and venules.
basal lamina of the endothelial cells. Pericytes possess
a small Golgi complex, mitochondria, RER, micro- Classification of Capillaries
tubules, and filaments extending into the processes.
These cells also contain tropomyosin, isomyosin, and Capillaries are of three types: (1) continuous, (2) fenes-
protein kinase, which are all related to the contractile trated, and (3) sinusoidal (Fig. 11-12). They differ in
process that regulates blood flow through the capillar- their location and structure.
Ch011-X2945.qxd 15/8/06 2:46 PM Page 262
A Continuous capillary
B Fenestrated capillary
Figure 11–11 Electron micrograph of a fenestrated capillary
and its pericyte in cross section. Note that the capillary endothelial
cells and the pericyte share the same basal lamina. (From Sato A,
Miyoshi S: Morphometric study of the microvasculature of the main
excretory duct subepithelia of the rat parotid, submandibular, and
sublingual salivary glands. Anat Rec 226:288-294, 1990.)
Continuous Capillaries
Continuous capillaries have no pores or fenestrae in
their walls.
Continuous capillaries are present in muscle, nervous,

and connective tissues; in the brain tissue they are clas-
sified as modified continuous capillaries. The inter- C Sinusoidal (discontinuous) capillary
cellular junctions between their endothelial cells are a
type of fasciae occludentes, which prevent passage Figure 11–12 The three types of capillaries: continuous, fenes-
of many molecules. Substances such as amino acids, trated, and sinosoidal (discontinuous).
glucose, nucleosides, and purines move across the
capillary wall via carrier-mediated transport. The cells
exhibit a polarity with the transport systems, such that
Na+,K+-ATPase is located in the adluminal cell mem- a pore diaphragm. These capillaries are found in the
brane only. There is evidence that barrier regulation pancreas, intestines, and endocrine glands.
resides within the endothelial cells but is influenced by The pores in fenestrated capillaries are bridged by
products formed by the astrocytes associated with the an ultrathin diaphragm. When viewed after processing
capillaries. with platinum-carbon shadowing, the diaphragm dis-
plays eight fibrils radiating out from a central area and
Fenestrated Capillaries forming wedge-like channels, each with an opening of
about 5.5 nm. These pore-diaphragm complexes are
Fenestrated capillaries possess pores (fenestrae) in their regularly spaced about 50 nm apart but are located in
walls that are covered by pore diaphragms. clusters; thus, most of the endothelial wall of the fen-
estrated capillary is without fenestrae (see Fig. 11-12B).
Fenestrated capillaries have pores (fenestrae) in their An exception is the renal glomerulus, composed of
walls that are 60 to 80 nm in diameter and covered by fenestrated capillaries that lack diaphragms.
Ch011-X2945.qxd 15/8/06 2:46 PM Page 263
Sinusoidal Capillaries those nerves in the AVAs are controlled by the ther-
moregulatory system in the brain.
Sinusoidal capillaries may possess discontinuous
endothelial cells and basal lamina and contain many Glomera
large fenestrae without diaphragms, enhancing
exchange between blood and tissue. Nail beds and the tips of the fingers and toes are vas-
cularized by glomera (singular, glomus). The glomus is
The vascular channels in certain organs of the body, a small organ that receives an arteriole devoid of an
including the bone marrow, liver, spleen, lymphoid elastic lamina and acquires a richly innervated smooth
organs, and certain of the endocrine glands, are called muscle cell layer that surrounds the vessel lumen, thus
sinusoids, irregular blood pools or channels that directly controlling blood flow to the region before
conform to the shape of the structure in which they are emptying into a venous plexus. The entire glomera
located. The peculiar conformation of a sinusoid is complex is not fully understood.
determined by its being shaped between the parenchy-
mal components of the organ during organogenesis. Central Channel
Because of their location, sinusoidal capillaries have
an enlarged diameter of 30 to 40 µm (Fig. 11-12C). Metarterioles form the proximal portion of a central
They also contain many large fenestrae that lack channel, and thoroughfare channels form the distal
diaphragms; the endothelial wall may be discontinuous, portion of a central channel.
as is the basal lamina, permitting enhanced exchange
between the blood and the tissues. Sinusoids are lined Blood flow from the arterial system is controlled either
by endothelium. In certain organs, the endothelium is by metarterioles (with precapillary sphincters) or by
thin and continuous (as in some lymphoid organs); in terminal arterioles. Thus, metarterioles form the
others it may have continuous areas mixed with fenes- proximal portion of a central channel, whereas the
trated areas (as in endocrine glands). Although the channel’s distal portion is formed by the thoroughfare
endothelial cells lack pinocytotic vesicles, macrophages channel, a structure so-named because it is without
may be located either in or along the outside of the precapillary sphincters. The thoroughfare channels
endothelial wall. drain the capillary bed and empty the blood into small
venules of the venous system (Fig. 11-13). When the
Regulation of Blood Flow into a precapillary sphincters are contracted, blood flows
through the central channels, bypassing the capillary
Capillary Bed bed and entering directly into the venules.
Arteriovenous Anastomoses
Histophysiology of Capillaries
Arteriovenous anastomoses are direct vascular
connections between arterioles and venules that bypass Capillaries are regions where blood flow is very slow,
the capillary bed. permitting exchange of material between the circulating
blood and the extravascular connective tissue.
Terminals of most arteries end in capillary beds, which
deliver their blood to venules for the return back to the The endothelial cells of capillaries may contain two dis-
venous side of the cardiovascular system. In many parts tinct pore systems: small pores (~9 to 11 nm in diam-
of the body, however, the artery simply joins with a eter) and large pores (~50 to 70 nm in diameter). The
venous channel, forming an arteriovenous anastomosis smaller pores are believed to be discontinuities between
(AVA). The structures of the arterial and venous ends endothelial cell junctions. The large pores are repre-
of the AVA are similar to those of an artery and sented by fenestrae and transport vesicles. Oxygen,
vein, respectively, whereas the intermediate segment carbon dioxide, and glucose may diffuse or be trans-
has a thickened tunica media and its subendothelial ported across the plasmalemma and then diffuse
layer is composed of plump polygonal cells that are through the cytoplasm and finally through the ablumi-
modified, longitudinally arranged smooth muscle cells. nal plasmalemma into the extravascular space. Water
When the AVAs are closed, the blood passes through and hydrophilic molecules (~1.5 nm) simply diffuse
the capillary bed; when shunts are open, a large amount through these intercellular junctions.
of blood bypasses the capillary bed and flows through Water-soluble molecules greater than 11 nm in diam-
the AVA. These shunts are useful in thermoregulation eter are transported from the adluminal plasmalemma
and are abundant in skin. The intermediate segments to the abluminal plasmalemma by the numerous
of the AVAs are richly innervated with adrenergic and pinocytotic vesicles adjacent to the cell membrane. This
cholinergic nerves. Whereas most peripheral nerves are process is called transcytosis (Fig. 11-14) because the
controlled somewhat by local environmental stimuli, material traverses the entire cell instead of remaining
Ch011-X2945.qxd 15/8/06 2:46 PM Page 264
Muscle fiber (cell) A Lumen
Arteriole
Metarteriole Precapillary
sphincter
Cytoplasm of
endothelial cell
True
capillaries
Connective tissue
B Lumen
Thoroughfare channel
Venule
Figure 11–13 The control of blood flow through a capillary bed.

The central channel, composed of the metarteriole on the arterial side Connective tissue
and the thoroughfare channel on the venous side, can bypass the cap-
illary bed by closure of the precapillary sphincters.
C
Lumen
within the cell. In continuous capillaries, substances are

taken up by open vesicles located on the adluminal plas-
malemma. The vesicles are then transported across
the cytoplasm to the abluminal plasmalemma, where Connective tissue
the vesicles fuse with it to deliver their contents into the
extravascular space. This is an efficient process because Figure 11–14 The various methods of transport across capillary
the number of vesicles in these endothelial cells may endothelia. A, Pinocytotic vesicles, which form on the luminal surface,
exceed 1000/mm2. It appears that these vesicles are traverse the endothelial cell, and their contents are released on the
members of a stable population of vesicles arising from opposite surface into the connective tissue spaces. B, Trans Golgi
network–derived vesicles possessing clathrin coats and receptor mol-
the Golgi complex via a fusion-fission mechanism of ecules fuse with the luminal surface of the endothelial cells and pick
renewal. up specific ligands from the capillary lumen. They then detach and
Leukocytes leave the bloodstream to enter the traverse the endothelial cell, fuse with the membrane of the opposite
extravascular space by passing through the junctions surface, and release their contents into the connective tissue spaces.
C, In regions where the endothelial cells are highly attenuated, the
via a process called diapedesis. Histamine and pinocytotic (or trans Golgi network–derived) vesicles may fuse with
bradykinin, whose levels are increased during the each other to form transient fenestrations through the entire thick-
inflammatory process, increase capillary permeability, ness of the endothelial cell, permitting material to travel between the
thus causing excessive fluid passage into the extravas- lumen and the connective tissue spaces. (A-C, Adapted from
cular spaces. This excess extravascular fluid causes the Simionescu N, Simionescu M: In Ussing H, Bindslev, N, Sten-
Knudsen O [eds]: Water Transport Across Epithelia. Copenhagen,
tissues to swell, a condition known as edema. Munksgaard, 1981.)
The endothelial cells of capillaries also secrete a
number of substances, including fibronectin, laminin,
and types II, IV, and V collagen, all of which are
released into and become part of the extracellular
matrix. Additionally, endothelial cells produce several
other important substances related to clotting, vascu-
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lar smooth muscle tone, lymphocyte circulation, Because veins not only outnumber arteries but also
and neutrophil movement. usually have larger luminal diameters, almost 70% of
A vasoconstrictor substance, endothelin I, secreted the total blood volume is in these vessels. In histologi-
by the capillary endothelial cells, attaches to vascular cal sections, veins parallel arteries; however, their walls
smooth muscle cells. Endothelin I acts as a hyperten- are usually collapsed because they are thinner and less
sive agent, keeping the smooth muscle cells contracted elastic than arterial walls because the venous return is
for long periods and thus elevating blood pressure. a low-pressure system.
Although endothelin I is much more effective than
angiotensin II, it is unclear how widespread its effects Classification of Veins
really are.
Adhesion molecules (L-selectin and β2-integrins) Veins are classified into three groups on the basis of
expressed on the plasma membranes of migrating their diameter and wall thickness: small, medium, and
leukocytes bind to receptors on the plasma membranes large.
of capillary endothelial cells at sites of inflammation.
The bound leukocytes then enter the connective tissue The structure of veins is not necessarily uniform, even
spaces, where they perform their functions in the for veins of the same size or for the same vein along its
inflammatory process. Prostacyclin, a potent vasodila- entire length. Veins are described as having the same
tor and inhibitor of platelet aggregation, is also relea- three layers ( tunicae intima, media, and adventitia) as
sed by capillaries. arteries (Table 11-2). Although the muscular and elastic
In addition to these functions, capillaries also serve layers are not as well developed, the connective tissue
a maintenance role in converting such substances as components in veins are more pronounced than in
serotonin, norepinephrine, bradykinin, prostaglandins, arteries. In certain areas of the body where the struc-
and thrombin into inactive compounds. tures housing the veins protect them from pressure
Enzymes on the luminal surface of endothelial cells (retina, meninges, placenta, penis), the veins have little
of the capillaries in adipose tissue degrade lipoproteins or no smooth muscle in their walls; moreover, the
into triglycerides and fatty acids for storage within boundaries between the tunica intima and the tunica
adipocytes. media of most veins are not clearly distinguishable.
Veins Venules and Small Veins

Veins are vessels that return blood to the heart. Venules are similar to but larger than capillaries; larger
venules possess smooth muscle cells instead of pericytes.
At the discharging ends of capillaries are small venules,
the beginning of the venous return, which conducts As the blood pools from the capillary bed, it is dis-
blood away from the organs and tissues and returns it charged into postcapillary venules, which are 15 to
to the heart. These venules empty their contents into 20 µm in diameter. Their walls are similar to those of
larger veins, and the process continues as the vessels capillaries, with a thin endothelium surrounded by
become larger and larger while going back to the heart. reticular fibers and pericytes (see Fig. 11-4). The peri-
TABLE 11–2 Characteristics of Veins
Type Tunica Intima Tunica Media Tunica Adventitia
Large veins Endothelium; basal lamina, Connective tissue; Smooth muscle cells oriented in
valves in some; subendothelial smooth muscle cells longitudinal bundles; cardiac muscle
connective tissue cells near their entry into the heart;
collagen layers with fibroblasts
Medium and Endothelium, basal lamina; Reticular and elastic Collagen layers with fibroblasts
small veins valves in some; subendothelial fibers, some smooth
connective tissue muscle cells
Venules Endothelium, basal lamina Sparse connective tissue Some collagen and a few fibroblasts
(pericytes, postcapillary and a few smooth
venules) muscle cells
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Figure 11–15 Large venule in guinea pig skin har-

vested 60 minutes after intradermal injection of 10−5 M
of N-formyl-methionyl-leucyl-phenylalanine. Many
neutrophils and a single eosinophil (eos) are captured
at various stages of attachment to and extravasation
across vascular endothelium and underlying pericytes
(p). Two neutrophils (joined arrows), one in another
lumen and another partway across the endothelium, are
tethered together. Another neutrophil (long arrow) has
projected a cytoplasmic process into an underlying
endothelial cell. Other neutrophils (arrowheads) and
the eosinophil have crossed the endothelial cell barrier
but remain superficial to pericytes, forming dome-like
structures that bulge into the vascular lumen (L). Still
another neutrophil (open arrow) that has already
crossed the endothelium has extended a process into
the basal lamina and indents an underlying pericyte.
Other neutrophils (n) have crossed both the endothe-
lial cell and pericyte barriers and have entered the sur-
n rounding connective tissues. Bar, 10 mm. (Modified
n from Feng D, Nagy JA, Pyne K, et al: Neutrophils emi-
n grate from venules by a transendothelial cell pathway in
response to FMLP. J Exp Med 187:903-915, 1998.)
cytes of postcapillary venules form an intricate, loose tunica intima includes the endothelium and its basal
network surrounding the endothelium. Pericytes are lamina and reticular fibers. Sometimes an elastic
replaced by smooth muscle cells in larger venules network surrounds the endothelium, but these elastic
(>1 mm in diameter), first as scattered smooth muscle fibers do not form laminae characteristic of an internal
cells; then, as venule diameter increases, the smooth elastic lamina. The smooth muscle cells of the tunica
muscle cells become more closely spaced, forming a media are in a loosely organized layer interwoven with
continuous layer in the largest venules and small veins. collagen fibers and fibroblasts. The tunica adventitia,
Materials are exchanged between the connective tissue the thickest of the tunicas, is composed of longitudinally
spaces and vessel lumina not only in the capillaries but arranged collagen bundles and elastic fibers, as well as
also in the postcapillary venules, whose walls are even a few scattered smooth muscle cells.
more permeable. Indeed, this is the preferred location
for emigration of the leukocytes from the bloodstream Large Veins
into the tissue spaces (Fig. 11-15). These vessels
respond to pharmacological agents such as histamine Large veins return venous blood directly to the heart
and serotonin. from the extremities, head, liver, and body wall.
The endothelial cells of venules located in certain
lymphoid organs are cuboidal rather than squamous and Large veins include the venae cavae and the pulmonary,
are called high-endothelial venules. These function portal, renal, internal jugular, iliac, and azygos veins.
in lymphocyte recognition and segregation by type- The tunica intima of the large veins is similar to that of
specific receptors on their luminal surface, ensuring the medium veins, except that large veins have a thick
that specific lymphocytes migrate into the proper subendothelial connective tissue layer, containing
regions of the lymphoid parenchyma. fibroblasts and a network of elastic fibers. Although only
a few major vessels (such as the pulmonary veins) have
Medium Veins a well-developed smooth muscle layer, most large
veins are without a tunica media; in its place is a well-
Medium veins are less than 1 cm in diameter. developed tunica adventitia. An exception are the
superficial veins of the legs, which have a well-defined
Medium veins are those draining most of the body, muscular wall, perhaps to resist the distention caused
including most of the regions of the extremities. Their by gravity.
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The tunica adventitia of large veins contains many

elastic fibers, abundant collagen fibers, and vasa
Superior vena cava
vasorum, whereas the inferior vena cava has longitudi- Aorta
nally arranged smooth muscle cells in its adventitia. As
SA node
the pulmonary veins and the venae cavae approach the
heart, their adventitia contains some cardiac muscle Right atrium AV node
cells. Left atrium
Left ventricle
Valves of Veins Right ventricle
Left bundle
A venous valve is composed of two leaflets, each branch
Bundle of His
composed of a thin fold of the intima jutting out from
the wall into the lumen. Right bundle
branch
Many medium veins have valves that function to Purkinje fibers
prevent the backflow of blood. These valves are espe-
cially abundant in the veins of the legs, where they act
against the force of gravity. A venous valve is composed Figure 11–16 Diagram of the heart showing locations of the
sinoatrial (SA) and atrioventricular (AV) nodes, Purkinje fibers, and
of two leaflets, each having a thin fold of the intima bundle of His.
jutting out from the wall into the lumen. The thin
leaflets are structurally reinforced by collagen and
elastic fibers that are continuous with those of the wall. pulmonary trunk, a large vessel that bifurcates into
As blood flows to the heart, the valve cusps are deflected the right and left pulmonary arteries to deliver deoxy-
in the direction of the blood flow toward the heart. genated blood to the lungs for gaseous exchange. Oxy-
Backward flow of blood forces the cusps to approximate genated blood from the lungs returns to the heart via
each other, thus blocking backflow. the pulmonary veins, which empty into the left
atrium. From here, the blood passes through the left
atrioventricular valve (bicuspid or mitral valve) to
CLINICAL CORRELATIONS enter the left ventricle. Again, ventricular contraction
expels the blood from the left ventricle into the aorta,
Varicose veins are abnormally enlarged tortu- from which many branches emanate to deliver blood to
ous veins, usually the superficial veins in the legs the tissues of the body.
of older persons. This condition results from loss The atrioventricular valves prevent regurgitation of
of muscle tone, degeneration of vessel walls, and the ventricular blood back into the atria, whereas the
valvular incompetence. Varicose veins may also semilunar valves, located in the pulmonary trunk and
occur in the lower end of the esophagus the aorta near their origins, prevent backflow from these
(esophageal varices) or at the terminus of the vessels into the heart.
anal canal (hemorrhoids).
Layers of the Heart Wall
The three layers that constitute the heart wall are
the endocardium, myocardium, and epicardium,
Heart homologous to the tunica intima, tunica media, and the
tunica adventitia, respectively, of the blood vessels.
The heart is a four-chambered pump of the
cardiovascular system. Endocardium
The muscular wall (myocardium) of the heart is com- The endocardium, a simple squamous epithelium and
posed of cardiac muscle (see Chapter 8). The heart con- underlying subendothelial connective tissue, lines the
sists of four chambers: two atria, which receive blood, lumen of the heart.
and two ventricles, which discharge blood from the
heart (Fig. 11-16). The superior and inferior venae The endocardium is continuous with the tunica intima
cavae return systemic venous blood to the right of the blood vessels entering and leaving the heart. It is
atrium of the heart. From here, the blood passes composed of an endothelium, consisting of a simple
through the right atrioventricular valve (tricuspid squamous epithelium and an underlying layer of fibro-
valve) into the right ventricle. As the ventricles con- elastic connective tissue with scattered fibroblasts.
tract, blood from the right ventricle is pumped out the Lying deeper is a layer of dense connective tissue,
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heavily endowed with elastic fibers interspersed with

smooth muscle cells. Deep to the endocardium is a
subendocardial layer of loose connective tissue that
contains small blood vessels, nerves, and Purkinje fibers
from the conduction system of the heart. The suben-
docardial layer forms the boundary of the endocardium
as it attaches to the endomysium of the cardiac muscle. CM
Children who have had rheumatic fever may
later develop rheumatic heart valve disease as
a result of scarring of the valves stemming from
the rheumatic fever episode. This condition
develops because the valves cannot properly
close (incompetence) or open (stenosis) because PF
of reduced elasticity as a result of rheumatic
fever. The bicuspid (mitral) valve, followed by
the aortic valve, is the valve most commonly
affected.
N
Myocardium
The thick middle layer of the heart (the myocardium) is
composed of cardiac muscle cells. CT
The myocardium, the middle and thickest of the three

layers of the heart, contains cardiac muscle cells arranged
in complex spirals around the orifices of the chambers.
Certain cardiac muscle cells attach the myocardium to
the fibrous cardiac skeleton, others are specialized for
endocrine secretions, and still others are specialized for
impulse generation or impulse conduction. Figure 11–17 Light micrograph of Purkinje fibers. Cardiac
muscle (CM) appears very dark, whereas Purkinje fibers (PF) with
The heart rate (~70 beats per minute) is controlled their solitary nuclei (N) appear light with this stain. Slender connec-
by the sinoatrial node (pacemaker) located at the tive tissue elements (CT) surround the Purkinje fibers (×270).
junction of the superior vena cava and the right atrium
(see Fig. 11-16). These specialized nodal cardiac muscle
cells can spontaneously depolarize 70 times per minute,
creating an impulse that spreads over the atrial chamber be confused with the Purkinje cells in the cerebellar
walls by internodal pathways to the atrioventricular cortex). It should be noted that although the autonomic
node, located in the septal wall just above the tricuspid nervous system does not initiate the heartbeat, it does
valve. Modified cardiac muscle cells of the atrioven- modulate the rate and stroke volume of the heartbeat.
tricular node, regulated by impulses arriving from the Stimulation of sympathetic nerves accelerates the heart
sinoatrial node, transmit signals to the myocardium of rate, whereas stimulation of the parasympathetic nerves
the atria via the atrioventricular bundle (bundle of serving the heart slows the heart rate.
His). Fibers from the atrioventricular bundle pass down Specialized cardiac muscle cells, located primarily in
the interventricular septum to conduct the impulse to the atrial wall and in the interventricular septum,
the cardiac muscle, thus producing a rhythmic contrac- produce an array of small secreted peptides (Fig. 11-
tion. The atrioventricular bundle travels in the suben- 18). These include atriopeptin, atrial natriuretic
docardial connective tissue as large, modified cardiac polypeptide, cardiodilatin, and cardionatrin, which
muscle cells, forming Purkinje fibers (Fig. 11-17), are released into the surrounding capillaries. These hor-
which transmit impulses to the cardiac muscle cells mones aid fluid maintenance and electrolyte balance
located at the apex of the heart (Purkinje fibers are not and decrease blood pressure.
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graph of a cardiac muscle cell containing
clusters of vesicles with atrial natriuretic
peptide. (From Mifune H, Suzuki S,
Honda J, et al: Atrial natriuretic peptide
[ANP]: A study of ANP and its mRNA
in cardiocytes, and of plasma ANP levels
in non-obese diabetic mice. Cell Tissue
Res 267:267-272, 1992.)
Epicardium 䡲 The annuli fibrosi, formed around the base of the

aorta, pulmonary artery, and the atrioventricular
The epicardium represents the homologue of the tunica orifices
adventitia in blood vessels. 䡲 The trigonum fibrosum, formed primarily in the
vicinity of the cuspal area of the aortic valve
Epicardium, the outermost layer of the heart wall, is 䡲 The septum membranaceum, constituting the
also called the visceral layer of the pericardium upper portion of the interventricular septum
(composed of a simple squamous epithelium known as
a mesothelium). The subepicardial layer of loose con- In addition to providing a structural framework for
nective tissue contains the coronary vessels, nerves, and the heart and attachment sites for the cardiac muscle,
ganglia. It also is the region where fat is stored on the the cardiac skeleton provides a discontinuity between
surface of the heart. At the roots of the vessels entering the myocardia of the atria and ventricles, thus ensuring
and leaving the heart, the visceral pericardium becomes a rhythmic and cyclic beating of the heart, controlled by
continuous with the serous layer of the parietal peri- the conduction mechanism of the atrioventricular
cardium. These two layers of the pericardium enclose bundles.
the pericardial cavity, a space containing a small amount
of serous fluid for lubricating the serous layer of the
pericardium and the visceral pericardium.
CLINICAL CORRELATIONS Ischemic (coronary) heart disease, especially
prevalent in older persons, is related to athero-
Infection in the pericardial cavity, called peri- sclerosis of the coronary vessels serving the
carditis, severely restricts the heart from myocardium. As atherosclerotic plaques reduce
beating properly because the space is obliterated the lumina of the coronary vessels, the patient
by adhesions between the epicardium and the may experience referred pain and pressure,
serous layer of the pericardium. known as angina pectoris, as a result of lack
of oxygen. Continued narrowing results in
ischemia of the heart wall, which may be fatal if
untreated. Angioplasty is the current mode of the
Cardiac Skeleton initial invasive treatment for partially occluded
The cardiac skeleton, composed of dense connective arteries.
tissue, includes three main components:
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phatic ducts is reached. From either of these ducts,

LYMPHATIC VASCULAR SYSTEM the lymph is emptied into the venous portion of the car-
diovascular system at the junctions of the internal
The lymphatic vascular system consists of vessels that jugular and the subclavian veins.
collect the excess interstitial fluid and return it to the Lymph nodes are interposed along the paths of
cardiovascular system. lymphatic vessels, and lymph must pass through them
to be filtered. Afferent lymphatic vessels deliver
The lymphatic vascular system is composed of a series lymph into the lymph nodes, where lymph is distributed
of vessels that remove excess extracellular fluid (lymph) into labyrinthine channels lined by an endothelium and
from the interstitial tissue spaces and return it to the abundant macrophages. Here the lymph is filtered and
cardiovascular system. Lymphatic vessels are present cleared of particulate matter. Lymphocytes are added to
throughout the body, except in the central nervous the lymph as it leaves by efferent lymphatic vessels,
system and a few other areas, including the orbit, inter- eventually reaching a lymphatic duct. Lymph nodes are
nal ear, epidermis, cartilage, and bone. Unlike the car- discussed in Chapter 12.
diovascular system, which contains a pump (the heart)
and circulates blood in a closed system, the lymphatic Lymphatic Capillaries and Vessels
vascular system is an open system in that there is no
pump and no circulation of fluid. Lymphatic capillaries are composed of a single layer of
The lymphatic vascular system begins in the tissues attenuated endothelial cells with an incomplete basal
of the body as blind-ended lymphatic capillaries (Fig. lamina.
11-19), which simply act as drain fields for excess inter-
stitial fluid. The lymphatic capillaries empty their The blind-ended, thin-walled lymphatic capillaries are
contents into lymphatic vessels, which empty into composed of a single layer of attenuated endothelial
successively larger vessels until one of the two lym- cells with an incomplete basal lamina (Fig. 11-20). The
endothelial cells overlap each other in places but have
intercellular clefts that permit easy access to the lumen
of the vessel. These cells do not have fenestrae and do
Lymphatic
anchoring not make tight junctions with each other. Bundles of
filaments lymphatic anchoring filaments (5 to 10 nm in diam-
eter) terminate on the abluminal plasma membrane. It
is thought that these filaments may play a role in main-
taining the luminal patency of these flimsy vessels.
Small and medium lymphatic vessels are characterized
by closely spaced valves. Large lymphatic vessels resem-
Basal
lamina
Figure 11–19 Diagram of ultrastructure of a lymphatic capil- Figure 11–20 Light micrograph of a lymph vessel in the villus
lary. (From Lentz TL: Cell Fine Structure: An Atlas of Drawings of core of the small intestine is known as a lacteal (L) (×270). Observe
Whole-Cell Structure. Philadelphia, WB Saunders, 1971.) endothelium lining the lacteal (arrows).
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ble small veins structurally, except that their lumina are The tunica intima of lymphatic ducts is composed of
larger and their walls thinner. Large lymphatic vessels an endothelium and several layers of elastic and colla-
have a thin layer of elastic fibers beneath their endothe- gen fibers. At the interface with the tunica media, there
lium and a thin layer of smooth muscle cells. This smooth is a layer of condensed elastic fibers that resembles an
muscle layer is then overlaid with elastic and collagen internal elastic lamina. Both longitudinal and circular
fibers that blend with the surrounding connective tissue, layers of smooth muscle are present in the media. The
much like a tunica adventitia. Although some histologists tunica adventitia contains longitudinally oriented
describe tunics similar to those in blood vessels, most do smooth muscle cells and collagen fibers that blend into
not concur, because there are no clear boundaries the surrounding connective tissue. Piercing the walls of
between the layers and because the walls are so varied. the thoracic duct are small vessels homologous to the
vasa vasorum of the arteries.
Lymphatic Ducts
Lymphatic ducts are similar to large veins; they empty
their contents into the great veins of the neck. CLINICAL CORRELATIONS
The lymphatic ducts, which are similar in structure to Malignant tumor cells (especially carcinomas)
large veins, are the final two collecting vessels of the are spread throughout the body by lymphatic
lymphatic vascular system. The short right lymphatic vessels. When the malignant cells reach a lymph
duct empties its contents into the venous system at the node, they are slowed and multiply there, even-
junction of the right internal jugular and subclavian tually leaving to metastasize to a secondary site.
veins. The larger, the thoracic duct, begins in the Therefore, in surgical removal of a cancerous
abdomen as the cisterna chyli and ascends through the growth, examination of the lymph nodes and
thorax and neck to empty its contents at the junction of the removal of both enlarged lymph nodes in the
the left internal jugular and subclavian veins. The right pathway and associated lymphatic vessels are
lymphatic duct collects lymph from the upper right essential in preventing secondary growth of the
quadrant of the body, whereas the thoracic duct collects tumor.
lymph from the remainder of the body.
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12 䡲䡲䡲
Lymphoid
(Immune) System
The lymphoid system is responsible for the immuno- cific invaders. Whereas a macrophage can phagocytose
logical defense of the body. Some of its component most bacteria, the adaptive immune system not only
organs—lymph nodes, thymus, and spleen—are sur- reacts against one specific antigenic component of a
rounded by connective tissue capsules, whereas its pathogen, but also its ability to react against that par-
other components, members of the diffuse lymphoid ticular component improves with subsequent con-
system, are not encapsulated. The cells of the lymphoid frontations with it.
system protect the body against foreign macromole- Although the two systems differ in their mode of
cules, viruses, bacteria, and other invasive microorgan- responses, they are intimately related to one another,
isms, and they kill virally transformed cells. and each affects the other’s activities.
OVERVIEW OF THE The Innate Immune System

IMMUNE SYSTEM The innate immune system responds rapidly, has no
immunological memory, and depends on Toll-like
The immune system has two components: the innate receptors for initiating inflammatory and immune
immune system and the adaptive immune system. responses.
The immune system provides the second and the third Although the innate immune system is much older
lines of defense against invading pathogens. The first than the adaptive immune system, it responds rapidly,
line of defense is the epithelial barrier, namely skin and usually within a few hours, to an antigenic invasion; it
mucosa, which forms a complete lining and covering responds in a nonspecific manner; and has no immuno-
of the body surfaces. Once this physical barrier is logical memory. The critical components of the innate
breached by a cut, tear, or abrasion, or even if foreign immune system are complement, antimicrobial pep-
substances are able to penetrate, but have not yet pen- tides, cytokines, macrophages, neutrophils, NK cells,
etrated, the intact barrier, the second and the third lines and Toll-like receptors (TLRs). (See Table 12-1 for
of defense may become activated; these are the innate acronyms and abbreviations used in this chapter).
and the adaptive immune systems. Complement is a series of blood-borne proteins
The innate immune system (natural immune that attack microbes that found their way into the
system) is nonspecific and is composed of (1) a system of bloodstream. As they precipitate on the surface of
blood-borne macromolecules known as complement; these invading pathogens, they form a membrane attack
(2) groups of cells known as macrophages and neu- complex (MAC) that damage the microbe’s cell mem-
trophils, which phagocytose invaders; and (3) another brane. Phagocytic cells, such as neutrophils and
group of cells, natural killer (NK) cells, which kill macrophages, of the host have receptors for a specific
tumor cells, virally infected cells, bacteria, and parasites. moeity of complement (i.e., C3b) and the presence of
The adaptive immune system (acquired immune C3b on the microbial surface facilitates phagocytosis of
system) is responsible for eliminating threats from spe- microbes by these host defense cells.
273
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274 䡲䡲䡲 Chapter 12 䡲 Lymphoid (Immune) System
TABLE 12–1 Acronyms and Abbreviations Used in this Chapter
Acronym/Abbreviation Definition
ADDC Antibody-dependent cellular cytotoxicity

AIDS Acquired immunodeficiency syndrome
APC Antigen-presenting cell
BALT Bronchus-associated lymphoid tissue
B lymphocyte Bursa-derived lymphocyte (Bone marrow–derived lymphocyte)
C3b Complement 3b
CD Cluster of differentiation molecule (usually followed by an Arabic numeral)
CLIP Class II–associated invariant protein
CSF Colony-stimulating factor
CTL Cytotoxic T lymphocyte (T killer cell)
Fab Antigen-binding fragment of an antibody
Fas protein CD95 (induces apoptosis)
Fc Crystallized fragment (constant fragment of an antibody)
GALT Gut-associated lymphoid tissue
G-CSF Granulocyte colony-stimulating factor
GM-CSF Granulocyte-monocyte colony-stimulating factor
HEVs High endothelial venules
HIV Human immunodeficiency virus
IFN-α Interferon-alpha
IFN-γ Interferon-gamma
Ig Immunoglobulin (usually followed by a capital letter: A, D, E, G, or M)
IL Interleukin (usually followed by an Arabic numeral)
M cell Microfold cell
MAC Membrane attack complex
MALT Mucosa-associated lymphoid tissue
MHC Major histocompatibility complex
MHC I and MHC II MHC class I molecules and class II molecules
MIIC vesicle MHC class II–enriched compartment
NK cell Natural killer cell
PALS Periarterial lymphatic sheath
RER Rough endoplasmic reticulum
sIgs Surface immunoglobulins
TAP Transporter protein (1 and 2)
TCM Central memory T cell
TCR T-cell receptor
TEM Effector T memory cell
TGF Tumor growth factor
TH cell T-helper cell (usually followed by an Arabic numeral)
TLR Toll-like receptor
T lymphocyte Thymus-derived lymphocyte
TNF-α Tumor necrosis factor-alpha
T reg cell Regulatory T cell
TSH Thyroid-stimulating hormone
Antimicrobial peptides, such as defensins, are as interleukins (ILs), whereas cytokines that possess
synthesized and released by epithelial cells and not only chemoattractant capabilities are usually referred to as
defend the body against gram-negative bacteria but also chemokines. Those cytokines that stimulate differen-
are chemoattractants for immature dendritic cells and tiation and mitotic activity of hemopoietic cells are
T lymphocytes. known as colony-stimulating factors (CSFs),
Cytokines are signaling molecules that are released whereas cytokines displaying antiviral properties are
by various cells of the innate and adaptive immune referred to as interferons.
systems to effect responses from their target cells. Macrophages possess receptors for the constant
Cytokines that are released by lymphocytes are known portions of antibodies (Fc receptors), complement
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Chapter 12 䡲 Lymphoid (Immune) System ■ ■ ■ 275
receptors, and receptors that recognize carbohydrates MHC I molecules prevents the killing of healthy cells
that are not usually present on the surface of vertebrate by NK cells.
cells. Macrophages are also antigen-presenting cells,
presenting antigens to both T and B lymphocytes. They
also release G-CSF and GM-CSF, which induce the for- CLINICAL CORRELATIONS
mation of neutrophils and their release into the circu-
lating blood. MHC I molecules are required to be present on
Neutrophils leave the vascular system in the region cell membranes of nucleated cells for cytotoxic T
of inflammation and enter the bacteria-laden connec- lymphocytes (CTLs) to recognize the cells as
tive tissue compartment where they phagocytose and targets for destruction. However, tumor cells and
destroy bacteria. Bacterial killing is effected either in an cells that are infected by viruses suppress the
oxygen-dependent manner, by the formation of hydro- production of MHC I molecules in order to
gen peroxide, hydroxyl radicals, and singlet oxygen prevent their recognition as targets for CTLs.
within the phagolysosomes, or via enzymatic digestion, This evasive maneuver allows tumor and virally
utilizing cationic proteins as well as myeloperoxidase infected cells to become targets of NK cells
and lysozymes. because their killer inhibitory receptors do not
NK cells are similar to cytotoxic T cells (members become activated.
of the adaptive immune system, as discussed later), but
they do not have to enter the thymus gland to become
mature killer cells. These are cells that use nonspecific Toll-like receptors (TLRs) are highly conserved
markers to recognize their target cells, and they do so integral proteins present in the membranes on cells of
by the use of two different methods: the innate immune system; humans have been shown to
䡲 NK cells possess Fc receptors that recognize the con- possess at least 12 different TLRs, each with different
stant portion of the IgG antibody and act as a signal roles (Table 12-2). It appears that TLRs function in
to kill the target cell. This is known as antibody- pairs, so that two TLR partners form a single active
dependent cellular cytotoxicity. receptor. Some of the TLRs are present on cell mem-
䡲 The NK cell surface also displays transmembrane branes so that they have both intracellular and extracel-
proteins known as killer-activating receptors that lular moieties, whereas other TLRs are located only
bind to certain markers on the surface of nucleated intracellularly and possess no extracellular moieties. All
cells. In order to control this killing process, NK cells TLRs (with the exception of TLR3) associate with and
also possess killer-inhibitory receptors that recog- activate the nuclear factor NF-κB pathway that acts
nize MHC I molecules (major histocompatibility through several cytosolic proteins, including MyD88,
complex type I molecules) that are located on the that induces an intracellular cascade of TLR-specific
plasma membranes of all cells. The presence of responses. This sequence of events results not only in
TABLE 12–2 Toll-Like Receptors and Their Putative Functions
Toll-Like Receptor
Domains (TLR) Pair Function
Intracellular and TLR1-TLR2 Binds to bacterial lipoprotein; also binds to certain proteins of parasites
extracellular (on TLR2-TLR6 Binds to lipoteichoic acid of gram-positive bacterial wall; also binds
cell membrane) to zymosan, a fungus-derived polysaccharide
TLR4-TLR4 Binds to lipoprotein saccharide of gram-negative bacteria
TLR5-?* Binds to flagellin of bacterial flagella
TLR11-?* Host recognition of Toxoplasmosis gondii
Intracellular only TLR3-?* Binds to double-stranded viral RNA

TLR7-?* Binds to single-stranded viral RNA
TLR8-?* Binds to single-stranded viral RNA
TLR9-?* Binds to bacterial and viral DNA
TLR10-?* Unknown
TLR12-?* Unknown
*Currently, TLR partner is unknown.

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the release of cytokines appropriate to the pathogen to the thymus to become immunocompetent; therefore,
being detected but also in the possible activation of bone marrow and the thymus are called the primary
B and T cells designed to mount a specific adaptive (central) lymphoid organs. After lymphocytes
immune response. Therefore, TLRs have the ability to become immunocompetent in the bone marrow or in
modulate the immune response, suggesting that the the thymus, they migrate to the secondary (periph-
innate immune system is not a static, one-fits-all type eral) lymphoid organs—diffuse lymphoid tissue,
of response but is dynamic in nature and is capable of lymph nodes, and spleen—where they come into
regulating both the inflammatory and immune res- contact with antigens.
ponses equally.
Immunogens and Antigens
Immunogens are molecules that always elicit an immune
CLINICAL CORRELATIONS response; antigens are molecules that bind to antibodies
Hypoactivity of TLRs can result in greater sus- but do not necessarily elicit an immune response.
ceptibility to pathogens, whereas their hyperac-
A foreign structure that can elicit an immune response
tivity may be responsible for some autoimmune
in a particular host is known as an immunogen; an
diseases such as systemic lupus erythematosus,
antigen is a molecule that can react with an antibody
cardiovascular diseases, and rheumatoid arthritis.
irrespective of its ability to elicit an immune response.
Although not all antigens are immunogens, in this
textbook the two terms are considered synonymous,
and only the term antigen is used.
The Adaptive Immune System The region of the antigen that reacts with an anti-
body, or T-cell receptor, is known as its epitope, or anti-
The adaptive immune system responds slower than the
genic determinant. Each epitope is a small portion of
innate immune system, has immunological memory, and
the antigen molecule and consists of only 8 to 12 or 15
depends on B and T lymphocytes to mount an immune
to 22 hydrophilic amino acid or sugar residues that are
response.
accessible to the immune apparatus. Large foreign
The adaptive immune response exhibits four distinc- invaders such as bacteria have several epitopes, each
tive properties: specificity, diversity, memory, and capable of binding to a different antibody.
self/nonself recognition—that is, the ability to distin-
guish between structures that belong to the organism,
self, and those that are foreign, nonself. T lympho- CLINICAL CORRELATIONS
cytes, B lymphocytes, and specialized macrophages
known as antigen-presenting cells (APCs) partici- The complexity of a foreign substance is also
pate in the (adaptive) immune response. These cells important in determining its antigenicity. Hence,
communicate with members of the innate immune large polymeric molecules that have relatively
system as well as with each other by signaling molecules simple chemical compositions, such as certain
(cytokines), which are released in response to encoun- man-made plastics, have minimal immunogenic-
ters with foreign substances called antigens. ity and are therefore used in the manufacture of
Recognition of a substance as foreign by the immune artificial implants (as in hip replacement).
system stimulates a complex sequence of reactions that
result either in the production of immunoglobulins
(also known as antibodies), which bind to the antigen,
or in the induction of a group of cells that specialize in Clonal Selection and Expansion
cytotoxicity, namely the killing of the foreign cell or
altered self-cell (e.g., tumor cell). The immune During embryonic development, an extremely large
response that depends on the formation of antibodies is number of small clusters (clones) of lymphocytes are
called the humoral immune response, whereas the formed. Each clone can recognize one specific foreign
cytotoxic response is known as the cell-mediated antigen.
immune response.
The cells that constitute the functional components The immune system can recognize and combat an
of the innate and adaptive immune system (T cells, B astonishing number of different antigens. The explana-
cells, macrophages, and their subcategory, APCs) are all tion for this capability is that, during embryonic devel-
formed in the bone marrow. B cells become immuno- opment, an enormous number (approximately 1015) of
competent in the bone marrow, whereas T cells migrate lymphocyte clones are formed by rearrangement of the
Ch012-X2945.qxd 15/8/06 3:54 PM Page 277
400 or so genes encoding immunoglobulins or TCRs. immunological tolerance depends on killing or disabling
All of the cells in a particular clone have identical cells that would react against the self. During embry-
surface markers and can react with a specific antigen, onic development, if a lymphocyte encounters the sub-
even though they have not yet been exposed to that stance to which it is designed to react, the cell is either
antigen. The cell-surface proteins that enable lympho- killed (clonal deletion) so that this particular clone
cytes to interact with antigens are membrane-bound does not form, or the lymphocyte is disabled (clonal
antibodies (B-cell receptors or surface immuno- anergy) and cannot mount an immune response, even
globulins [sIgs]) in the case of B cells and T-cell though it is present.
receptors (TCRs) in the case of T cells. Although the
molecular structures of antibodies and TCRs differ,
they are functionally equivalent in their ability to rec- CLINICAL CORRELATIONS
ognize and interact with specific epitopes.
The first time the organism encounters an antigen, Autoimmune diseases involve a malfunction
the adaptive immune response is slow to begin and of the immune system that results in the loss
not very robust; this response is called the primary of immunological tolerance. One example is
immune response. Subsequent exposures to the same Graves’ disease, in which the receptors for
antigen elicit the secondary immune response, thyroid-stimulating hormone (TSH) on the fol-
which begins rapidly and is much more intense than licular cells of the thyroid gland are perceived to
the primary response. The increased potency of the be antigens. Antibodies formed against TSH
secondary reaction is due to the process of immuno- receptors bind to these receptors and stimulate
logical memory, which is inherent to the immune the cells to release an excess amount of thyroid
system. Both B and T cells are said to be virgin cells hormone. Patients with Graves’ disease have an
(naïve cells) before exposure to antigens. Once a virgin enlarged thyroid gland and exophthalmos (pro-
cell comes in contact with an antigen, it proliferates to truding eyeballs).
form activated cells and memory cells.
Activated cells, also known as effector cells, are
responsible for carrying out an immune response.
Effector cells derived from B cells are called plasma Immunoglobulins
cells and produce and release antibodies. Effector cells
Immunoglobulins are antibodies that are manufactured
derived from T cells either secrete cytokines or destroy
by plasma cells. A typical immunoglobulin has one pair
foreign cells or altered self-cells.
of heavy chains and one pair of light chains attached to
Memory cells, similar to virgin lymphocytes,
each other by disulfide bonds.
express either B-cell receptors (sIgs) or TCRs, which
can interact with specific antigens. Memory cells are not Immunoglobulins (antibodies) are glycoproteins that
directly involved in the immune response during which inactivate antigens (including viruses) and elicit an
they are generated. However, these cells live for months extracellular response against invading microorganisms.
or years and have a much greater affinity for antigens The response may involve phagocytosis in the connec-
than do virgin lymphocytes. Moreover, formation of tive tissue spaces by macrophages (or neutrophils) or
memory cells after first exposure to an antigen increases the activation of the blood-borne complement system.
the size of the original clone, a process called clonal
expansion. Because of the presence of an expanded
population of memory cells with an increased affinity
for the antigen, subsequent exposure to the same CLINICAL CORRELATIONS
antigen induces a secondary response (anamnestic
response) that is much faster, more potent, and longer The complement system is composed of 20
in duration than the primary response. plasma proteins that assemble in a specific
sequence and fashion on the surface of invading
microorganisms to form a membrane attack
Immunological Tolerance complex (MAC) that lyses the foreign cell. The
key component of the complement system is
Macromolecules of the self are not viewed as antigens
protein C3. Deficiency of protein C3 predis-
and therefore do not elicit an immune response. poses a person to recurring bacterial infections.
The immune system can recognize macromolecules
that belong to the self and does not attempt to mount
an immune response against them. This lack of action Immunoglobulins are manufactured in large
is due to immunological tolerance. The mechanism of numbers by plasma cells, which release them into the
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NH2 NH2 ticular epitope are identical. It is believed that after the
NH2 Variable regions NH2
clones against the “self” are eliminated, there remain
106 to 109 different types of antibodies in a person, each
Constant
regions
specific against one particular antigen. Each type of
antibody is manufactured by members of the same
Hinge clone. Thus there are 106 to 109 clones whose members
area discern and react to a particular epitope (or a small
Light chain
number of similar epitopes).
As noted earlier, small amounts of immunoglobulins
HOOC COOH are made by B cells and inserted into their plas-
Disulfide bonds malemma; these are known as sIgs or B-cell receptors;
they function as antigen-receptor molecules. They are
Heavy chain slightly different from antibodies in that they possess a
membrane-binding component composed of two pairs
of membrane-spanning chains, Igββ and Igβ, which
bind the heavy chains of the antibody molecule to the
cell membrane.
COOH COOH
Classes of Immunoglobulins
Figure 12–1 An antibody and its regions.
Humans have five isotypes (classes) of immunoglobu-
lins (Table 12-3):
lymph or blood vascular system. The typical antibody is IgM, which resembles five IgG molecules bound to
immunoglobulin G (IgG). Each IgG is a Y-shaped mol- each other (pentameric form of immunoglobulin)
ecule, composed of two long, identical 55- to 70-kDa IgA, which resembles two IgG molecules bound to
polypeptides, known as heavy chains, and two shorter, each other (dimeric form of immunoglobulin)
identical 25-kDa polypeptides, the light chains. The IgG, the monomeric form of immunoglobulin
four chains are bound to each other by several disulfide described earlier
bonds and noncovalent bonds in such a way that the IgD, which is present in very low concentration in the
stem of the Y is composed only of heavy chains and the blood, but is found on the B-cell surface as a
diverging arms consist of both light and heavy chains monomeric form of immunoglobulin known as
(Fig. 12-1). surface IgD (sIgD)
The region in the vicinity of the sulfide bonds IgE, a monomeric form of immunoglobulin present on
between the two heavy chains—the hinge region—is the surface of basophils and mast cells
flexible and permits the arms to move away from or
The classes of immunoglobulins are also determined
toward each other. The distal regions on the tips of the
by the amino acid sequences of their heavy chains. The
arms (the four amino-terminal segments) are responsi-
various heavy chains are designated by the Greek letters
ble for binding to the epitope; hence, each antibody
α, δ, γ, ε, and µ.
molecule can bind two identical epitopes.
The enzyme papain cleaves the antibody molecule at
its hinge regions (see Fig. 12-1), forming three frag-
Cells of the Adaptive and Innate
ments: one Fc fragment composed of the stem of the Immune Systems
Y and containing equal parts of the two heavy chains, The cells of the adaptive and innate immune system are
and two Fab fragments, each composed of the remain- B lymphocytes, T lymphocytes, macrophages, antigen-
ing part of one heavy chain and one entire light chain. Fc presenting cells, and natural killer cells.
fragments are easily crystallized (hence the “c” designa-
tion), whereas the Fab fragment is the antigen-binding B Lymphocytes
region of the antibody (hence the “ab” designation).
The amino acid sequence of the Fc fragment is B lymphocytes originate and become immunocompetent
mostly constant in its class; thus the stem of an antibody in the bone marrow. They are responsible for the
binds to Fc receptors of many different cells. The amino humorally mediated immune system.
acid sequence of the Fab region is variable, and it is the
alterations of that sequence that determine the speci- B lymphocytes, also known as B cells, are small lym-
ficity of the antibody molecule for its specific antigen. phocytes (see Chapter 10) that both originate and
Each antibody is specific against a specific epitope; become immunocompetent in the bone marrow.
thus the Fab regions of all antibodies against that par- However, in birds, in which B cells were first identified,
TABLE 12–3 Properties of Human Immunoglobulins
Ig in
No. of Blood Crosses Binds to
Class Cytokines* Units† (%) Placenta Cells Biological Characteristics
IgA TGFβ 1 or 2 10-15 No Epithelial cells Also known as secretory antibody because it is secreted into tears, saliva
(temporarily) the lumen of the gut, and the nasal cavity as dimers; individual units
during of the dimer are held together by J protein manufactured by plasma
secretion cells and protected from enzymatic degradation by a secretory
Ch012-X2945.qxd 15/8/06 3:54 PM Page 279
component manufactured by the epithelial cell; combats antigens

and microorganisms in the lumen of gut, nasal cavity, vagina, and
conjunctival sac; secreted into milk, thus protecting neonate with
passive immunity; monomeric form in bloodstream; assists
eosinophils in recognizing and killing parasites
IgD 1 <1 No B-cell plasma Surface immunoglobulin; assists B cells in recognizing antigens for
membrane which they are specific; functions in the activation of B cells
subsequent to antigenic challenge to differentiate into plasma cells
IgE IL-4, IL-5 1 <1 No Mast cells and Reaginic antibody; when several membrane-bound antibodies are
basophils cross-linked by antigens, IgE facilitates degranulation of basophils
and mast cells, with subsequent release of pharmacological agents,
such as heparin, histamine, eosinophil and neutrophil chemotactic
factors, and leukotrienes; elicits immediate hypersensitivity reactions;
assists eosinophils in recognizing and killing parasites
IgG IFN-γ, IL-4, 1 80 Yes Macrophages Crosses placenta—thus protects fetus with passive immunity; secreted
IL-6 and in milk—thus protects neonate with passive immunity; fixes
neutrophils complement cascade; functions as opsonins—that is, by coating
microorganisms; facilitates their phagocytosis by macrophages and
neutrophils, cells that possess Fc receptors for the Fc region of these
antibodies; also participates in antibody-dependent cell-mediated
cytotoxicity by activating NK cells; produced in large quantities
during secondary immune responses
IgM 1 or 5 5-10 No B cells (in Pentameric form is maintained by J-protein links, which bind Fc
monometric regions of each unit; activates cascade of the complement system; is
Chapter 12 䡲 Lymphoid (Immune) System
form) the first isotype to be formed in the primary immune response

■
*Cytokines responsible for switching to this isotype.

■
†A unit is a single immunoglobulin composed of two heavy and two light chains; thus, IgA exists both as a monomer and as a dimer.
■
Fc, crystallizable fragment; IFN, interferon; Ig, immunoglobulin; IL, interleukin; NK, natural killer; TGF, tumor growth factor.
279
Ch012-X2945.qxd 15/8/06 3:54 PM Page 280
they become immunocompetent in a diverticulum of independent antigens. They cannot induce formation
the cloaca, known as the bursa of Fabricius (hence of B memory cells and can elicit only IgM-antibody for-
“B” cells). During the process of becoming immuno- mation. However, most antigens require participation of
competent, each cell manufactures 50,000 to 100,000 a T-cell intermediary before they can induce a humoral
IgM and IgD immunoglobulins and inserts these in its immune response (see below).
plasma membrane so that the epitope-binding sites of
the antibodies face the extracellular space. The Fc T Lymphocytes
region of the antibody is embedded in the phospholipid
bilayer with the assistance of two pairs of transmem- T lymphocytes originate in the bone marrow and
brane proteins, Igβ and Igα, whose carboxyl termini are migrate to the thymus to become immunocompetent.
in contact with intracellular protein complexes. Every They are responsible for the cellularly mediated immune
member of a particular clone of B cells has antibodies response.
that bind to the same epitope.
When the surface immunoglobulin reacts with its T lymphoctes (T cells) also are formed in the bone
epitope, the Igβ and Igα transduce (relay) the informa- marrow, but they migrate to the thymic cortex, where
tion to the intracellular protein complex with which they become immunocompetent by expressing specific
they are in contact, initiating a chain of events that molecules on their cell membranes that permit them to
results in activation of the B cell. The activated B perform their functions. The process whereby T cells
cell undergoes mitosis, forming antibody-producing become immunocompetent is discussed later (see
plasma cells and B memory cells, as discussed earlier. Thymus).
Because the antibodies produced by plasma cells are Although histologically T cells appear to be identical
released either into the blood or into the lymph circu- to B cells, there are important differences between
lation, B cells are responsible for the humorally medi- them:
ated immune response. 䡲 T cells have TCRs rather than sIgs on their cell
As naïve B cells first become activated, they make surface.
IgM, which, when bound to the surface of an invading 䡲 T cells recognize only epitopes presented to them by
pathogen, is able to activate the complement system other cells (APCs).
(complement fixation). IgM molecules can also bind to 䡲 T cells respond only to protein antigens.
viruses, preventing them from contacting the cell 䡲 T cells perform their functions only at short
surface, thus protecting the cells from viral invasion. distances.
Once IgM is produced, the B cell can manufacture
a different class of immunoglobulin. This capability is Similar to sIgs on B cells, TCRs on the plasmalemma
known as class switching (isotype switching) and is of T cells function as antigen receptors. The constant
determined by the particular cytokines that are present regions of the TCR are membrane-bound, whereas the
in the B cell’s microenvironment. These cytokines are variable amino-terminal regions containing the
released by T-helper (TH) cells as a function of the type antigen-binding sites extend from the cell surface. In
of pathogens present: addition to TCR molecules, T cells express clusters of
differentiation proteins (CD molecules or CD
䡲 During parasitic worm invasion, T-helper cells
markers) on their plasmalemma. These accessory pro-
release IL-4 and IL-5, and B cells differentiate into
teins bind to specific ligands on target cells. Although
plasma cells and after class switching form IgE to
almost 200 CD molecules are known, Table 12-4 lists
elicit mast cell degranulation on the surface of the
only those that are immediately pertinent to the subse-
parasites.
quent discussion of cellular interactions in the immune
䡲 During bacterial and viral invasions, T-helper cells
process. The membrane-bound portion of the TCR
release interferon-γ (IFN-γ) and IL-6, and B cells
associates with the membrane proteins, CD3, and
switch to forming IgG, which opsonizes bacteria,
either CD4 or CD8, forming the TCR complex.
fixes complement, and stimulates NK cells to kill
Several other membrane proteins play roles in signal
virally altered cells (antibody-dependent cell-
transduction and in strengthening the interaction
mediated cytotoxicity [ADCC]).
between the TCR and an epitope, thus facilitating
䡲 During viral or bacterial invasion of mucosal surfaces,
antigen-stimulated T-cell activation.
T-helper cells release tumor growth factor-β (TGF-
A TCR can recognize an epitope only if the epitope
β), and B cells switch to IgA formation, which is
is a polypeptide (composed of amino acids) and if the
secreted onto the mucosal surface.
epitope is bound to a major histocompatibility
Certain antigens (e.g., polysaccharides of microbial complex (MHC) molecule, such as those in the plas-
capsules) can elicit a humoral immune response without malemma of an APC. There are two classes of these gly-
a T-cell intermediary. These are known as thymic- coproteins: MHC class I and MHC class II. Most
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TABLE 12–4 Selected Surface Markers Involved in the Immune Process
Ligand and
Protein Cell Surface Target Cell Function
CD3 All T cells None Transduces MHC-epitope complex binding into intracellular
signal, activating T cell
CD4 T-helper cells MHC II on APCs Coreceptor for TCR binding to MHC II–epitope complex,
activation of T-helper cell
CD8 Cytotoxic T cells MHC I on most Coreceptor for TCR binding to MHC I–epitope complex;
and suppressor nucleated cells activation of cytotoxic T cell
T cells
CD28 T-helper cells B7 on APCs Assists in the activation of T-helper cells

CD40 B cells CD40 receptor Binding of CD40 to CD40 receptor permits T-helper cell to
molecule expressed activate B cell to proliferate into B memory cells and
on activated plasma cells
T-helper cells
APC, antigen-presenting cell; CD, cluster of differentiation molecule; MHC, major histocompatibility complex; TCR, T-cell receptor.
nucleated cells express MHC I molecules on their Memory T cells, unlike naïve T cells, express CD45R0
surface, whereas APCs (discussed later) can express molecules on their cell membrane. They form the
both MHC I and MHC II molecules on their plas- immunological memory of the adaptive immune system
malemma. The MHC molecules are unique in each because they form a clone whose members are identi-
individual (except for identical twins), and to be acti- cal and have the capability of combating a particular
vated, T cells must recognize not only the foreign antigen. These memory cells can become activated and
epitope but also the MHC molecule as self. If a T cell express effector capabilities. There are two types of
recognizes the epitope but not the MHC molecule, it memory T cells: those that express CR7 + molecules on
does not become stimulated; hence, the T cell’s capac- their surface, known as central memory T cells
ity to act against an epitope is MHC-restricted. (TCMs), and CR7 − cells, known as effector memory
There are three types of T cells, some with two or T cells (TEMs). TCMs populate and remain in the T
more subtypes: cell–rich area of lymph nodes, they are incapable of
immediate effector function, and they interact with and
䡲 Naïve T cells
stimulate antigen-presenting cells and cause them to
䡲 Memory T cells
release IL-12. This signaling molecule binds to IL-12
䡲 Effector T cells
receptors of TCMs and stimulates TCMs to differenti-
ate into effector memory T cells. TEMs express recep-
Naïve T Cells
tors that permit these cells to migrate to regions of
Naïve T cells possess CD45RA molecules on their cell inflammation, where they have immediate effector
surface and they leave the thymus programmed as function by differentiating into effector T cells.
immunologically competent cells, but they are not as yet
ready to function in that capacity until they become Effector T cells
activated T cells. When a T lymphocyte becomes acti-
vated it undergoes cell division and forms both memory There are three types of effector T cells: TH cells,
T cells and effector T cells. cytotoxic T lymphocytes, and regulatory T (T reg) cells.
These are the cells that are able to respond to an
Memory T Cells immunological challenge.
There are two types of memory T cells: central memory
Effector T cells are immunologically competent cells
T cells and effector memory T cells. They are responsible
that are capable of responding to and mounting an
for the immunological memory of the adaptive immune
immune response. There are three types of effector T
system.
cell: TH cells, T killer cells (cytotoxic T lymphocytes
Ch012-X2945.qxd 15/8/06 3:54 PM Page 282
[CTLs]), and T reg cells; TH and T reg cells have their 䡲 IL 5 induces the production of eosinophils
own cell subtypes. 䡲 IL-6 combats asthma and systemic lupus erythe-
matosus
T-HELPER CELLS
The three subtypes of TH cells display CD4 molecules on CYTOTOXIC T LYMPHOCYTES

their cell membrane and are responsible for the
Cytotoxic T lymphocytes (CTLs, T killer cells) display CD8
recognition of foreign antigens as well as for mounting
molecules on their cell membrane and are responsible
an immunological response against them.
for killing foreign cells, tumor cells, and virally altered
cells.
TH cells possess CD4 molecules as their cell membrane
markers, are capable of interacting with other cells of CTLs possess CD8 molecules on their cell membrane.
the innate and adaptive immune systems, and can acti- They recognize epitopes that are displayed on the
vate cells of the cell-mediated immune system to cell membranes of foreign cells, tumor cells, as well as
mount a response to invading pathogens and eliminate cells that have been altered by viruses and display viral
them. TH cells also play a major role in stimulating the epitopes on their plasmalemmae, and kill these cells.
humorally mediated immune system by interacting The killing of these cells is performed in one of two
with B cells and stimulating them to become antibody- ways:
producing plasma cells. There are three subtypes
of Th cells: TH0, TH1, and TH2; an additional subtype, 䡲 CTLs place perforins into the cell membranes of the
Th3, has been reclassified as an inducible T reg virally altered cell:
cell. 䡲 Perforins stimulate the formation of pores in the plas-
TH0 cells are precursor cells that have the capabil- malemma.
ity of manufacturing and releasing a large number of 䡲 CTLs transfer granzymes into the cytoplasm of the
cytokines. These cells can differentiate into either TH1 virally altered cell.
or TH2 cells, and then their repertoire of cytokine 䡲 Granzymes stimulate capsases to induce apoptosis,
release becomes limited. thus killing the virally altered cell.
TH1 cells secrete IL-2, IFN-γ, and TNF-β: 䡲 CTLs express Fas L, also known as CD95L (the
death ligand), on their cell membrane.
䡲 IL-2 stimulates CD4 and CD8 T cell proliferation as 䡲 Fas, also known as CD95 (death receptor), on the
well as cytotoxicity by CD8 T cells (CTLs) surface of the target cell is activated.
䡲 IFN-γ stimulates macrophages so that they can 䡲 Once Fas is activated, it stimulates an apoptotic
destroy pathogens, such as mycobacteria, protozoa, cascade, resulting in the death of the target cell.
and fungi, that they have phagocytosed; this cytokine
also activates NK cells of the innate immune system
to become cytotoxic. Macrophages release IL-12, T REG CELLS
which induces the proliferation of TH1 cells and
inhibits the proliferation of TH2 cells T reg cells possess CD 4 molecules on their cell
䡲 TNF-β stimulates neutrophils to facilitate the induc- membrane and function in suppressing the immune
tion of acute inflammation response.
䡲 TH1 cells are crucial for the control of intracellular
T reg cells display CD4 molecules on their cell mem-
pathogens and are also responsible for the induction
brane and function in suppressing the immune
of the cell-mediated immune response, as in acute
response. Historically, the role of suppressing the
allograft rejection and in the cases of multiple
immune response was ascribed to a theoretical T sup-
sclerosis.
pressor cell; however, many immunologists did not
TH2 cells secrete IL-4, IL-5, IL-6, IL-9, IL-10, and accept the existence of these cells. Recent investiga-
IL-13, and many of these interleukins facilitate the pro- tions, however, showed that there are cells that suppress
duction of antibodies by plasma cells. TH2 cells elicit a the immune function, and these cells were named
response against a parasitic (IgE) or mucosal (IgA) regulatory T (T reg) cells. There are two types of T
infection. reg cells: natural (constitutive) and inducible (adap-
The secreted interleukins have varied effects, includ- tive). Both express CD4 molecules on their plasma
ing the following functions: membrane.
䡲 IL 4 stimulates B cells to switch to IgE synthesis; thus 䡲 Natural T reg cells develop in the thymus; they
it plays an important role in allergic reactions leave the thymus and, when their TCRs bind to an
䡲 IL 10, acting in concert with IL 4, suppresses the dif- APC, they suppress the immune response in a
ferentiation of TH0 cells to TH1 cells non–antigen-specific manner.
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䡲 Inducible T reg cells (also known as TH3 cells) are Loading Epitopes on MHC I Molecules
derived from naïve T cells; they secrete cytokines,
such as IL-10 and TGF-β, that inhibit the formation Epitopes derived from endogenous proteins are
of TH1 cells. transported by specialized transporter proteins into the
rough endoplasmic reticulum cisternae.
It is possible that the two types of T reg cells have
overlapping functions and that they act in concert to Proteins manufactured by a cell, whether they belong
suppress the autoimmune response to self-molecules. to the cell or to a virus or a parasite that has overtaken
the protein synthetic machinery of the cell, are known
NATURAL T KILLER CELLS as endogenous proteins. The quality of the proteins
Natural T killer cells are effector T cells that resemble that the cell manufactures is controlled by protea-
NK cells but must enter the thymic cortex to become somes, which are modified to splice defective or
immunocompetent effector cells. They release these foreign proteins into the proper-sized polypeptide frag-
cytokines: IFNγ, IL-4, and IL-10. Similar to NK cells, ments (8 to 12 amino acids in length). These fragments,
they can be activated almost immediately. These are known as epitopes, are transported by specialized
very unusual cells because they are able to recognize transporter proteins (TAP1 and TAP2) into the cister-
lipid antigens that are presented to them on the nae of the rough endoplasmic reticulum (RER), where
surfaces of immature dendritic cells. In order for they are complexed to MHC I molecules that were
natural T killer cells to recognize antigenic lipids, the manufactured on the RER surface. The MHC I–epitope
lipids must be presented to them in conjunction with complex is transported to the Golgi apparatus and is
CDI molecules. There are four isoforms of CDI mol- packaged, within the trans Golgi network, into clathrin-
ecules, and they are located either on the cell surface coated vesicles for transport to and insertion into the
or are monitoring lysosomal and late endosomal cell membrane. In this fashion, TCLs “look” at the cell
compartments. surface and “see” whether the cell is producing self-
proteins or nonself-proteins.
Major Histocompatibility
Complex Molecules Loading Epitopes on MHC II Molecules
MHC molecules present epitopes of pathogens to T cells. Epitopes derived from proteins endocytosed by
There are two classes of MHC molecules: MHC I and macrophages and APCs are loaded onto MHC II
MHC II. molecules within specialized intracellular compartments
known as MHC II compartment (MIIC).
The prime importance of MHC molecules is to permit
APCs and cells under viral attack (or cells already virally Macrophages and APCs endocytose proteins from their
transformed) to present the epitopes of the invading extracellular milieu by the formation of pinocytotic vesi-
pathogen to the T cells. These epitopes are short cles or phagosomes. The contents of these vesicles,
polypeptides that fit into a groove on the surface of the known as exogenous proteins, are delivered to early
MHC molecule. endosomes, where they are enzymatically cleaved into
There are two classes of MHC molecules: polypeptide fragments. The polypeptide fragments are
transported to late endosomes, where they are further
䡲 MHC I molecules function in presenting short
cleaved to become the proper size (13 to 25 amino acids
polypeptide fragments (8 to 12 amino acids in length)
in length) so that they can fit into the groove of the
derived from endogenous proteins (i.e., proteins
MHC II molecule.
manufactured by the cell).
MHC II molecules are synthesized on the RER. As
䡲 MHC II molecules function in presenting longer
they are assembled in the RER cisternae, a protein known
polypeptide fragments (13 to 25 amino acids in
as class II–associated invariant protein (CLIP) is
length) derived from exogenous proteins (i.e., pro-
loaded into the groove of the MHC II molecule, prevent-
teins that were phagocytosed and cleaved by these
ing the accidental loading of the molecule with an
cells from the extracellular space).
endogenous epitope. The MHC II–CLIP complex is
Almost every cell synthesizes and displays MHC I transported to the Golgi apparatus and is sorted into
proteins, but only APCs synthesize and display MHC II clathrin-coated vesicles within the trans Golgi network
proteins. In humans, MHC I and MHC II molecules for delivery to MHC II–enriched compartments (MIIC
exist in many forms, which permits T cells to recognize vesicles), specialized vesicles that function in loading
the MHC molecules of an individual as belonging to epitopes onto the MHC II molecule.
that particular individual—that is, T cells are capable of The MIIC vesicle receives not only the MHC
distinguishing “self.” II–CLIP complex but also the epitopes from the
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processed antigens from the late endosomes. Within the monocytes and therefore belong to the mononuclear
MIIC vesicle, the CLIP is enzymatically dissociated phagocyte system. APCs include macrophages, dendritic
from the MHC II molecule and is replaced by an cells (such as Langerhans cells of the epidermis and oral
epitope. The MHC II–epitope complex is then trans- mucosa), and two types of non–monocyte-derived cells
ported to and inserted into the cell membrane. In this (B cells and epithelial reticular cells of the thymus).
fashion, TH cells can “look” at the cell surface and “see” Similar to TH cells, APCs manufacture and release
whether the cell is encountering nonself-proteins. cytokines. These signaling molecules are needed to
activate target cells to perform their specific functions,
Antigen-Presenting Cells (APCs) not only in the immune response but also in other
processes. Table 12-5 lists some of these cytokines but
APCs express both MHC I and MHC II on their includes only those properties that relate specifically to
plasmalemmae, and they phagocytose, catabolize, the immune response.
process, and present antigens.
Interaction among the Lymphoid Cells
APCs phagocytose, catabolize, and process antigens,
attach their epitopes to MHC II molecules, and present Cells of the lymphoid system interact with each other
this complex to T cells. Most APCs are derived from to effect an immune response. The process of interac-
TABLE 12–5 Origin and Selected Functions of Some Cytokines
Cytokine Cell Origin Target Cell Function
IL-1a Macrophages T cells and Activate T cells and macrophages

IL-1b and epithelial macrophages
cells
IL-2 TH1 cells Activated T cells and Promotes proliferation of activated T cells and activated B
activated B cells cells
IL-4 TH2 cells B cells Promotes proliferation of B cells and their maturation to
plasma cells; also facilitates switch from production of
IgM to IgG and IgE
IL-5 TH2 cells B cells Promotes B-cell proliferation and maturation; also facilitates
switch from production of IgM to IgE
IL-6 APCs and TH2 T cells and activated Activates T cells; promotes B-cell maturation to IgG-
cells B cells producing plasma cells
IL-10 TH2 cells TH1 cells Inhibits development of TH1 cells and inhibits them from
secreting cytokines
IL-12 B cells and NK cells and T cells Activates NK cells and induces the formation of TH1-like
macrophages cells
TNF-α Macrophage Macrophages Self-activates macrophages to release IL-12

TH1 cells Hyperactive Stimulates hyperactive macrophages to produce oxygen
macrophages radicals, thereby facilitating bacterial killing
IFN-α Cells under viral NK cells and Activates macrophages and NK cell
attack macrophages
IFN-β Cells under viral NK cells and Activates macrophages and NK cells
attack macrophages
IFN-γ TH1 cells Macrophages and T Promotes cell killing by cytotoxic T cells and phagocytosis by
cells macrophages
APCs, antigent-presenting cells; Ig, immunoglobulin; IL, interleukin; IFN, interferon; NK, natural killer; TH, T-helper; TNF, tumor necrosis
factor.
Ch012-X2945.qxd 15/8/06 3:54 PM Page 285
Antigen CD4 molecule

Antibody T cell receptor
CD40 receptor
MHC II–
epitope complex Plasma cells Antibodies
Cytokines IL-4, IL-5,
IL-6, and IL-10
CD40 TH2 cell
B cell B cell
CD28
CD28 CD80
B cell becomes activated TH2 cell recognizes the MHC II– IL-4, IL-5, and IL-6 facilitate the
by the cross-linking of epitope complex presented by the activation and differentiation of B memory cells
surface antibodies by the B cell, using its TCR and CD4 B cells into B memory cells and
antigen. B cell places molecules. Additionally, the TH2 antibody-forming plasma cells.
MHC II–epitope complex CD40 receptor binds to the CD40 IL-10 inhibits the proliferation of
on its surface. molecule on the B cell plasmalemma TH1 cells.
and CD28 binds to CD80.
Binding of CD40 to CD40 receptor

causes proliferation of B cells.
The TH2 cell releases cytokines
IL-4, IL-5, IL-6, and IL-10. Binding of
CD28 of B cell to CD80 of TH2 cell
activates more TH2 cells.
Figure 12–2 The interaction between B cells and a T-helper cell (TH2 cell) in a thymus-dependent, antigen-induced, B memory, and plasma
cell formation. CD, cluster of differentiation molecule; IL, interleukin; MHC, major histocompatibility complex; TCR, T-cell receptor.
tion is regulated by recognition of surface molecules; if If both signaling events are properly executed, the B
the molecules are not recognized, the cell is eliminated cell becomes activated and rapidly proliferates. During
to prevent an incorrect response. If the surface mole- proliferation, the TH2 cell releases IL-4, IL-5, IL-6, and
cules are recognized, the lymphocytes proliferate and IL-10. The first three of these cytokines facilitate the
differentiate. The initiation of these two responses is differentiation of the newly formed B cells into B
called activation. At least two signals are required for memory cells and antibody-secreting plasma cells,
activation: whereas IL-10 inhibits the proliferation of TH1 cells.
The interaction of CD40 with the CD40 ligand facili-
䡲 Recognition of the antigen (or epitope)
tates isotype switching from IgM to IgG, and the inter-
䡲 Recognition of a second, costimulatory signal, which
action between CD28 and CD80 enhances TH2 cell
may be mediated by a cytokine or by a membrane-
activity. IL-4 facilitates the isotype switching to IgE.
bound signaling molecule
T-Helper Cell–Mediated (TH1 cells)
T-Helper Cell–Mediated (TH 2 cells)
Killing of Virally Transformed Cells
Humoral Immune Response
In most cases, CTLs need to receive a signal from a TH1
Except for thymus-independent antigens, B cells can cell to be capable of killing virally transformed cells.
respond to an antigen only if instructed to do so by the Before that signal can be given, however, the TH1 cell
TH2 cell subtype (Fig. 12-2). When the B cell binds anti- must be activated by an APC that offers the proper
gens on its sIgs, it internalizes the antigen-antibody epitope (Fig. 12-3).
complex, removes the epitope and attaches it to MHC
II molecules, and places the epitope–MHC II complex Signal 1. The TCR and the CD4 molecule of the TH1
on its surface and presents it to a TH2 cell. cell must recognize the epitope–MHC II complex on
the surface of an APC. If these events occur, the APC
Signal 1. The TH2 cell not only must recognize the expresses a molecule called B7 on its surface.
epitope with its TCR but also must recognize the
Signal 2. The CD28 molecule of the TH1 cell binds to
MHC II molecule with its CD4 molecule. the B7 molecule of the APC.
Signal 2. The TH2 cell’s CD40 receptor must bind to
the B cell’s CD40 molecule, and the TH2 cell’s CD28 The TH1 cell is now activated and releases IL-2,
has to contact the B cell’s CD80 molecule. IFN-γ, and TNF. IFN-g causes activation and
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T cell CD4 molecule

receptor B7
MHC II–epitope complex CD28 Virus-
Cytotoxic T transformed
lymphocyte cell
Antigen-
presenting
TH1 cell
cell
B7
molecule MHC I– CTL
TNF CD28 epitope complex
IL-2 molecule CD8 molecule
IFN-γ Granzymes Perforins
TH1 cell TCR binds to MHC II–epitope The same APC also has MHC I–epitope The newly formed CTLs attach to the
complex of antigen-presenting cell. complex expressed on its surface that MHC I–epitope complex via their TCR
The CD4 molecule of the TH1 cell is bound by a CTL’s CD8 molecule and and CD8 molecules and secrete
recognizes MHC II. These two events T-cell receptor. Additionally, the CTL has perforins and granzymes, killing the
cause the APC to express B7 molecules CD28 molecules bound to the APC’s B7 virus-transformed cells. Killing occurs
on its surface, which bind to CD28 of molecule. The CTL also possesses IL-2 when granzymes enter the cell through
the TH1 cell, causing it to release IL-2, receptors, which bind the IL-2 released the pores established by perforins and
IFN-γ, and TNF. by the TH1 cell, causing the CTL to act on the intracellular components to
undergo proliferation, and IFN-γ causes drive the cell into apoptosis.
its activation.
Figure 12–3 T-helper cell (TH1 cell) activation of cytotoxic T cells in killing virus-transformed cells. APC, antigen-presenting cell; CD,
cluster of differentiation molecule; CTL, cytotoxic T lymphocyte; IFN-γ, interferon-gamma; MHC, major histocompatibility complex; TCR, T-
cell receptor; TNF, tumor necrosis factor.
proliferation of the CTL if that CTL is bound to the enzymes enter the transformed cells via the perforin-
same APC and if the following conditions are met: formed pores and drive the cells into apoptosis,
Signal 1. The TCR and the CD8 molecule of the CTL killing them within a few minutes.
must recognize the epitope–MHC I complex of 3 Binding can also bring the CTL’s Fas ligand into
the APC; also, the CD28 molecule of the CTL must contact with the target cell membrane’s Fas protein
bind with the B7 molecule of the APC. (CD95). When a threshold number of these Fas
Signal 2. IL-2 released by the TH1 cell binds to the IL- ligands and Fas proteins bond, the clustering of the
2 receptors of the CTL. Fas proteins induces the intracellular protein cascade
that leads to apoptosis.
The CTL is now activated and rapidly proliferates.
The newly formed CTLs seek out virally transformed Note that certain highly vigorous APCs can act as the
cells by binding with their TCR and CD8 to the trans- first signal. In such an instance, the CTL does not
formed cell’s epitope–MHC I complex. Target cell require a TH cell intermediary but can release IL-2 and
killing may occur in one of the following ways: can activate itself.
1 Binding (in the presence of calcium) causes release

of perforins, a group of glycoproteins that are TH1 Cells Assist Macrophages in
closely related to the C9 fraction of the complement
membrane attack complex. Perforins embed them-
Killing Bacteria
selves into the cell membranes of the transformed Bacteria that are phagocytosed by macrophages can
cells and, by aggregating, form hydrophilic pores. readily proliferate within the phagosome (becoming
These pores may become so large and so abundant infected) because macrophages cannot destroy these
that the target cell cannot maintain its cytoplasmic microorganisms unless they are activated by TH1 cells
integrity and the cells undergo necrosis. It is inter- (Fig. 12-4).
esting to note that the CTL is protected from auto-
destruction by perforin because the proteoglycan Signal 1. The TCR and CD4 molecules of the TH1 cell
chondroitin sulfate A is present in the vesicles that must recognize the epitope–MHC II complex of the
contain granzymes. macrophage that phagocytosed the bacteria.
2 Binding (in the presence of calcium) causes the Signal 2. The TH1 cell expresses IL-2 receptors on its
release of perforins and granzymes. Granzymes are surface and releases IL-2, which binds to the recep-
released from the storage granules of the CTL; these tors, thus activating itself.
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TH1 Cell Activation of Infected Macrophages

MHC II–epitope complex TNF-α
CD4 molecule
Bacteria T-cell TNF-α
Macrophage Lysosomes receptor receptor
TH1 cell TH1 cell
IL-2
Bacteria proliferating Macrophage
in phagosomes IFN-γ Activated
lysosome
TH1 cell's TCR and CD4 molecules recognize the The newly formed TH1 cells contact infected
MHC II–epitope complex presented by a macrophage macrophages (TCR and CD4 recognition of
that was infected by bacteria. The TH1 cell becomes MHC II–epitope complex) and release inter-
activated, expresses IL-2 receptors on its surface, and feron-γ (IFN-γ). IFN-γ activates the macrophage
releases IL-2. Binding of IL-2 results in proliferation of to express TNF-α receptors on its surface as
the TH1 cells. well as to release TNF-α. Binding of IFN-γ
and TNF-α on the macrophage cell membrane
facilitates the production of oxygen radicals
by the macrophage resulting in killing of bacteria.
Figure 12–4 Macrophage activation by T cells. CD, cluster of differentiation molecule; IL, interleukin; IFN-γ, interferon-gamma; MHC,
major histocompatibility complex; TCR, T-cell receptor; TNF-α, tumor necrosis factor-alpha.
The activated TH1 cell rapidly proliferates, and the

newly formed TH1 cells contact macrophages that are LYMPHOID ORGANS
infected with bacteria. The lymphoid organs are classified into two categories:
Signal 1. The TCR and CD4 molecules of the TH1 cell 1 Primary (central) lymphoid organs are responsi-
must recognize the epitope–MHC II complex of the ble for the development and maturation of lympho-
infected macrophage, and the T cell releases IFN-γ. cytes into mature, immunocompetent cells.
Signal 2. The IFN-γ activates the macrophage, which 2 Secondary (peripheral) lymphoid organs are
then expresses TNF-α receptors on its surface and responsible for the proper environment in which
releases the cytokine TNF-α. immunocompetent cells can react with each other, as
When these two factors, IFN-γ and TNF-α, bind to well as with antigens and other cells, to mount an
their receptors on macrophages, they facilitate the pro- immunological challenge against invading antigens or
duction of oxygen radicals by the macrophage, resulting pathogens.
in killing of bacteria. In humans, the fetal liver, prenatal and postnatal
bone marrow, and thymus constitute the primary lym-
phoid organs. The lymph nodes, spleen, and mucosa-
associated lymphoid tissues (as well as the postnatal
CLINICAL CORRELATIONS bone marrow) constitute the secondary lymphoid organs.
Human immunodeficiency virus (HIV), the
cause of acquired immunodeficiency syn- Thymus
drome (AIDS), binds to CD4 molecules of TH
The thymus is a primary lymphoid organ that is the site
cells and injects its core into the cell. The virus
of maturation of T lymphocytes.
incapacitates the cell, and as the virus spreads, it
infects other TH cells, thereby reducing their The thymus, situated in the superior mediastinum and
numbers. As a result, infected persons eventually extending over the great vessels of the heart, is a small
become incapable of mounting an immune encapsulated organ composed of two lobes. Each lobe
response against bacterial or viral infections. arises separately in the third (and possibly fourth)
Victims succumb to secondary infections due to pharyngeal pouches of the embryo. The T lymphocytes
opportunistic microorganisms or to malignancies. that enter the thymus to become instructed to achieve
immunological competence arise from mesoderm.
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The thymus originates early in the embryo and con- The cortex of the thymus appears much darker histo-
tinues to grow until puberty, when it may weigh as much logically than does the medulla because of the presence
as 35 to 40 g. After the first few years of life, the thymus of a large number of T lymphocytes (thymocytes)
begins to involute (atrophy) and becomes infiltrated by (Fig. 12-6; also see Fig. 12-5). Immunologically incom-
adipose cells. However, it may continue to function petent T cells leave the bone marrow and migrate to
even in older adults. the periphery of the thymic cortex, where they undergo
The capsule of the thymus, composed of dense, extensive proliferation and instruction to become
irregular collagenous connective tissue, sends septa into immunocompetent T cells. In addition to the lympho-
the lobes, subdividing them into incomplete lobules cytes, the cortex houses macrophages and epithelial
(Fig. 12-5). Each lobule is composed of a cortex and a reticular cells. It is believed that in humans epithelial
medulla, although the medullae of adjacent lobules are reticular cells are derived from the endoderm of the
confluent with each other. third (and possibly fourth) pharyngeal pouch. Three
types of epithelial reticular cells are present in the
Thymic Cortex thymic cortex:
䡲 Type I cells separate the cortex from the connective
Immunological competency of T cells, elimination of self-
tissue capsule and trabeculae and surround vascular
intolerant T lymphocytes, and MHC recognition occur in
elements in the cortex. These cells form occluding
the thymic cortex.
junctions with each other, completely isolating the
Medulla Cortex
Capsule
Capsular
vessels
in capsule
Cortex
Medulla
Hassall’s Epithelial
corpuscle reticular
cells Septal vessels
Septum Figure 12–5 Diagram of the
Lymphocytes thymus demonstrating its blood
Capillaries in cortex supply and histological arrangement.
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cells participate in the formation of occluding junc-

tions with each other and with epithelial reticular
cells of the medulla; this isolates the cortex from the
medulla.
These three types of epithelial reticular cells com-
pletely isolate the thymic cortex and thus prevent devel-
oping T cells from contacting foreign antigens. Type II
and III cells as well as bone marrow–derived interdigi-
tating cells (APCs) also present self-antigens, MHC I
molecules, and MHC II molecules to the developing T
cells. Developing T lymphocytes whose TCRs recognize
self-proteins, or whose CD4 or CD8 molecules cannot
recognize the MHC I or MHC II molecules, undergo
H apoptosis before they can leave the cortex. It is inter-
M esting that 98% of developing T cells die in the cortex
and are phagocytosed by resident macrophages, which
are referred to as tingible body macrophages. The
surviving cells enter the medulla of the thymus as naïve
T lymphocytes, and from there (or from the corti-
comedullary junction) they are distributed to secondary
lymphoid organs via the vascular system.
Medulla
The medulla is characterized by the presence of Hassall’s
corpuscles. All thymocytes of the medulla are
immunocompetent T cells.
C
The thymic medulla stains much lighter than the cortex
because its lymphocyte population is not nearly as
profuse and because it houses a large number of
endothelially derived epithelial reticular cells (see Figs.
Figure 12–6 Light micrograph of a lobule of the thymus (×124).
The peripheral cortex (C) stains darker than the central medulla (M) 12-5 and 12-6). There are three types of epithelial retic-
that is distinguished by the presence of Hassall’s corpuscles (H). ular cells in the medulla:
䡲 Type IV cells are found in close association with
type III cells of the cortex and assist in the formation
thymic cortex from the remainder of the body. The of the corticomedullary junction. The nuclei of
nuclei of type I cells are polymorphous and have a these cells have a coarse chromatin network, and
well-defined nucleolus. their cytoplasm is dark-staining and richly endowed
䡲 Type II cells are located in the midcortex. These with tonofilaments.
cells have long, wide, sheath-like processes that 䡲 Type V cells form the cytoreticulum of the medulla.
form desmosomal junctions with each other. Their The nuclei of these cells are polymorphous, with a
processes form a cytoreticulum that subdivides the well-defined perinuclear chromatin network and a
thymic cortex into small, lymphocyte-filled compart- conspicuous nucleolus.
ments. The nuclei of type II cells are large, pale 䡲 Type VI cells compose the most characteristic
structures with little heterochromatin. The cytoplasm feature of the thymic medulla. These large, pale-
is also pale and is richly endowed with tonofilaments. staining cells coalesce around each other, forming
䡲 Type III cells are located in the deep cortex and at whorl-shaped thymic corpuscles (Hassall’s cor-
the corticomedullary junction. The cytoplasm and puscles), whose numbers increase with a person’s
the nuclei of these cells are denser than those of type age (see Figs. 12-5 and 12-6). Type VI cells may
I and type II epithelial reticular cells. The RER of become highly cornified and even calcified. Unlike
type III cells displays dilated cisternae, which is types IV and V, type VI epithelial reticular cells may
indicative of protein synthesis. Type III epithelial be ectodermal in origin. The function of thymic cor-
reticular cells also have wide, sheath-like processes puscles is not known, although they may be the site
that form lymphocyte-filled compartments. These of T lymphocyte cell death in the medulla.
Ch012-X2945.qxd 15/8/06 3:54 PM Page 290
Vascular Supply believed to be released into the bloodstream. These

hormones include thymosin, thymopoietin, thy-
The cortical vascular supply forms a very powerful blood- mulin, and thymic humoral factor, and they facilitate
thymus barrier to prevent developing T cells from T-cell proliferation and the expression of their surface
contacting blood-borne macromolecules. markers. Additionally, hormones from extrathymic
sources, especially the gonads and the pituitary, thyroid,
The thymus receives numerous small arteries, which and suprarenal glands, influence T-cell maturation. The
enter the capsule and are distributed throughout the most potent effects are due to (1) adrenocortico-
organ via the trabeculae between adjacent lobules. steroids, which decrease T-cell numbers in the thymic
Branches of these vessels do not gain access to the cortex; (2) thyroxin, which stimulates the cortical
cortex directly; instead, from the trabeculae they enter epithelial reticular cells to increase thymulin produc-
the corticomedullary junction, where they form capil- tion; and (3) somatotropin, which promotes T-cell
lary beds that penetrate the cortex. development in the thymic cortex.
The capillaries of the cortex are of the continuous
type, possess a thick basal lamina, and are invested by
a sheath of type I epithelial reticular cells that form a
blood-thymus barrier. Thus, the developing T cells of CLINICAL CORRELATIONS
the cortex are protected from contacting blood-borne Congenital failure of the thymus to develop is
macromolecules. However, self-macromolecules are called DiGeorge’s syndrome. Patients with this
permitted to cross the blood-thymus barrier (probably disease cannot produce T cells. Therefore their
controlled by the epithelial reticular cells), possibly to cellularly mediated immune response is non-
eliminate those T cells that are programmed against functional, and these patients die at an early age
self-antigens. The cortical capillary network drains into from infection. Because these patients also lack
small venules in the medulla. parathyroid glands, death also may be caused by
Newly formed, immunologically incompetent T cells tetany.
arriving from the bone marrow leave the vascular supply
at the corticomedullary junction and migrate to the
periphery of the cortex. As these cells mature, they
move deeper into the cortex and enter the medulla as
naïve but immunocompetent cells. They leave the Lymph Nodes
medulla via veins draining the thymus. Lymph nodes are small, encapsulated, oval structures
that are interposed in the path of lymph vessels to serve
Histophysiology of the Thymus as filters for the removal of bacteria and other foreign
substances.
The primary function of the thymus is to instruct
immunoincompetent T cells to achieve Lymph nodes are located in various regions of the body
immunocompetence. but are most prevalent in the neck, in the axilla, in the
groin, along major vessels, and in the body cavities.
The developing T cells proliferate extensively in the Their parenchyma is composed of collections of T and
cortex, begin to express their surface markers, and are B lymphocytes, APCs, and macrophages. These lym-
tested for their ability to recognize self–MHC mole- phoid cells react to the presence of antigens by mount-
cules and self-epitopes. T cells that are unable to rec- ing an immunological response in which macrophages
ognize self–MHC I and self–MHC II molecules are phagocytose bacteria and other microorganisms that
destroyed by being driven into apoptosis. Additionally, enter the lymph node by way of the lymph.
those T lymphocytes whose TCRs are programmed Each lymph node is a relatively small, soft structure
against self-macromolecules are also destroyed. that is less than 3 cm in diameter and that has a fibrous
The process of testing for self-MHC molecules and connective tissue capsule, usually surrounded by
self-epitopes is believed to be a function of type II and adipose tissue (Fig. 12-7). It has a convex surface that is
type III epithelial reticular cells and of bone marrow– perforated by afferent lymph vessels that have valves,
derived dendritic cells, because these three cell types which ensure that lymph from those vessels enters the
express both classes of the epitope–MHC molecule substance of the node. The concave surface of the node,
complex on their surface. the hilum, is the site of arteries and veins entering and
The epithelial reticular cells of the thymus produce exiting the node. Additionally, lymph leaves the node via
at least four hormones that are necessary for the matu- the efferent lymph vessels, which are also located at
ration of T cells. These are probably paracrine the hilum. The efferent lymph vessels have valves that
hormones, acting at short range, although some are prevent regurgitation of lymph back into the node.
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Afferent lymph vessel

Lymphoid nodule
Cortex
Capsule
Subcapsular sinus
Paracortex
Medulla
Medullary sinus
Lymph
Arterial blood
Lymph
Venous blood
Artery
Efferent lymphatic
vessels
Vein
Subcapsular sinus
Postcapillary venules
Capillary bed
Trabecular sinus
Figure 12–7 A typical lymph node. Trabecula
the capsule and trabeculae is a three-dimensional

CLINICAL CORRELATIONS network of reticular connective tissue that forms the
architectural framework of the entire lymph node.
In the presence of antigens or bacteria, lympho- The afferent lymph vessels pierce the capsule on the
cytes of the lymph node rapidly proliferate, and convex surface of the node and empty their lymph into
the node may increase to several times its normal the subcapsular sinus, which is located just deep to
size, becoming hard and palpable to the touch. the capsule. This sinus is continuous with the cortical
sinuses (paratrabecular sinuses) that parallel the tra-
beculae and deliver the lymph into the medullary
Histologically, a lymph node is subdivided into three sinuses, eventually to enter the efferent lymphatic
regions: cortex, paracortex, and medulla. All three regions vessels. These sinuses have a network of stellate retic-
have a rich supply of sinusoids, enlarged endothelium- ular cells whose processes contact those of other cells
lined spaces through which lymph percolates. and the endothelium-like simple squamous epithelium.
Macrophages, attached to the stellate reticular cells,
Lymph Node Cortex avidly phagocytose foreign particulate matter. Addition-
ally, lymphoid cells can enter or leave the sinusoids by
The cortex of the lymph node is subdivided into passing between their squamous cell lining.
compartments that house B cell–rich primary and
secondary lymphoid nodules. Lymphoid Nodules
The dense, irregular, collagenous connective tissue There are two types of lymphoid nodules: primary and
capsule sends trabeculae into the substance of the secondary. Secondary lymphoid nodules have a germinal
lymph node, subdividing the outer region of the cortex center.
into incomplete compartments that extend to the vicinity
of the hilum (Fig. 12-8; also see Fig. 12-7). The capsule is The incomplete compartments within the cortex house
thickened at the hilum, and as vessels enter the sub- primary lymphoid nodules, which are spherical
stance of the node, they are surrounded by a connective aggregates of B lymphocytes (both virgin B cells and B
tissue sheath derived from the capsule. Suspended from memory cells) that are in the process of entering or
Ch012-X2945.qxd 15/8/06 3:54 PM Page 292
undergo hypermutation to become more proficient at

S forming antibodies against the antigen. Cells that do not
synthesize the proper sIgs are forced into apoptosis and
are destroyed by macrophages. The newly formed cen-
trocytes that are permitted to survive enter the apical
C light zone, where they become either B memory cells
or plasma cells and subsequently leave the secondary
follicle.
Paracortex
G
The region of the lymph node between the cortex and
the medulla is the paracortex. It houses mostly T cells
and is the thymus-dependent zone of the lymph node.
APCs (e.g., Langerhans cells from skin or dendritic cells

from the mucosa) migrate to the paracortex region of
the lymph node to present their epitope–MHC II
complex to TH cells. If TH cells become activated, they
proliferate, increasing the width of the paracortex to
such an extent that it may intrude deep into the
medulla. Newly formed T cells then migrate to the
medullary sinuses, leave the lymph node, and proceed
P to the area of antigenic activity.
High endothelial venules (HEVs) are located in
the paracortex. Lymphocytes leave the vascular supply
by migrating between the cuboidal cells of this unusual
endothelium and enter the substance of the lymph
node. B cells migrate to the outer cortex, whereas most
T cells remain in the paracortex.
Figure 12–8 Light micrograph of the lymph node cortex (×132), The lymphocyte plasma membrane expresses surface
displaying the subcapsular sinus (S), a secondary lymphoid nodule molecules, known as selectins, that aid the cell in recog-
with its corona (C), germinal center (G), and the paracortex (P).
nizing the endothelial cells of HEVs and permit it to roll
along the surface of these cells. When the lymphocyte
contacts additional signaling molecules that are located
leaving the lymph node (see Figs. 12-7 and 12-8). Fre- on the endothelial cell plasmalemma, the selectins
quently, the centers of the lymphoid nodules are stained become activated, bind firmly to the endothelial cell, and
pale and house germinal centers, and these lymph stop the rolling action of the lymphocyte. Then, via dia-
nodules are then known as secondary lymphoid pedesis, the lymphocyte migrates between the cuboidal
nodules. Secondary lymphoid nodules form only in endothelial cells to leave the lumen of the postcapillary
response to an antigenic challenge; it is believed that venule and enter the lymph node parenchyma.
they are the sites of B memory cell and plasma cell
generation. Medulla
The region of the lymphoid nodule peripheral to the
germinal center is composed of a dense accumulation The medulla is composed of large, tortuous lymph
of small lymphocytes that are migrating away from their sinuses surrounded by lymphoid cells that are organized
site of origin within the germinal center. This periph- in clusters known as medullary cords.
eral region is called the corona (mantle).
Germinal centers display three zones: a dark zone, a The cells of the medullary cords (lymphocytes, plasma
basal light zone, and an apical light zone. The dark cells, and macrophages) are enmeshed in a network of
zone is the site of the intense proliferation of closely reticular fibers and reticular cells (Fig. 12-9; also see
packed B cells (that do not possess sIgs). These cells, Fig. 12-7). The lymphocytes migrate from the cortex to
know as centroblasts, migrate into the basal light enter the medullary sinuses, from which they enter the
zone, express sIgs, switch immunoglobulin class, and efferent lymphatic vessels to leave the lymph node. His-
are known as centrocytes. These cells are exposed tological sections of the medulla also display the pres-
to antigen-bearing follicular dendritic cells and ence of trabeculae arising from the thickened capsule
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As lymph enters the lymph node, the flow rate is re-

duced, which gives the macrophages that reside in (or
have their processes intrude into) the sinuses more time
to phagocytose foreign particulate matter. In this fashion,
99% of the impurities found in lymph are removed.
Lymph nodes also function as sites of antigen recog-
nition, because APCs that contact antigens migrate to
the nearest lymph node and present their epitope–
MHC complex to lymphocytes. Additionally, antigens
percolating through the lymph node are trapped by
follicular dendritic cells, and lymphocytes that are in
S the lymph node or migrate into the lymph node recog-
nize the antigen.
If an antigen is recognized and a B cell becomes acti-
vated, that B cell migrates to a primary lymphoid
nodule and proliferates, forming a germinal center, and
C the primary lymphoid nodule becomes known as a sec-
ondary lymphoid nodule. The newly formed cells
differentiate into B memory and plasma cells, leave
the cortex, and form the medullary cords. About 10%
of the newly formed plasma cells stay in the medulla
T and release antibodies into the medullary sinuses. The
remainder of the plasma cells enter the sinuses and go
to the bone marrow, where they continue to manufac-
ture antibodies until they die. Some B memory cells stay
in the primary lymphoid nodules of the cortex, but most
leave the lymph node to take up residence in other sec-
ondary lymphatic organs of the body. Therefore, if there
is a second exposure to the same antigen, a large
number of memory cells are available so that the body
Figure 12–9 Light micrograph of the lymph node medulla can mount a prompt and potent secondary response.
(×132) with its medullary sinusoids (S), medullary cords (C), and
trabecula (T).
of the hilum, conveying blood vessels into and out of
the lymph node. Lymph nodes are located along the paths of
lymph vessels and form a chain of lymph nodes
Vascularization of the Lymph Node so that lymph flows from one node to the next.
For this reason, infection can spread and malig-
The arterial supply enters the substance of lymph nodes nant cells may metastasize through a chain of
at the hilum. The vessels course through the medulla nodes to remote regions of the body.
within trabeculae and become smaller as they repeat-
edly branch. Eventually, they lose their connective
tissue sheath, travel within the substance of medullary
cords, and contribute to the formation of the medullary Spleen
capillary beds. The small branches of the arteries con-
The spleen, the largest lymphoid organ in the body, is
tinue in the medullary cords until they reach the cortex.
invested by a collagenous connective tissue capsule. It
Here they form a cortical capillary bed, which is drained
has a convex surface and a concave aspect known as the
by postcapillary venules. Blood from postcapillary
hilum.
venules drains into larger veins, which exit the lymph
node at the hilum. The spleen, the largest lymphoid organ in the body, is
located in the peritoneum in the upper left quadrant of
Histophysiology of Lymph Nodes the abdominal cavity. Its dense, irregular fibroelastic
connective tissue capsule, occasionally housing smooth
Lymph nodes filter lymph and act as sites for antigen
muscle cells, is surrounded by visceral peritoneum.
recognition.
The simple squamous epithelium of the peritoneum
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provides a smooth surface for the spleen. The spleen The spleen has a convex surface as well as a concave
functions not only in the immunological capacity of anti- aspect known as the hilum. The capsule of the spleen
body formation and T-cell and B-cell proliferation but is thickened at the hilum, and it is here where arteries
also as a filter of the blood in destroying old erythrocytes. and their accompanying nerve fibers enter and veins
During fetal development, the spleen is a hemopoietic and lymph vessels leave the spleen.
organ; if necessary, it can resume that function in the The trabeculae, arising from the capsule, carry
adult. Additionally, in some animals (but not in humans), blood vessels into and out of the parenchyma of the
the spleen acts as a reservoir of red blood cells, which spleen (Fig. 12-10). Histologically, the spleen has a
may be released into circulation as the need arises. three-dimensional network of reticular fibers and
Lymphoid nodule
Capsule
RED PULP
Pulp cords
Venous sinusoids
WHITE PULP
Germinal center
Corona
Periarterial lymphatic sheath
Trabecula
Trabecular vein
Venous sinusoid Venous sinusoid
Terminal arterial capillary PENICILLAR ARTERY
Terminal arterial capillary
Sheathed arteriole
Sheathed arteriole
Pulp arteriole
Lymphocytes
LYMPHOID NODULE Marginal zone
Germinal center
Periarterial lymphatic sheath
Corona
Central artery Marginal zone
Marginal sinusoid
Figure 12–10
Schematic diagram of the spleen. Top, Low-magnification view of white pulp and red pulp. Bottom, Higher-magnification view of the central
arteriole and its branches.
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Capsule
Germinal
center
Terminal
arterial White pulp
capillary
Ca
Sinusoid
Trabecular
vein Marginal
sinus
Trabecula
Trabecular
Ln artery
Red pulp Open

circulation
Pulp cord Closed
circulation
Pulp vein
Figure 12–12 Open and closed circulation in the spleen.
Ln titia of these vessels that left the trabeculae become

loosely organized, and they become infiltrated by a
sheath of lymphocytes, the periarterial lymphatic
sheath (PALS). Because this vessel occupies the center
of the PALS, it is called the central artery.
Figure 12–11 Silver-stained photomicrograph of the reticular At its termination, the central splenic artery loses its
fiber architecture of the spleen (×132). Note the capsule (Ca) and lymphatic sheath and subdivides into several short, par-
lymphoid nodule (Ln). allel branches, known as penicillar arteries, which
enter the red pulp. The penicillar arteries have three
regions: (1) the pulp arteriole, (2) the sheathed arte-
associated reticular cells. The reticular fiber network riole (a thickened region of the vessel surrounded by a
is attached to the capsule as well as to the trabeculae sheath of macrophages termed the Schweigger-Seidel
and forms the architectural framework of this organ sheath), and (3) the terminal arterial capillaries.
(Fig. 12-11). Although it is known that the terminal arterial capil-
The interstices of the reticular tissue network are laries deliver their blood into the splenic sinuses, the
occupied by venous sinuses, trabeculae conveying method of delivery is not completely understood,
blood vessels, and the splenic parenchyma. The cut which has prompted the formulation of three theories
surface of a fresh spleen shows gray areas surrounded of spleen circulation: (1) closed circulation, (2) open
by red areas; the former are called white pulp and the circulation, and (3) a combination of the first two
latter are known as red pulp. Central to the apprecia- theories.
tion of the organization and function of the spleen is an Proponents of the closed circulation theory
understanding of its blood supply. believe that the endothelial lining of the terminal arte-
rial capillaries is continuous with the sinus endothelium
Vascular Supply of the Spleen (Fig. 12-12). Investigators who subscribe to the open
circulation theory believe that the terminal arterial
The spleen is supplied by the splenic artery and is capillaries terminate prior to reaching the sinusoids, and
drained by the splenic vein; both vessels enter and leave blood from these vessels percolates through the red
the spleen at the hilum. pulp into the sinuses. Still other investigators believe
that some vessels connect to the sinusoids and that
The splenic artery branches repeatedly as it pierces the other vessels terminate as open-ended channels in the
connective tissue capsule at the hilum of the spleen. red pulp, suggesting that the spleen has both open and
Branches of these vessels, trabecular arteries, are closed systems of circulation.
conveyed into the substance of the spleen by trabecu- Splenic sinuses are drained by small veins of the
lae of decreasing sizes (see Fig. 12-10). When the tra- pulp, which are tributaries of larger and larger veins
becular arteries are reduced to about 0.2 mm in that merge to form the splenic vein, a tributary of the
diameter, they leave the trabeculae. The tunica adven- portal vein.
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White Pulp and Marginal Zone red pulp (Fig. 12-14; see Figs. 12-10 and 12-13). This
zone is composed of plasma cells, T and B lymphocytes,
The white pulp is composed of the periarterial lymphatic macrophages, and interdigitating dendritic cells
sheath housing T cells, and lymphoid nodules housing (APCs). Additionally, numerous small vascular chan-
B cells. The marginal zone houses B cells that are nels, marginal sinuses, are present in the marginal
specialized to recognize thymic-independent antigens. zone, especially surrounding lymphoid nodules. Slender
blood vessels, radiating from the central arteriole, pass
The structure of the white pulp is closely associated into the red pulp, recur, and deliver their blood into the
with the central arteriole. The PALS that surrounds the marginal sinuses.
central arteriole is composed of T lymphocytes. Fre- Because the spaces between the endothelial cells of
quently, enclosed within the PALS are lymphoid these sinuses may be as wide as 2 to 3 µm, it is here that
nodules, which are composed of B cells and displace blood-borne cells, antigens, and particulate matter have
the central arteriole to a peripheral position. Lymphoid their first free access to the parenchyma of the spleen.
nodules may display germinal centers, indicative of Thus the following events occur at the marginal zone:
antigenic challenge (Fig. 12-13; see Fig. 12-10). The
PALS and lymphoid nodules constitute the white pulp, 1 APCs sample the material traveling in blood, search-
and as in the lymph node, the T and B cells are sta- ing for antigens.
tioned in specific locations. 2 Macrophages attack microorganisms present in the
The white pulp is surrounded by a marginal zone, blood.
100 µm in width, that separates the white pulp from the 3 The circulating pool of T and B lymphocytes leaves
the bloodstream to enter its preferred locations
within the white pulp.
4 Lymphocytes come into contact with the inter-
digitating dendritic cells; if they recognize their
epitope-MHC complex, the lymphocytes initiate an
immune response within the white pulp.
5 B cells recognize and react to thymus-independent
antigens (such as polysaccharides of bacterial cell
walls).
Red Pulp
The red pulp of the spleen is composed of splenic
sinuses and splenic cords (of Billroth).
The red pulp resembles a sponge, in that the spaces

within the sponge represent the sinuses and the sponge
material among the spaces denotes the splenic cords
(see Fig. 12-10).
G The endothelial lining of splenic sinuses is unusual
in that its cells are fusiform, resembling staves of a
barrel (Fig. 12-15). Moreover, spaces (2 to 3 µm wide)
between adjoining cells are common. The sinuses are
surrounded by reticular fibers (continuous with those of
the splenic cords) that wrap around the sinuses as indi-
M vidual, thin strands of thread. The reticular fibers are
arranged perpendicular to the longitudinal axis of the
sinuses and are coated by basal lamina. Thus, splenic
sinuses have a discontinuous basal lamina.
The splenic cords are composed of a loose network
of reticular fibers, whose interstices are permeated by
extravasated blood. The reticular fibers are enveloped
by stellate reticular cells, which isolate the type III
Figure 12–13 Light micrograph of the white pulp and marginal collagen fibers from blood, preventing a platelet reac-
zone of the spleen (×116). G, germinal center; M, marginal zone. tion to the collagen (coagulation). Macrophages are
Note the central artery (arrow). particularly numerous in the vicinity of the sinusoids.
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Figure 12–14 Scanning electron micrograph of

the marginal zone and adjoining red pulp of the
spleen (×680). Note the periarterial flat reticular cells
(arrows). A, central artery; BC, marginal zone bridg-
ing channel; MZ, marginal zone; PA, penicillar artery;
RP, red pulp; S, venous sinus. (From Sasou S, Sugai
T: Periarterial lymphoid sheath in the rat spleen: A
light, transmission, and scanning electron micro-
scopic study. Anat Rec 232:15-24, 1992.)
Histophysiology of the Spleen Macrophages kill aged platelets and monitor eryth-
rocytes as they migrate from the splenic cords between
The spleen filters the blood, forms lymphoid cells, the endothelial cells into the sinuses (Fig. 12-16).
eliminates or inactivates blood-borne antigens, destroys Because older erythrocytes lose their flexibility (as do
aged platelets and erythrocytes, and participates in erythrocytes infected by the malarial parasite), they
hemopoiesis. cannot penetrate the spaces between the endothelial
cells and are phagocytosed by macrophages. The phago-
As blood enters the marginal sinuses of the marginal cytes also monitor the surface coats of red blood cells,
zone, it flows past a macrophage-rich zone. These cells which are destroyed in the following manner:
phagocytose blood-borne antigens, bacteria, and other
1 Old erythrocytes lose sialic acid residues from their
foreign particulate matter. Material that is not elimi-
surface macromolecules, exposing galactose moieties.
nated in the marginal zone is cleared in the red pulp at
2 Galactose moieties that are exposed on erythrocyte
the periphery of the splenic sinuses.
membranes induce their phagocytosis.
Lymphoid cells are formed in the white pulp in
3 Erythrocytes phagocytosed by macrophages are
response to an antigenic challenge. B memory cells and
destroyed within phagosomes.
plasma cells are formed in lymphoid nodules, whereas
4 Hemoglobin is catabolized into its heme and globin
T cells of various subcategories are formed in the PALS.
portions.
The newly formed B and T cells enter the marginal
5 The globin moiety is disassembled into its constituent
sinuses and migrate to the site of antigenic challenge or
amino acids, which become part of the circulating
become part of the circulating pool of lymphocytes.
amino-acid pool of the blood.
Some plasma cells may stay in the marginal zone, man-
6 Iron molecules are conveyed to the bone marrow by
ufacture antibodies, and release immunoglobulins into
transferrin and are used in the formation of new red
the marginal sinuses. Most plasma cells, however,
blood cells.
migrate to the bone marrow to manufacture and release
7 Heme is converted to bilirubin and excreted by the
their antibodies into the bone marrow sinuses.
liver in bile.
Soluble blood-borne antigens are inactivated by the
8 Macrophages also phagocytose damaged or defunct
antibodies formed against them, whereas bacteria
platelets and neutrophils.
become opsonized and are eliminated by macrophages
or neutrophils. Virus-transformed cells are killed by During the second trimester of gestation, the spleen
CTLs formed in the PALS of the white pulp. actively participates in hemopoiesis; after birth,
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Figure 12–15 Scanning electron micrograph

of sinusoidal lining cells bounded by splenic cords
(×500). C, splenic cords; S, venous sinuses; Sh,
sheathed arteriole. (From Leeson TS, Leeson CR,
Paparo AA: Text-Atlas of Histology. Philadelphia,
WB Saunders, 1988.)
however, blood cell formation occurs only in the bone Mucosa-Associated

marrow. If the necessity arises, the spleen can resume Lymphoid Tissue
its hemopoietic function.
Mucosa-associated lymphoid tissue (MALT) is com-
posed of a nonencapsulated, localized lymphocyte infil-
tration and lymphoid nodules in the mucosa of the
gastrointestinal, respiratory, and urinary tracts. The best
examples of these accumulations are those associated
Because the spleen is a friable (fragile) organ, with the mucosa of the gut: gut-associated lymphoid
major trauma to the upper left abdominal quad- tissue (GALT), bronchus-associated lymphatic
rant may cause rupture of the spleen. In severe tissue (BALT), and the tonsils.
cases, the spleen may be removed surgically,
without compromising a person’s life. Aged red Gut-Associated Lymphoid Tissue
blood cells are then phagocytosed by macro-
phages of the liver and bone marrow. The most prominent accumulation of GALT is located in
the ileum and is known as Peyer’s patches.
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Bronchus-Associated
Lymphoid Tissue
BALT is similar to Peyer’s patches, except that it is
located in the walls of bronchi, especially in regions
where bronchi and bronchioles bifurcate. As in GALT,
the epithelial cover over these lymphoid nodules
changes from a pseudostratified ciliated columnar with
goblet cells to M cells.
Afferent lymph vessels are absent, although lymph
drainage has been demonstrated. The rich vascular
supply of BALT indicates its possible systemic as well
as localized role in the immune process. Most of the
cells are B cells, although APCs and T cells are present.
Lymphocytes destined to enter BALT have homing
receptors that are specific for the HEVs of this lym-
phoid tissue.
The Tonsils
The tonsils (palatine, pharyngeal, and lingual) are
incompletely encapsulated aggregates of lymphoid
nodules that guard the entrance to the oral pharynx.
Because of their locations, the tonsils are interposed
into the path of airborne and ingested antigens. They
react to these antigens by forming lymphocytes and
mounting an immune response.
Figure 12–16 Electron micrograph of a macrophage containing The bilateral palatine tonsils are located at the
phagocytosed materials, including a crystalloid body. Mp, macro- boundary of the oral cavity and the oral pharynx,
phage; Mit, cell undergoing mitosis; Lyc, lymphocyte; Eb, erythro-
blast; Ret, reticular fibers in the interstitial spaces; Ri, ribosome.
between the palatoglossal and the palatopharyngeal
(From Rhodin JAG: An Atlas of Ultrastructure. Philadelphia, WB folds. The deep aspect of each palatine tonsil is isolated
Saunders, 1963.) from the surrounding connective tissue by a dense,
fibrous capsule. The superficial aspect of the tonsils
is covered by a stratified squamous nonkeratinized
epithelium that dips into the 10 to 12 deep crypts that
GALT is composed of lymphoid follicles along the invaginate the tonsilar parenchyma. The crypts fre-
length of the gastrointestinal tract. Most of the lym- quently contain food debris, desquamated epithelial
phoid follicles are isolated from each other; in the cells, dead leukocytes, bacteria, and other antigenic
ileum, however, they form lymphoid aggregates, known substances.
as Peyer’s patches (Fig. 12-17). The lymphoid follicles The parenchyma of the tonsil is composed of numer-
of Peyer’s patches are composed of B cells surrounded ous lymphoid nodules, many of which display germinal
by a looser region of T cells and numerous APCs. centers, indicative of B-cell formation.
Although the ileum is lined by a simple columnar The single pharyngeal tonsil is in the roof of the
epithelium, the regions immediately adjacent to the nasal pharynx. It is similar to the palatine tonsils, but its
lymphoid follicles are lined by squamous-like cells, incomplete capsule is thinner. Instead of crypts, the
known as M cells (microfold cells). It is believed that pharyngeal tonsil has shallow, longitudinal infoldings
M cells capture antigens and transfer them (without called pleats. Ducts of seromucous glands open into
first processing them into epitopes) to macrophages the base of the pleats. Its superficial surface is covered
located in Peyer’s patches (see Chapter 17). by a pseudostratified ciliated columnar epithelium that
Peyer’s patches have no afferent lymphatic vessels, is interspersed with patches of stratified squamous
but they do have efferent lymph drainage. They receive epithelium (Fig. 12-18).
small arterioles that form a capillary bed, drained by The parenchyma of the pharyngeal tonsil is com-
HEVs. Lymphocytes destined to enter Peyer’s patches posed of lymphoid nodules, some of which have germi-
have homing receptors that are specific for the HEVs nal centers. When this type of tonsil is inflamed, it is
of GALT. called the adenoid.
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Figure 12–17 Transmission elec-

tron micrographs. A, ALPA vessel (L)
of the interfollicular area full of lym-
phocytes that has an intraendothelial
channel that includes lymphocytes
(arrow) in the endothelial wall
(×3000). Note the postcapillary high
endothelium venula (HEV). B-D,
Ultrathin serial sections that docu-
ment various stages of lymphoctye
migration through an intraendothelial
channel composed of one (1) and
two (2) endothelial cells (×9000). 艎,
lymphocyte. (From Azzali G, Arcari
MA: Ultrastructural and three-
dimensional aspects of the lymphatic
vessels of the absorbing peripheral lym-
phatic apparatus in Peyer’s patches of
the rabbit. Anat Rec 258:76; 2000.)
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The lingual tonsil is located on the dorsal surface

of the posterior one third of the tongue and is covered,
on its superficial aspect, by a stratified squamous
E nonkeratinized epithelium. The deep aspect of the
lingual tonsil has a flimsy capsule that separates it from
the underlying connective tissue. The tonsil has numer-
ous crypts, whose bases receive the ducts of mucous
minor salivary glands. The parenchyma of the lingual
tonsil is composed of lymphoid nodules, which fre-
quently have germinal centers.
Ln
Figure 12–18 Light micrograph of a lymphoid nodule (Ln) of

the pharyngeal tonsil, displaying its pseudostratified ciliated colum-
nar epithelium (E) and a germinal center of the secondary nodule
(×132).
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13 䡲䡲䡲
Endocrine System
The endocrine system regulates metabolic activities in their target cells (e.g., short-term and long-term
certain organs and tissues of the body, thereby helping effects). Hormones are classified into three types based
to bring about homeostasis. The autonomic nervous on their composition:
system regulates certain organs and tissues via impulses 䡲 Proteins and polypeptides—mostly water-soluble
that initiate the release of neurotransmitter substances, (e.g., insulin, glucagon, and follicle-stimulating
that produce rapid responses in the tissues that are hormone [FSH]).
affected. However, the endocrine system produces a 䡲 Amino-acid derivatives—mostly water-soluble (e.g.,
slow and diffused effect via chemical substances called thyroxine and epinephrine).
hormones, which are released into the bloodstream 䡲 Steroid and fatty acid derivatives—mostly lipid-
to influence target cells at remote sites. Although the soluble (e.g., progesterone, estradiol, and testosterone).
nervous and endocrine systems function in different
ways, the two systems interact to modulate and coordi- Once a hormone has been released into the blood-
nate the metabolic activities of the body. stream and has arrived in the vicinity of its target cells,
The endocrine system consists of ductless glands, it first binds to specific receptors on (or in) the target
distinct clusters of cells within certain organs of the cell. Receptors for certain hormones (mostly protein
body, and endocrine cells, isolated in the epithelial and peptide hormones) are located on the plas-
lining of the digestive tract and in the respiratory malemma (cell-surface receptors) of the target cell,
system. (The latter are discussed in Chapters 17 and 15, whereas other receptors are located in the cytoplasm
respectively.) The endocrine glands, the subject of and bind only to hormones that have diffused through
this chapter, are abundantly and richly vascularized so the plasmalemma. The binding of a hormone to its
that their secretory product may be released into receptor communicates a message to the target cell, ini-
slender connective tissue spaces between cells and the tiating signal transduction, or translation of the signal
capillary beds from which they enter the bloodstream. into a biochemical reaction.
The endocrine glands include the pineal body, the Thyroid and steroid hormones bind to cytoplasmic
pituitary gland, the thyroid gland, the parathyroid receptors. The resulting hormone-receptor complex
glands, and the suprarenal glands. Unlike the endo- translocates to the nucleus, where it binds directly to
crine glands, which are ductless, the various exocrine deoxyribonucleic acid (DNA) close to a promoter site,
glands (discussed in other chapters) empty their secre- thereby stimulating gene transcription. However, at
tions in a duct system and exert only local effects. least some steroid hormones may bind to receptors that
are located in the target cell plasma membrane, and
thus the hormone’s actions may be mediated directly
HORMONES without gene transcription or protein synthesis. Neither
the hormone nor the receptor alone can initiate the
Hormones are chemical messengers that are produced by target cell response.
endocrine glands and delivered by the bloodstream to Hormones that bind to cell-surface receptors located
target cells or organs. in the plasmalemma use several different mechanisms
to elicit a response in their target cells. In each instance,
The chemical nature of a hormone dictates its mecha- the hormone-receptor complex is believed to induce a
nism of action. Most hormones elicit several effects on protein kinase to phosphorylate certain regulatory
303
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304 䡲䡲䡲 Chapter 13 䡲 Endocrine System
proteins, thereby generating a biological response to the from neural ectoderm as a downgrowth of the dien-
hormone. For example, some hormone-receptor com- cephalon. Subsequently, both the adenohypophysis and
plexes stimulate adenylate cyclase to synthesize cyclic the neurohypophysis are joined and encapsulated into
adenosine monophosphate (cAMP), which stimulates a single gland. Because each subdivision has a distinctly
protein kinase A in the cytosol. In such an instance, different embryonic origin, however, the cellular con-
cAMP acts as a second messenger. Several additional stituents and the functions of each differ.
second messengers have been identified, including: (1) The pituitary gland lies below the hypothalamus of
cyclic guanosine 3¢,5¢-monophosphate (cGMP), (2) the brain, to which it is connected extending inferiorly
metabolites of phosphatidylinositol, (3) calcium from the diencephalon. It sits in the hypophyseal fossa,
ions, and (4) sodium ions (in neurons). a bony depression in the sella turcica of the sphenoid
Some hormone receptor complexes are associated bone that is lined by dura mater and covered over by
with guanosine triphosphate-binding proteins (G pro- a portion of the dura mater called the diaphragma
teins), which couple the receptor to the hormone- sellae. The gland measures approximately 1 cm by 1 to
induced responses of the target cells. The receptors for 1.5 cm; it is 0.5 cm thick and weighs about 0.5 g in men
epinephrine, thyroid-stimulating hormone (TSH), and and slightly more in women.
serotonin, for example, use G proteins to activate a The pituitary is connected to the brain by neural
second messenger, which elicits a metabolic response. pathways; it also has a rich vascular supply from vessels
Other hormones, such as insulin and growth hormone, that supply the brain, attesting to the intercoordination
use catalytic receptors that activate protein kinases to of the two systems in maintaining a physiological
phosphorylate target proteins. balance. Indeed, secretion of nearly all of the hormones
Once a hormone activates its target cell, an inhibitory produced by the pituitary gland is controlled by either
signal is generated and returned to the endocrine gland hormonal or nerve signals from the hypothalamus. In
(feedback mechanism), either directly or indirectly, addition to controlling the pituitary, the hypothalamus
to halt hormone secretion. The feedback mechanism also receives input from various areas of the central
also operates in another way: When the hormone level nervous system (i.e., information regarding plasma cir-
is inadequate to elicit a sufficient metabolic response in culating levels of electrolytes and hormones) and con-
the target, a positive feedback signal is released, travels trols the autonomic nervous system; therefore, the
to the endocrine gland, and initiates an increase in hypothalamus is the brain center for the maintenance
hormone secretion. Through the feedback mechanism, of homeostasis.
therefore, regulation of the endocrine glands maintains Within each subdivision of the hypophysis are
homeostasis. various regions having specialized cells that release dif-
Many of the hormones that circulate in the blood- ferent hormones (Figs. 13-1 and 13-2). The subdivisions
stream are in oversupply. They are usually bound to of the hypophysis and the names of the regions are:
plasma proteins, which makes them biologically inac- 䡲 Adenohypophysis (anterior pituitary)
tive, but they can be released from their bound state 䡲 Pars distalis (pars anterior)
quickly, thus becoming active. Hormones become per- 䡲 Pars intermedia
manently inactivated in their target tissue; additionally,
䡲 Pars tuberalis
they may be degraded and destroyed in the liver and 䡲 Neurohypophysis (posterior pituitary)
kidneys.
䡲 Median eminence
䡲 Infundibulum
䡲 Pars nervosa
PITUITARY GLAND (HYPOPHYSIS)
Interposed between the anterior and posterior lobes
The pituitary gland, composed of portions derived from of the pituitary gland are remnants of Rathke’s pouch
oral ectoderm and from neural ectoderm, produces (epithelial cells), which surround an amorphous colloid.
hormones that regulate growth, metabolism, and The pars tuberalis forms a sleeve around the stem of the
reproduction. infundibulum.
The pituitary gland, or hypophysis, is an endocrine

gland that produces several hormones that are respon- Blood Supply and Control
sible for regulating growth, reproduction, and metabo- of Secretion
lism. It has two subdivisions, which develop from
The hypophyseal portal system of veins delivers
different embryologic sources: (1) the adenohypoph-
neurosecretory hormones from the primary capillary
ysis develops from an evagination of the oral ectoderm
plexus of the median eminence to the secondary
(Rathke’s pouch) that lines the primitive oral cavity
capillary plexus of the pars distalis.
(stomadeum), and (2) the neurohypophysis develops
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Chapter 13 䡲 Endocrine System ■ ■ ■ 305
Neurosecretory cells
Paraventricular located in hypothalamus
nuclei (oxytocin) secrete releasing and
inhibitory hormones
Hypothalamus
Supraoptic
nuclei (ADH)
Median eminence
Secretion
Water
absorption
Hypophyseal
Portal system stalk
Adrenal Pars Pars

cortex distalis nervosa
ACTH Kidney
ADH
Secretion TSH Basophil

Oxytocin Contraction
Acidophil
Thyroid
Spermato- FSH Uterus

genesis
LH
Androgen
secretion
Testis Growth hormone

via somatomedins
Prolactin
Follicular Mammary
development: Gland
estrogen Myoepithelial
secretion contraction
Ovulation:
progesterone
secretion
Ovary
Mammary Adipose Muscle Bone

gland tissue
Growth
Milk Elevation of free Hyperglycemia

secretion fatty acids
Figure 13–1 The pituitary gland and its target organs. ACTH, adrenocorticotropic hormone; ADH, antidiuretic hormone; FSH, follicle-
stimulating hormone; LH, luteinizing hormone; TSH, thyroid-stimulating hormone.
The arterial supply for the pituitary gland is provided supply the posterior lobe, although they also send a few
from two pairs of vessels that arise from the internal branches to the anterior lobe.
carotid artery (see Fig. 13-2). The superior hypo- Hypophyseal portal veins drain the primary
physeal arteries supply the pars tuberalis and the capillary plexus of the median eminence, which deliv-
infundibulum. They also form an extensive capillary ers its blood into the secondary capillary plexus,
network, the primary capillary plexus, in the median located in the pars distalis (see Fig. 13-2). The capillar-
eminence. Inferior hypophyseal arteries primarily ies of both plexuses axe fenestrated. Hypothalamic
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Hypothalamic neurosecretory Hypothalamic neurosecretory

cells: producing vasopressin cells: releasing and inhibiting
and oxytocin hormone production
Primary capillary Median eminence

plexus
Pars tuberalis
Hypothalamohypo-
physeal tract
Superior hypophyseal
artery Infundibulum (stalk)
Portal system of veins

carrying releasing and Inferior hypophyseal
inhibiting hormones artery
released in the median
eminence
Herring bodies (storing
Secondary capillary ADH and oxytocin)
plexus
Pars nervosa
Chromophil
Hypophyseal veins
Pars distalis
Figure 13–2 The pituitary gland
and its circulatory system. ADH, anti-
diuretic hormone.
neurosecretory hormones, manufactured in the 䡲 Corticotropin-releasing hormone (CRH) stimu-

hypothalamus and stored in the median eminence, lates the release of adrenocorticotropin.
enter the primary capillary plexus and are drained by 䡲 Somatotropin-releasing hormone (SRH) stimu-
the hypophyseal portal veins, which course through the lates the release of somatotropin (growth hormone).
infundibulum and connect to the secondary capillary 䡲 Luteinizing hormone–releasing hormone
plexus in the anterior lobe. Here the neurosecretory (LHRH) stimulates the release of luteinizing
hormones leave the blood to stimulate or inhibit the hormone (LH) and FSH.
parenchymal cells. Thus, the hypophyseal portal system 䡲 Prolactin-releasing hormone (PRH) stimulates
is the vascular supply system that is used for hormonal the release of prolactin.
regulation of the pars distalis by the hypothalamus. 䡲 Prolactin inhibitory factor (PIF) inhibits prolactin
Axons of neurons that originate in various portions secretion.
of the hypothalamus terminate around these capillary
The physiological effects of pituitary hormones are
plexuses. The endings of these axons differ from other
summarized in Table 13-1.
axons of the body, because instead of delivering a
signal to another cell, they liberate either releasing
or inhibiting hormones (factors) directly into the Adenohypophysis
primary capillary bed. These hormones are taken by the The anterior pituitary gland, the adenohypophysis,
hypophyseal portal system and delivered to the second- develops from Rathke’s pouch, a diverticulum of the
ary capillary bed of the pars distalis, where they regu- oral ectoderm. The adenohypophysis consists of the
late secretion of various anterior pituitary hormones. pars distalis, the pars intermedia, and the pars tuberalis.
The following are the main releasing and inhibitory
hormones (factors): Pars Distalis
䡲 Thyroid-stimulating hormone–releasing hormone
The parenchymal cells of the pars distalis consist of the
(thyrotropin-releasing hormone [TRH]) stimu-
chromophils and chromophobes.
lates the release of TSH.
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TABLE 13–1 Physiological Effects of Pituitary Hormones
Hormon Releasing/Inhibiting Function
Pars Distalis
Somatotropin (growth hormone) Releasing: SRH Generalized effect on most cells is to increase
Inhibiting: Somatostatin metabolic rates, stimulate liver cells to release
somatomedins (insulin-like growth factors I and
II), which increases proliferation of cartilage and
assists in growth in long bones
Prolactin Releasing: PRH Promotes development of mammary glands during

Inhibiting: PIF pregnancy; stimulates milk production after
parturition (prolactin secretion is stimulated by
suckling)
Adrenocorticotropic hormone Releasing: CRH Stimulates synthesis and release of hormones

(ACTH, corticotropin) (cortisol and corticosterone) from suprarenal
cortex
Follicle-stimulating hormone Releasing: LHRH Stimulates secondary ovarian follicle growth and
(FSH) Inhibiting: Inhibin (in estrogen secretion; stimulates Sertoli cells in
males) seminiferous tubules to produce androgen-
binding protein
Luteinizing hormone (LH) Releasing: LHRH Assists FSH in promoting ovulation, formation of
the corpus luteum, and secretion of progesterone
and estrogen, forming a negative feedback to the
hypothalamus to inhibit LHRH in women
Interstitial cell-stimulating Stimulates Leydig cells to secrete and release

hormone (ICSH) in men testosterone, which forms a negative feedback to
the hypothalamus to inhibit LHRH in men
Thyroid-stimulating hormone Releasing: TRH Stimulates synthesis and release of thyroid

(TSH) (thyrotropin) Inhibiting: Negative hormone, which increases metabolic rate
feedback suppresses
via the central nervous
system
Pars Nervosa
Oxytocin Stimulates smooth muscle contractions of the uterus
during orgasm; causes contractions of pregnant
uterus at parturition (stimulation of cervix sends
signal to hypothalamus to secrete more oxytocin);
suckling sends signals to hypothalamus, resulting
in more oxytocin, causing contractions of
myoepithelial cells of the mammary glands,
assisting in milk ejection
Vasopressin (antidiuretic Conserves body water by increasing resorption of

hormone [ADH]) water by kidneys; thought to be regulated by
osmotic pressure; causes contraction of smooth
muscles in arteries, thus raising the blood
pressure; may restore normal blood pressure after
severe hemorrhage
CRH, corticotropin-releasing hormone; LHRH, luteinizing hormone–releasing hormone; PIF, prolactin inhibitory factor; PRH, prolactin-
releasing hormone; SRH, somatotropin-releasing hormone; TRH, thyrotropin-releasing hormone.
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ACIDOPHILS
Acidophils, whose granules stain orange-red with eosin,

are of two varieties: somatotrophs and mammotrophs.
C
The most abundant cells in the pars distalis are acid-
ophils, whose granules are large enough to be seen by
the light microscope and stain orange-to-red with eosin
(Fig. 13-4).
Somatotrophs, one of the two varieties of the acid-
ophils, have a centrally placed nucleus, a moderate
Golgi complex, small rod-shaped mitochondria,
A abundant rough endoplasmic reticulum (RER), and
numerous secretory granulesthat are 300 to 400 nm in
diameter. These cells secrete somatotropin (growth
B hormone); thus, they are stimulated by SRH and
inhibited by somatostatin. Somatotropin has a gener-
alized effect of increasing cellular metabolic rates.
This hormone also induces liver cells to produce
somatomedins (insulin-like growth factors I and
II), which stimulate mitotic rates of epiphyseal plate
chondrocytes and thus promote elongation of long
bones and, hence, growth.
Mammotrophs, the other variety of acidophils, are
arranged as individual cells rather than as clumps or clus-
Figure 13–3 Light micrograph of the pituitary gland displaying ters. These small, polygonal acidophils have the usual
chromophobes (C), acidophils (A), and basophils (B) (×470).
unremarkable organelle population; during lactation,
however, the organelles enlarge and the Golgi complex
may become as large as the nucleus. These cells can be
distinguished by their large secretory granules, formed
The pars distalis, or anterior lobe of the pituitary gland, by the fusion of smaller granules that are released by the
is covered by a fibrous capsule and is composed of cords trans Golgi network. These fused granules, which may
of parenchymal cells that are surrounded by reticular be 600 nm in diameter, contain the hormone prolactin,
fibers; these fibers also surround the large sinusoidal which promotes mammary gland development during
capillaries of the secondary capillary plexus. Scant con- pregnancy as well as lactation after birth.
nective tissue is located primarily around the hypo- During pregnancy, circulating estrogen and proges-
physeal arteries and the portal veins. The endothelial terone inhibit secretion of prolactin. Following birth,
lining of the sinusoids is fenestrated, which facilitates estrogen and progesterone levels drop; thus their
the diffusion of releasing factors to the parenchymal inhibitory effect is lost. The number of mammotrophs
cells and provides entry sites for their released secre- also increases at this time. At the conclusion of nursing,
tions. The parenchymal cells of the pars distalis that the granules are degraded and the excess mammotrophs
have an affinity for dyes are called chromophils, regress. Release of prolactin from mammotrophs is
whereas those parenchymal cells that have no affinity stimulated by prolactin-releasing factor (PRH) and
for dyes are called chromophobes. Chromophils are oxytocin, especially when nursing is taking place, and is
further subdivided into acidophils (staining with acid inhibited by PIF.
dyes) and basophils (staining with basic dyes), which
constitute the main secretory cells of the pars distalis BASOPHILS
(Fig. 13-3). However, it should be noted that these
latter designations refer to the affinity of the secretory Basophils, the granules of which stain blue with basic
granules within the cells to the dyes, not to the dyes, are of three varieties: corticotrophs, thyrotrophs,
parenchymal cell cytoplasm. and gonadotrophs.
Basophils stain blue with basic dyes (especially with

Chromophils
periodic acid–Schiff reagent) and are usually located at
Secretory granules of chromophils have an affinity for the periphery of the pars distalis (see Fig. 13-3).
histological dyes: those that stain orange-red with acid Corticotrophs, which are scattered throughout
dyes and those that stain blue with basic dyes. the pars distalis, are round to ovoid cells, each with an
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Figure 13–4 Light and electron micrographs of

mouse adenohypophysis (×4000). Observe the mam-
motropes (cells 3, 6-9, 12-15) and somatotropes (cells
2, 5, 11), and note the secretory granules of these
cells. (From Yamaji A, Sasaki, F, Iwama Y, Yamauchi
S: Mammotropes and somatotropes in the adeno-
phyophysis of androgenized female mice: Mor-
phological and immunohistochemical studies by
light microscopy correlated with routine electron
microscopy. Anat Rec 233:103-110, 1992.)
eccentric nucleus and relatively few organelles. Their Gonadotrophs are round cells that have a well-
secretory granules are 250 to 400 nm in diameter. developed Golgi complex and abundant RER and
Corticotrophs secrete adrenocorticotropic hormone mitochondria. Their secretory granules vary in diame-
(ACTH) and lipotropic hormone (LPH). Secretion is ter from 200 to 400 nm. Gonadotrophs, situated near
stimulated by CRH. The hormone ACTH stimulates sinuses, secrete FSH and LH; sometimes LH is called
cells of the suprarenal cortex to release their secretory interstitial cell–stimulating hormone (ICSH),
products. because it stimulates steroid hormone production in
Thyrotrophs are deeply embedded within cords of interstitial cells of the testes. It remains unclear whether
the parenchymal cells at a distance from sinusoids. there are two subpopulations of gonadotrophs, one
These cells can be distinguished by their small secretory secreting FSH and the other LH, or whether both hor-
granules (150 nm in diameter), which contain TSH, also mones are produced by one cell in different phases of
known as thyrotropin. Secretion is stimulated by TRH the secretory cycle. Secretion is stimulated by LHRH
and inhibited by the presence of thyroxine (T4) and tri- and is inhibited by various hormones that are produced
iodothyronine (T3) (thyroid hormones) in the blood. by the ovaries and testes.
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Chromophobes of pia arachnoid–like connective tissue separate the pars

tuberalis from the infundibular stalk. The pars tuberalis
Chromophobes have very little cytoplasm; therefore, is highly vascularized by arteries and the hypophyseal
they do not take up stain readily. portal system, along which lie longitudinal cords of
cuboidal to low-columnar epithelial cells. The cyto-
Groups of small, weakly staining cells in the pars distalis plasm of these basophilic cells contains small, dense
are called chromophobes (see Fig. 13-3). These cells granules, lipid droplets, interspersed colloid droplets,
generally have less cytoplasm than chromophils do, and and glycogen. Although no specific hormones are
they may represent either nonspecific stem cells or known to be secreted by the pars tuberalis, some cells
partly degranulated chromophils, although some retain contain secretory granules that possibly contain FSH
secretory granules. Because there is evidence for the and LH.
cyclic nature of the secretory function of the chro-
mophils, it is probable that chromophobes are degran- Neurohypophysis
ulated chromophils.
The posterior pituitary gland, the neurohypophysis,
Folliculostellate Cells develops from a downgrowth of the hypothalamus. The
neurohypophysis is divided into the median eminence,
Nonsecretory folliculostellate cells constitute a large
the infundibulum (continuation of the hypothalamus),
population of cells in the pars distalis. Although their
and the pars nervosa (see Fig. 13-1).
function is not clear, they have long processes that form
gap junctions with those of other folliculostellate cells.
Whether they physically support parenchymal cells of Hypothalamohypophyseal Tract
the anterior pituitary or provide a network of inter-
Axons of neurosecretory cells of supraoptic and
communication with each other is not known.
paraventricular nuclei extend into the posterior pituitary
Pars Intermedia as the hypothalamohypophyseal tract.
The pars intermedia lies between the pars distalis and Unmyelinated axons of neurosecretory cells, the cell
the pars nervosa and contains cysts that are remnants of bodies of which lie in the supraoptic and paraven-
Rathke’s pouch. tricular nuclei of the hypothalamus, enter the
posterior pituitary to terminate in the vicinity of the
The pars intermedia is characterized by many cuboidal, capillaries. These axons form the hypothalamohy-
cell-lined, colloid-containing cysts (Rathke’s cysts), pophyseal tract and constitute the bulk of the posterior
which are remnants of the ectoderm of the evaginating pituitary gland. Neurosecretory cells of the supraoptic
Rathke’s pouch. The pars intermedia, or more accu- and paraventricular nuclei synthesize two hormones:
rately in the adult human, the zona intermedia, some- vasopressin (antidiuretic hormone [ADH]) and
times houses cords of basophils along the networks of oxytocin. A carrier protein, neurophysin, also pro-
capillaries. These basophils synthesize the prohormone duced by the cells of these nuclei, binds to each of these
pro-opiomelanocortin (POMC), which undergoes hormones as they travel down the axons to the poste-
post-translational cleavage to form a-melanocyte- rior pituitary, where they are released into the blood-
stimulating hormone (a-MSH), corticotropin, β- stream from the axon terminals.
lipotropin, and β-endorphin. However, it has been
suggested that POMC is actually produced by corti- Pars Nervosa
cotropin cells of the anterior lobe and that the inter-
mediate lobe (or zone) is rudimentary in humans. The pars nervosa of the posterior pituitary gland
Although α-MSH stimulates melanin production in receives terminals of the neurosecretory
lower animals, in humans it may stimulate the release hypothalamohypophyseal tract.
of prolactin and is therefore referred to as prolactin-
Technically, the pars nervosa of the posterior pituitary
releasing factor.
gland is not an endocrine gland. The distal terminals of
Pars Tuberalis the axons of the hypothalamohypophyseal tract (Fig. 13-
5) end in the pars nervosa and store the neurosecretions
The pars tuberalis surrounds the hypophyseal stalk and that are produced by their cell bodies, which are located
is composed of cuboidal to low-columnar basophilic in the hypothalamus. These axons are supported by glia-
cells. like cells known as pituicytes. Although only the nuclei
of the pituicytes stain well enough to be evident by light
The pars tuberalis surrounds the hypophyseal stalk but microscopy, electron micrographs reveal that one pop-
frequently is absent on its posterior aspect. Thin layers ulation of axons contains membrane-bound granules of
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brane permeability, which has the effect of lowering

urine volume but increasing its concentration (see
Chapter 19). The target for oxytocin is the myometrium
of the uterus, where it is released in the late phases of
pregnancy. During labor, oxytocin is believed to play
a role in parturition by stimulating contraction of the
smooth muscles of the uterus. Additionally, oxytocin
P functions in milk ejection from the mammary gland by
stimulating contraction of the myoepithelial cells sur-
rounding the glandular alveoli and the ducts of the
mammary gland (see Chapter 20).
Pituicytes occupy about 25% of the volume of the
pars nervosa. They are similar to neuroglial cells and
help support the axons of the pars nervosa by ensheath-
ing them as well as their dilations. Pituicytes contain
lipid droplets, lipochrome pigment, and intermediate
filaments; they have numerous cytoplasmic processes
that contact and form gap junctions with each other.
Beyond supporting the neural elements in the pars
nervosa, additional functions of pituicytes have not been
elucidated. However, it is believed that they may con-
tribute a trophic function to the normal operation of the
neurosecretory axon terminals and neurohypophysis.
Pituitary adenomas are common tumors of
the anterior pituitary gland. Their growth and
Figure 13–5 Light micrograph of the pars nervosa of the pitu- enlargement may suppress hormonal production
itary gland displaying pituicytes (P) and Herring bodies (arrows)
(×132). Herring bodies are the expanded terminals of the nerve in other secretory cells of the pars distalis. When
fibers where the neurosecretory products, vasopressin (antidiuretic left unattended, these adenomas may erode sur-
hormone) and oxytocin are stored. rounding bone and other neural tissues.
Diabetes insipidus may be caused by lesions
in the hypothalmus or pars nervosa that reduce
vasopressin and that another population contains oxy- the production of ADH by neurosecretory
tocin. Cell bodies of neurons that secrete vasopressin cells whose axon terminals are located in the
are located chiefly in the supraoptic nucleus of the neurohypophysis. This condition leads to renal
hypothalamus, whereas cell bodies of neurons that dysfunction, which leads to inadequate water
secrete oxytocin are located mostly in the paraventricu- resorption by the kidneys, resulting in polyuria
lar nucleus of the hypothalamus. Each of these peptide (high urinary output) and dehydration.
hormones travel down the axons of their respective
neurons in association with a precursor protein known
as a neurophysin. By the time that they reach the pars
nervosa of the hypophysis, the hormones have matured THYROID GLAND
and cleaved from their precursors Chrome-alum hema-
toxylin staining reveals blue-black distentions of the The thyroid gland, located in the anterior portion of the
axons by light microscopy; these are called Herring neck, secretes the hormones thyroxine, triiodothyronine,
bodies, which represent accumulations of neurosecre- and calcitonin.
tory granules (see Fig. 13-5) not only at the termini but
also along the length of the axons. In response to nerve The hormones T4 and T3, the secretions of which are
stimulation, the contents of these granules are released under the control of TSH secreted by the anterior pitu-
into the perivascular space near the fenestrated capil- itary gland, stimulate the rate of metabolism. Another
laries of the capillary plexus. hormone, calcitonin, aids in decreasing blood calcium
The target for vasopressin (ADH) are the collecting levels and facilitates the storage of calcium in bones
ducts of the kidney, where it modulates plasma mem- (Table 13-2).
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TABLE 13–2 Hormones and Functions of the Thyroid, Parathyroid, Adrenal, and Pineal Glands
Regulating
Hormone Cell Source Hormone Function
Thyroid Gland
Thyroxine (T4) and Follicular Thyroid-stimulating Facilitate nuclear transcription of genes
triiodothyronine (T3) cells hormone (TSH) responsible for protein synthesis; increase
cellular metabolism, growth rates; facilitate
mental processes; increase endocrine gland
activity; stimulate carbohydrate and fat
metabolism; decrease cholesterol,
phospholipids, and triglycerides; increase
fatty acids; decrease body weight; increase
heart rate, respiration, muscle action
Calcitonin Parafollicular Feedback mechanism Lowers plasma calcium concentration by
(thyrocalcitonin) cells with parathyroid suppressing bone resorption
hormone
Parathyroid
Gland
Parathyroid hormone Chief cells Feedback mechanism Increases calcium concentration in body fluids
(PTH) with calcitonin
Suprarenal
(Adrenal) Glands
Suprarenal Cortex
Mineralocorticoids: Cells of the zona Angiotensin II and Control body fluid volume and electrolyte
aldosterone and glomerulosa adrenocorticotropic concentrations by acting on distal tubules
deoxycorticosterone hormone (ACTH) of the kidney, causing excretion of
potassium and resorption of sodium
Glucocorticoids: Cells of the zona ACTH Regulate metabolism of carbohydrates, fats,
cortisol and fasciculata and proteins; decrease protein synthesis,
corticosterone (spongiocytes) increasing amino acids in blood; stimulate
gluconeogenesis by activating liver to
convert amino acids to glucose; release
fatty acid and glycerol; act as anti-
inflammatory agents; reduce capillary
permeability; suppress immune response
Androgens: Cells of the ACTH Provides weak masculinizing characteristics
dehydroepiandros- zona
terone and reticularis
androstenedione
Suprarenal
Medulla
Catecholamines: Chromaffin Preganglionic, Epinephrine:
epinephrine and cells sympathetic, and Operates the “fight or flight” mechanism
norepinephrine splanchnic nerves preparing the body for severe fear or stress;
increases cardiac heart rate and output,
augmenting blood flow to the organs and
release of glucose from the liver for energy;
Norepinephrine:
Causes an elevation in blood pressure by
vasoconstriction
Pineal Gland
Melatonin Pinealocytes Norepinephrine May influence cyclic gonadal activity
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Parafollicular Follicular
cell cell
TG
F
THYROID GLAND
PG
Oxyphil cell
Figure 13–7 Light micrograph of the thyroid and parathyroid
glands (×132). Observe the colloid-filled follicles (F) of the thyroid
Chief cell gland (TG) in the upper portion of the figure. At bottom is the
parathyroid gland (PG), as evidenced by the presence of chief and
oxyphil cells.
Capsule
Blood vessel
PARATHYROID GLAND
Figure 13–6 The thyroid and parathyroid glands.

Unlike most of the endocrine glands, which store their
secretory substances within the parenchymal cells, the
thyroid gland stores its secretory substances in the
The thyroid gland lies just inferior to the larynx, ante- lumina of follicles (Fig. 13-7). These cyst-like struc-
rior to the junction of the thyroid and cricoid cartilages tures, ranging from 0.2 to 0.9 mm in diameter, are com-
(Fig. 13-6). It is composed of a right lobe and a left posed of a simple cuboidal epithelium surrounding
lobe, which are connected across the midline by an a central colloid-filled lumen. Each follicle can store
isthmus. In some people, the gland has an additional several weeks’ supply of hormone within the colloid.
lobe, called the pyramidal lobe, that ascends from the The hormones T4 and T3 are stored in the colloid, which
left side of the isthmus. The pyramidal lobe is an embry- is bound to a large (660,000 Da) secretory glycoprotein
ological remnant of the path of descent of the thyroid called thyroglobulin. When the hormones are to be
primordium from its origin in the forming tongue by released, the hormone-bound thyroglobulin is endocy-
way of the thyroglossal duct. tosed and the hormones are cleaved from it by lysoso-
The thyroid gland is surrounded by a slender, dense, mal proteases.
irregular collagenous connective tissue capsule, a deriv- Connective tissue septa derived from the capsule
ative of the deep cervical fascia. Septa derived from the invade the parenchyma and provide a conduit for blood
capsule subdivide the gland into lobules. Embedded vessels, lymphatic vessels, and nerve fibers. Slender
within the capsule, on the posterior aspect of the gland, connective tissue elements, composed mostly of reticu-
are the parathyroid glands. lar fibers and housing a rich capillary plexus, surround
each follicle but are separated from the follicular and
Cellular Organization parafollicular cells by a thin basal lamina. Occasion-
ally, follicular cells of neighboring follicles may come
The thyroid follicle is the structural and functional unit
into contact with each other and disrupt the continuity
of the thyroid gland.
of the basal lamina.
Ch013-X2945.qxd 12/8/06 3:35 PM Page 314
Follicular Cells (Principal Cells) The synthesis of thyroid hormone is regulated by the
iodide levels in the follicular cell as well as by the
Follicular (principal) cells are squamous to low-columnar binding of TSH to TSH receptors of the follicular cells.
in shape and are tallest when stimulated. The occupation of TSH receptors triggers cAMP
production, resulting in protein kinase A activity and
Follicular cells have a round to ovoid nucleus with two synthesis of T3 and T4. Figure 13-9 outlines the pathway
nucleoli and basophilic cytoplasm. Frequently, their for the synthesis and release of thyroid hormones.
RER is distended and displays zones that are ribosome- Thyroglobulin is synthesized in the RER and subse-
free. These cells also have numerous apically located quently glycosylated in both the RER and the Golgi
lysosomes, rod-shaped mitochondria, a supranuclear apparatus. The modified protein is packaged in the
Golgi complex, and numerous short villi that extend trans Golgi network. The vesicles containing thyroglob-
into the colloid (Fig. 13-8). Numerous small vesicles, dis- ulin are transported to the apical plasmalemma, where
persed throughout the cytoplasm, are believed to contain their contents are released into the colloid and stored
thyroglobulin that was packaged in the Golgi complex in the lumen of the follicle.
and is destined for exocytosis into the follicle lumen. Iodine is reduced to iodide (I −) within the alimen-
Iodide is essential for the synthesis of the thyroid hor- tary canal and is preferentially absorbed and trans-
mones (T3 and T4); iodination of tyrosine residues occurs ported by the bloodstream to the thyroid gland. Iodide
in the follicles at the colloid-follicular cell interface. Thus is actively transported via sodium/iodide symporters,
follicular cells secrete triiodothyronine (T3) and thyrox- which are located in the basal plasmalemma of the fol-
ine (T4), which increases basal metabolic rates. licular cells, so that the intracellular iodide concentra-
During great demand for thyroid hormone, follicu- tion is 20-fold to 40-fold that of plasma. Once in the
lar cells extend pseudopods into the follicles to envelop cytosol, iodide is transferred to the colloid-cell mem-
and absorb the colloid. When demand for the hormone brane interface, where iodide oxidation occurs by the
declines, the amount of colloid in the follicle lumen enzyme thyroid peroxidase, a process that requires
increases. the presence of hydrogen peroxide (H2O2). The acti-
vated iodide enters the colloid and iodinates tyrosine
Synthesis of Thyroid Hormones residues of thyroglobulin at the interface of the colloid
(T3 and T4) and the apical plasmalemma of the thyroid follicular
cell. Tyrosine residues of thyroglobulin are iodinated,
Thyroid hormone synthesis is regulated by iodide levels
forming monoiodinated tyrosine (MIT) and diiodi-
and by TSH binding to TSH receptors of follicular cells.
nated tyrosine (DIT). Triiodinated and tetraiodinated

graph of a thyroid follicular cell
bordering the colloid (dark area,
upper left corner) (×10,700). (From
Mestdagh C, Many MC, Haalpern S,
et al: Correlated autoradiographic
and ion-microscopic study of the
role of iodine in the formation of
“cold” follicles in young and old
mice. Cell Tissue Res 260:449-457,
1990.)
Ch013-X2945.qxd 12/8/06 3:35 PM Page 315
A Iodinated thyroglobulin B Uptake of colloid

in colloid by endocytosis
Colloid Lysosomes
Lysosome and
Apical vesicle colloid droplet
containing Iodide fuse
thyroglobulin oxidation
Digestion by
enzymes releases
thyroid hormones
Mannose (T3, T4)
incorporation
Thyroglobulin T3, T4
synthesis
Amino acids Iodide Lysosomal Thyroid-stimulating

enzyme hormone bound
synthesis to receptor
Figure 13–9 The synthesis and iodination of thyroglobulin (A) and release of thyroid hormone (B).
tyrosines are then formed by the coupling of an MIT Physiological Effects of

and a DIT or of two DITs, respectively. Each thy- Triiodothyronine and Thyroxine
roglobulin molecule has fewer than four T4 molecules
and fewer than 0.3 T3 residues. The iodinated thy- Once they enter the bloodstream, T3 and T4 bind to
roglobulin is released by the follicular cells to be stored plasma-binding proteins and are slowly released to the
in the colloid. tissues and contact cells. As they enter the cytoplasm,
they are bound to intracellular proteins and slowly used
Release of Thyroid Hormones over a period of several days to weeks. Because only
(T3 and T4) the free hormone has the ability to enter the cell and
because T3 is bound less avidly, more of it gains entry
TSH stimulates follicular cells of the thyroid gland to into the cytoplasm than does T4. Moreover, both T3 and
release T3 and T4 into the bloodstream. T4 bind to nuclear thyroid hormone receptor pro-
teins, but T3 binds with a much greater affinity than
TSH, released from the basophils of the anterior pitu- does T4, which also accounts for the greater biological
itary, binds to TSH receptors on the basal plasmalemma activity of T3.
of the follicular cells. Binding of TSH facilitates forma- These hormones stimulate transcription of many
tion of filopodia at the apical cell membrane, resulting genes that encode various types of proteins (see Table
in endocytosis of aliquots of the colloid. Cytoplasmic 13-2), resulting in a generalized increase in cellular
vesicles containing colloid fuse with early (or late) metabolism that may be as great as twice the resting
endosomes. Within the endosomes, iodinated residues rate. T3 and T4 also increase the growth rate in the
are cleaved from thyroglobulin by proteases and are young, facilitate mental processes, and stimulate
transferred into the cytosol as free MIT, DIT, T3, endocrine gland activity.
and T4. Generally, thyroid hormones stimulate carbohydrate
MIT and DIT are stripped of their iodine by the metabolism. They decrease synthesis of cholesterol,
enzyme iodotyrosine dehalogenase, and both the phospholipids, and triglycerides but increase synthesis
iodine and the amino acid tyrosine become part of their of fatty acids and the uptake of various vitamins.
respective pools within the cytosol, to be used later. Increased thyroid hormone production also decreases
T3 and T4 are released at the basal plasmalemma of body weight and increases heart rate, metabolism,
the follicular cells, entering the connective tissue spaces respiration, muscle function, and appetite. Excessive
of the thyroid for distribution by the bloodstream. amounts of thyroid hormone cause muscle tremor,
T4 constitutes about 90% of the released hormone, tiredness, impotence in men, and reduced or absence
although it is not as effective as T3. of menstrual bleeding in women.
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The pale-staining parafollicular cells lie singly or in clus-

CLINICAL CORRELATIONS ters among the follicular cells, but they do not reach the
lumen of the follicle. Although these cells are two to
Graves’ disease is characterized by hyperplasia three times larger than follicular cells, they account for
of the follicular cells, increasing the size of the only about 0.1% of the epithelium. Electron micro-
thyroid gland two to three times above normal. graphs display a round nucleus, moderate amounts of
Thyroid hormone production is also greatly RER, elongated mitochondria, a well-developed Golgi
increased, from 5 to 15 times normal (hyper- complex, and small, dense secretory granules (0.1 to
thyroidism). Other symptoms include exoph- 0.4 µm in diameter) located in the basal cytoplasm.
thalmos, protrusion of the eyeballs. Although These secretory granules contain calcitonin (thyro-
Graves’ disease may develop from several causes, calcitonin), a peptide hormone that inhibits bone
the most common agent is the binding of autoim- resorption by osteoclasts, thereby lowering calcium con-
mune immunoglobulin G (IgG) antibodies to centrations in blood. When the circulating level of
TSH receptors, which stimulates thyroid follicu- calcium is high, release of calcitonin is stimulated (see
lar cells. Chapter 7).
Insufficient dietary intake of iodine causes
the thyroid gland to enlarge, a condition called
simple goiter. Goiter usually is not associated
PARATHYROID GLANDS
with hyperthyroidism or hypothyroidism. This
condition can be treated with supplementation The absence of parathyroid glands is incompatible with
of iodine in the diet. life because parathyroid hormone (PTH) regulates blood
Hypothyroidism is characterized by such calcium levels.
conditions as fatigue, sleeping for up to 14 to
The parathyroid glands, usually four in number, are
16 hours a day, muscular sluggishness, slowed
located on the posterior surface of the thyroid gland;
heart rate, decreased cardiac output and blood
each gland is enveloped in its own thin, collagenous
volume, mental sluggishness, failure of body
connective tissue capsule (see Fig. 13-6). The glands
functions, constipation, and loss of hair growth.
function in producing PTH, which acts on bone,
Patients with severe hypothyroidism may
kidneys, and the intestines in maintaining the optimal
develop myxedema, which is characterized by
concentrations of calcium within blood and interstitial
bagginess under the eyes and a swollen face
tissue fluid.
that is due to nonpitting edema of the skin,
Normally, one parathyroid gland is located on both
infiltration of excess glycosaminoglycans, and
poles (superior and inferior) of the right and left lobes
proteoglycans into the extracellular matrix. Cre-
of the thyroid gland. Because of their embryological
tinism is an extreme form of hypothyroidism
origin and descent in the neck with the primordium of
occurring in fetal life through childhood that is
the thymus and thyroid tissues, the parathyroid glands
characterized by failure of growth and mental
may be located anywhere along the pathway of descent,
retardation owing to a congenitally missing
even in the thorax, and there may also be supernumer-
thyroid gland.
ary parathyroid glands.
The nerves supplying the laryngeal muscula-
The parathyroid glands develop from the third and
ture (i.e., external laryngeal nerves and recurrent
fourth pharyngeal pouches during embryogenesis. The
laryngeal nerves) are closely applied to the
parathyroid glands that develop in the third pharyngeal
thyroid gland and must be isolated and protected
pouches descend with the thymus (also developing in
during thyroidectomy. Damage to either of
the third pouches) to become the inferior parathy-
these two nerves results in hoarseness and, pos-
roid glands. The parathyroid glands that develop in
sibly, loss of speech.
the fourth pharyngeal pouches descend only a short
distance to become the superior parathyroid glands.
The glands grow slowly, reaching the adult size at about
20 years of age.
Parafollicular Cells (Clear Cells, Parathyroid Cellular Organization

C Cells) The parenchyma of the parathyroid glands consists of
Parafollicular cells secrete calcitonin. They are found two cell types: chief cells and oxyphil cells.
individually or may form small clusters of cells at the
Each parathyroid gland is a small, ovoid structure about
periphery of the follicle.
5 mm in length, 4 mm wide, and 2 mm in thickness and
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weighs about 25 to 50 mg. Extensions of the connective chief cells do. Oxyphils appear in groups and as isolated
tissue capsule enter the gland as septa, accompanied by cells. They have more abundant mitochondria than do
blood vessels, lymphatics, and nerves. The septa serve chief cells, but their Golgi apparatus is small and there
mainly to support the parenchyma and consist of cords is little RER. Glycogen is also located in the cytosol and
or clusters of epithelial cells surrounded by reticular is surrounded by mitochondria.
fibers, which also support the parenchyma and a
rich capillary network. The connective tissue stroma in Physiological Effect of
older adults often contains several to many adipose Parathyroid Hormone
cells, which may occupy up to 60% of the gland. The
parenchyma of the parathyroid glands is composed PTH, produced by chief cells of the parathyroid glands,
of two cell types: chief cells and oxyphil cells (see helps to maintain the extracellular fluid as well as
Fig. 13-7). the plasma concentration of calcium ions (8.5 to
10.5 mg/dL). This hormone acts on cells of the bones,
the kidneys, and, indirectly, the intestines, leading to an
Chief Cells increased calcium ion concentration in body fluids (see
Table 13-2). When calcium ion concentration in body
Chief cells synthesize parathyroid hormone.
fluids falls below normal, the chief cells increase their
The major functional parenchymal cells of the para- production and release of PTH, quickly increasing their
thyroid glands are the slightly eosinophilic-staining normal secretion rate 10-fold. This rapid response is
chief cells (5 to 8 µm in diameter), which contain gran- especially important because of the many functions of
ules of lipofuscin pigment that is scattered throughout calcium in homeostasis, including its role in stabilizing
the cytoplasm. Smaller, dense granules, 200 to 400 nm ion gradients across the plasmalemmae of muscle and
in diameter, arising from the Golgi complex and nerve cells and its role in the release of neurotransmit-
moving to the cell periphery, represent the secretory ter at axon terminals.
granules and contain parathyroid hormone (PTH). The interplay of PTH and calcitonin represents a
Electron micrographs also reveal a juxtanuclear Golgi dual mechanism for regulating calcium levels in the
complex, elongated mitochondria, and abundant RER. blood: PTH acts to increase serum calcium levels,
Occasionally, desmosomes join adjacent chief cells. whereas calcitonin has the opposite effect.
A single cilium may extend into the intercellular In bone, PTH binds to receptors on osteoblasts, sig-
space. Some chief cells have a smaller Golgi com- naling the cells to increase their secretion of osteoclast-
plex, scant secretory granules, and large amounts of stimulating factor. This factor induces activation of
glycogen; these cells are thought to be in an inactive osteoclasts, thereby increasing bone resorption and
phase. the ultimate release of calcium ions into the blood
The precursor, preproparathyroid hormone, is (see Chapter 7). In the kidneys, PTH prevents loss of
synthesized on ribosomes of the RER and rapidly calcium in the urine. Finally, PTH controls the rate
cleaved as it is transported to the lumen of the RER to of calcium uptake in the gastrointestinal tract by indi-
form proparathyroid hormone and a polypeptide. On rectly regulating the production of vitamin D in the
reaching the Golgi complex, the proparathyroid kidneys; vitamin D is necessary for intestinal uptake
hormone is cleaved again into PTH and a small of calcium. Vitamin D functions to stimulate the intes-
polypeptide. The hormone is packaged into secretory tinal mucosa to reabsorb calcium by inducing epithelial
granules and is released from the cell surface by cells of the intestinal villus to form calcium-binding
exocytosis. protein that becomes localized on the microvilli that
facilitates the transport of calcium into the epithelial
cells.
Oxyphil Cells
Oxyphil cells are believed to be the inactive phase of
chief cells. SUPRARENAL (ADRENAL)
GLANDS
The second cell type located in the parathyroid glands
is the oxyphil cell. Its function is unknown, although it Suprarenal glands produce two different groups of
is believed that oxyphil cells and a third cell, described hormones: steroids and catecholamines.
as an intermediate cell, probably represent inactive
phases of a single cell type, with chief cells being the The suprarenal glands are located at the superior poles
actively secreting phase. of the kidneys and are embedded in adipose tissue. The
Oxyphil cells are less numerous, larger (6 to 10 µm right and left suprarenal glands are not mirror images
in diameter), and stain more deeply with eosin than of each other; rather, the right suprarenal gland is
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tive tissue capsule that contains large amounts of

CLINICAL CORRELATIONS adipose tissue. Each gland has a thick capsule of
connective tissue that sends septa into the parenchyma
A condition called primary hyperparathy- of the gland, accompanied by blood vessels and
roidism, which may be caused by a tumor in nerves.
one of the parathyroid glands, is marked by high
blood calcium levels, low blood phosphate levels, Blood Supply to the
loss of bone mineral, and sometimes kidney
stones. Secondary hyperparathyroidism
Suprarenal Glands
may develop in patients with rickets, because Arteries from three separate sources provide the
calcium cannot be absorbed from the intestines suprarenal glands with an abundant blood supply:
owing to vitamin D deficiency; therefore,
calcium ion concentrations in the blood are low. The suprarenal glands have one of the richest blood
Hypoparathyroidism results from defi- supplies in the body (Fig. 13-11). Each suprarenal gland
ciency in secretion of PTH, commonly caused is served by three separate arteries that arise from three
by injury of the parathyroid glands or by separate sources:
their removal during thyroid gland surgery.
䡲 The inferior phrenic arteries, from which the
Hypoparathyroidism is marked by low blood
calcium levels, retention of bone calcium, and superior suprarenal arteries originate.
䡲 The aorta, from which the middle suprarenal
increased phosphate resorption in the kidney.
The main symptoms are numbness, tingling, car- arteries originate.
䡲 The renal arteries, from which the inferior
popedal spasms (muscle cramps) in the hands
and feet, muscle tetany (tremors) in the facial suprarenal arteries originate.
and laryngeal muscles, mental confusion, and These branches pass over the capsule, penetrate it,
memory loss. The only treatment for survival is and form a subcapsular plexus.
large intravenous doses of calcium gluconate, Arising from the plexus are short cortical arteries,
vitamin D, and oral calcium. which, in the cortical parenchyma, form a network of
sinusoidal fenestrated capillaries (with diaphragms).
The pore diameters of the fenestrated endothelial
walls of the capillaries increase from 100 nm at the
pyramid-shaped and sits directly on top of the right outer cortex to 250 nm in the deep cortex, where the
kidney, whereas the left suprarenal gland is more cres- sinusoidal capillaries become confluent with a venous
cent-shaped and lies along the medial border of the left plexus. Small venules arising from this area pass through
kidney from the hilus to its superior pole. the suprarenal medulla and drain into a suprarenal vein,
Both glands are about 1 cm in thickness, 2 cm in emerging from the hilus. The right suprarenal vein joins
width at the apex, and up to 5 cm at the base; each the inferior vena cava, and the left suprarenal vein
weighs 7 to 10 g. The parenchyma of the gland is drains into the left renal vein.
divided into two histologically and functionally different Additional long cortical arteries pass unbranched
regions: an outer yellowish portion, accounting for through the cortex and into the medulla, where they
about 80% to 90% of the organ, called the suprarenal form networks of capillaries. Thus, the medulla receives
cortex, and a small, dark, inner portion called the a dual blood supply: (1) an arterial supply from the long
suprarenal medulla (Fig. 13-10). Although both enti- cortical arteries and (2) numerous vessels from the cor-
ties are endocrine in function, each develops from a dif- tical capillary beds.
ferent embryological origin and performs a different
role. The suprarenal cortex, arising from mesoderm, Suprarenal Cortex
produces a group of hormones called corticosteroids,
which are synthesized from cholesterol. Secretion of The suprarenal cortex is subdivided into three zones that
these hormones, including cortisol and corticos- produce three classes of steroids.
terone, is regulated by ACTH, a hormone secreted by
the anterior pituitary gland. The suprarenal medulla, The suprarenal cortex contains parenchymal cells that
arising from neural crest, is functionally related to and synthesize and secrete several steroid hormones
regulated by the sympathetic nervous system; it pro- without storing them. The cortex is subdivided histo-
duces the hormones epinephrine and norepineph- logically into three concentric zones named, from the
rine (see Table 13-2). capsule inward, the zona glomerulosa, the zona fas-
The suprarenal glands are retroperitoneal, located ciculata, and the zona reticularis (Fig. 13-12; also see
behind the peritoneum, and surrounded by a connec- Fig. 13-10). Although each of the three identified zones
Ch013-X2945.qxd 12/8/06 3:35 PM Page 319
Capsule
Zona glomerulosa
Zona fasciculata Cortex
Zona reticularis
Medulla
Hormones:
Capsular
artery Mineralocorticoids
(e.g.,
aldosterone)
Capsule
Zona
glomerulosa
Glucocorticoids
(e.g.,
cortisone)
and
Sex hormones
(e.g.,
Zona dehydroepi-
fasciculata androsterone)
Preganglionic
sympathetic terminal
Zona Adrenalin
reticularis
Preganglionic
sympathetic terminal
Medulla Noradrenalin
Figure 13–10 The suprarenal Medullary

gland and its cell types. vein
of the suprarenal cortex is said to secrete specific hor- The three classes of adrenocortical hormones—
mones, it should be remembered that the boundaries mineralocorticoids, glucocorticoids, and andro-
between these zone overlap; thus it is better to remem- gens—are all synthesized from cholesterol, the major
ber the cortex as a secreting unit for the three classes component of low-density lipoprotein. Cholesterol is
of adrenocortical hormones (of course, the student’s taken up from the blood and stored esterified in lipid
instructor may deem otherwise, in which case it is in the droplets within the cytoplasm of the cortical cells. When
student’s best interest to follow the instructor’s point of these cells are stimulated, cholesterol is freed and used
view). in hormone synthesis in the smooth endoplasmic
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Figure 13–11 Scanning electron micrograph

of the rat adrenal gland demonstrating microcircu-
lation in the cortex and medulla (×80). (From
Kikuta A, Murakami T: Microcirculation of the rat
adrenal gland: A scanning electron microscope
study of vascular casts. Am J Anat 164:19-28, 1982.)
reticulum (SER) by enzymes that are located there join cells to each other, and some cells have short
and in the mitochondria. The intermediate products of microvilli.
the hormone that is being synthesized are transferred The parenchymal cells of the zona glomerulosa syn-
between the SER and the mitochondria until the final thesize and secrete the mineralocorticoid hormones,
hormone is produced. principally aldosterone and some deoxycorticos-
terone. Synthesis of these hormones is stimulated by
Zona Glomerulosa angiotensin II and ACTH, both required for normal
existence of glomerulosa cells. The mineralocorticoid
Parenchymal cells of the zona glomerulosa, when hormones function in controlling fluid and electrolyte
stimulated by angiotensin II and ACTH, synthesize and balance in the body by affecting the function of the
release the hormones aldosterone and renal tubules, specifically the distal convoluted tubules
deoxycorticosterone. (see Chapter 19).
The outer concentric ring of capsular parenchymal Zona Fasciculata
cells, located just beneath the suprarenal capsule, is
the zona glomerulosa, which constitutes approximately Parenchymal cells of the zona fasciculata (spongiocytes),
13% of the total adrenal volume (see Fig. 13-10). The when stimulated by ACTH, synthesize and release the
small columnar cells composing this zone are arranged hormones cortisol and corticosterone.
in cords and clusters. Their small, dark-staining nuclei
contain one or two nucleoli, and their acidophilic cyto- The intermediate concentric layer of cells in the
plasm contains an abundant and extensive SER, short suprarenal cortex is the zona fasciculata, the largest
mitochondria with shelf-like cristae, a well-developed layer of the cortex, which accounts for up to 80% of the
Golgi complex, abundant RER, and free ribosomes. total volume of the gland. This zone contains sinusoidal
Some lipid droplets also are dispersed in the cyto- capillaries that are arranged longitudinally between the
plasm. Occasional desmosomes and small gap junctions columns of parenchymal cells. The polyhedral cells in
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The darkly staining acidophilic cells in this layer are

arranged in anastomosing cords. They are similar to the
spongiocytes of the zona fasciculata but are smaller with
fewer lipid droplets. They frequently contain large
G amounts of lipofuscin pigment granules. Several cells
near the suprarenal medulla are dark with electron-
G dense cytoplasm and pyknotic nuclei, which suggests
that this zone contains degenerating parenchymal
cells.
Cells of the zona reticularis synthesize and secrete
androgens, principally dehydroepiandrosterone
and some androstenedione. Additionally, these cells
may synthesize and secrete small amounts of glucocor-
F ticoids. The secretion of these hormones is stimulated
by ACTH. Both dehydroepiandrosterone and andro-
F stenedione are weak, masculinizing hormones with neg-
ligible effects under normal conditions.
Histophysiology of the
Suprarenal Cortex
The three classes of hormones that are secreted by the
suprarenal cortex are steroids: (1) mineralocorticoids,
(2) glucocorticoids, and (3) weak androgens. ACTH
from the pars distalis of the pituitary is the trophic
hormone that stimulates secretion of the suprarenal
cortex hormones.
Figure 13–12 Light micrograph of the cortex of the suprarenal Mineralocorticoids

gland (×132). Observe the zona glomerulosa (G) and the zona fascic-
ulata (F). The mineralocorticoids secreted by the zona glomeru-
losa include aldosterone predominantly and some
deoxycorticosterone. The targets of these hormones
include the gastric mucosa, salivary glands, and sweat
this layer are larger than the cells of the zona glomeru- glands, where they stimulate absorption of sodium.
losa and are arranged in radial columns, one to two However, their main target are the cells of the distal
layers thick, and stain lightly acidophilic. Because they convoluted tubules of the kidney, where they function
have many lipid droplets in their cytoplasm, which are to stimulate the regulation of water balance and the
extracted during histological processing, these cells homeostasis of sodium and potassium by absorbing
appear vacuolated and are called spongiocytes. Spon- sodium and excreting potassium.
giocytes have spherical mitochondria with tubular
and vesicular cristae, extensive networks of SER, some Glucocorticoids
RER, lysosomes, and granules of lipofuscin pigment.
Cells of the zona fasciculata synthesize and secrete Glucocorticoids, secreted by the zona fasciculata,
the glucocorticoid hormones cortisol and corticos- include hydrocortisone (cortisol) and corticos-
terone. The synthesis of these hormones is stimulated terone. These steroid hormones have a wide range of
by ACTH. Glucocorticoids function in the control of functions that affect most tissues of the body as well
carbohydrate, fat, and protein metabolism. as control general metabolism. Glucocorticoids exert
an anabolic effect in the liver that promotes the uptake
Zona Reticularis of fatty acids, amino acids, and carbohydrates for
glucose synthesis and glycogen polymerization; in other
The cells of the zona reticularis, when stimulated by tissues, however, the effect is catabolic. For example,
ACTH, synthesize and release dehydroepiandrosterone, in adipocytes glucocorticoids stimulate lipolysis, and
androstenedione, and some glucocorticoids. in muscle these hormones stimulate proteolysis.
Glucocorticoids, when circulating at above normal
The innermost layer of the suprarenal cortex is the levels, also influence anti-inflammatory responses by
zona reticularis, constituting about 7% of gland volume. inhibiting macrophage and leukocyte infiltration at sites
Ch013-X2945.qxd 12/8/06 3:35 PM Page 322
of inflammation. These hormones also suppress the

immune response by inducing atrophy of the lymphatic
system, thereby reducing the circulating lymphocyte
population.
The negative feedback mechanism for the gluco-
corticoids is partly controlled by their plasma concen-
tration. When blood glucocorticoid levels are high, n
corticotropin-releasing hormone (CRH) cells of the N
hypothalamus are inhibited, which in turn inhibits cor-
ticotrophs of the pars distalis of the pituitary gland
from releasing ACTH.
Weak Androgens
Androgens secreted by the zona reticularis include
dehydroepiandrosterone and androstenedione, both CC
weak, masculinizing sex hormones that are only a small
fraction as effective as the androgens that are produced
in the testes. Under normal conditions, the influence of
these hormones is insignificant. V
Addison’s disease is characterized by decreased Figure 13–13 Light micrograph of the medulla of the
secretion of the adrenocortical hormones as a suprarenal gland (×270). Note the chromaffin cells (CC) whose
result of destruction of the suprarenal cortex. nucleus (N) houses a single nucleolus (n). Observe the rich arterial
This disease is most often caused by an autoim- supply and venous drainage (V) of the suprarenal medulla.
mune process; it also can develop as a sequela of
tuberculosis or of some other infectious diseases.
Death occurs if steroid treatment is not ganglion cells, which are scattered throughout the
provided. connective tissue.
Cushing’s disease (hyperadrenocorticism)
is caused by small tumors in the basophils of the Chromaffin Cells
anterior pituitary gland that lead to an increase in
the output of ACTH. The excess ACTH causes The suprarenal medulla functions as a modified
enlargement of the suprarenal glands and hyper- sympathetic ganglion, housing postganglionic
trophy of the suprarenal cortex, resulting in sympathetic cells that lack dendrites and axons.
overproduction of cortisol. Patients are obese,
predominantly in the face, neck, and trunk, and Chromaffin cells of the suprarenal medulla are large
exhibit osteoporosis and muscle wasting. Males epithelioid cells, arranged in clusters or short cords;
become impotent, and females have amenorrhea. they contain granules that stain intensely with chro-
maffin salts. The reaction of the granules, which turn
deep brown when exposed to chromaffin salts, indicates
that the cells contain catecholamines, transmitters
Suprarenal Medulla produced by postganglionic cells of the sympathetic
nervous system. Thus, the suprarenal medulla functions
Chromaffin cells of the suprarenal medulla are modified as a modified sympathetic ganglion, housing postgan-
postganglionic neurons that have a secretory function. glionic sympathetic cells that lack dendrites and axons.
The catecholamines synthesized by the chromaffin cells
The central portion of the suprarenal gland, the are the sympathetic transmitters epinephrine and
suprarenal medulla, is completely invested by the norepinephrine (Fig. 13-14). These transmitters are
suprarenal cortex. The suprarenal medulla, which secreted by the chromaffin cells in response to stimula-
develops from ectodermal neural crest cells, comprises tion by preganglionic sympathetic (cholinergic)
two populations of parenchymal cells: chromaffin cells splanchnic nerves. Each chromaffin cell of primates,
(Fig. 13-13), which produce the catecholamines (epi- including the human, has the capability of producing
nephrine and norepinephrine), and sympathetic both epinephrine and norepinephrine and storing them
Ch013-X2945.qxd 12/8/06 3:35 PM Page 323
ER
M
SG
Figure 13–14 Electron micrograph of baboon

adrenal medulla (×14,000). The different osmio-
philic densities of the vesicles may be a reflection of
their maturational phases. ER, endoplasmic reticu-
lum; H, high-electron-density vesicle; L, low-
electron-density vesicle; M, mitochondrion; SG,
small granule cell. (From Al-Lami F, Carmichael
SW: Microscopic anatomy of the baboon [Papio
hamadryas] adrenal medulla. J Anat 178:213-221,
1991.)
in secretory vesicles. Although in electron micrographs the granules of chromaffin cells storing epinephrine
two types of secretory vesicles, high-electron-density are more homogeneous and less dense. Primate
and low-electron-density, are evident, the density dif- chromaffin cells have a well-developed juxtanuclear
ferential may be one of the maturational state of epi- Golgi complex, some RER, and numerous mitochon-
nephrine and not necessarily indicative of the presence dria. The identifying characteristic of the chromaffin
of two types of catecholamines. cells is the 30,000 or so small, membrane-bound, dense
In some animals, but not in primates including granules in the cytoplasm; approximately 20% of
humans, two types of chromaffin cells have been iden- these granules contain either epinephrine or norepi-
tified by histochemical staining: those producing and nephrine. The remaining granules are composed of
storing norepinephrine and those producing and storing adenosine triphosphate, enkephalins, and soluble
epinephrine. The granules of the norepinephrine- proteins called chromagranins. Chromagranins are
storing cells have an eccentric, electron-dense core proteins that are believed to bind epinephrine and
within the limiting membrane of the granule, whereas norepinephrine.
Ch013-X2945.qxd 12/8/06 3:35 PM Page 324
Histophysiology of the heart rate, as well as increase the release of glucose

Suprarenal Medulla from the liver.
Epinephrine is most effective in controlling cardiac
The secretory activity of the suprarenal medulla is con- output, heart rate, and increasing blood flow through
trolled by the splanchnic nerves. Release of the aggre- organs. Norepinephrine has little effect on these
gated catecholamines from chromaffin cells is induced but brings about an elevation in blood pressure by
by stimulation of the sympathetic ganglion cells in the vasoconstriction.
suprarenal medulla. Release of acetylcholine from Norepinephrine is also produced in the brain and in
these preganglionic sympathetic nerve endings depo- peripheral nerves, functioning as a neurotransmitter;
larizes the chromaffin cell membranes, leading to an however, norepinephrine produced in the suprarenal
influx of calcium ions. The rise in intracellular calcium medulla has a short half-life because it is destroyed in
then induces release of epinephrine or norepineph- the liver shortly after its release.
rine via exocytosis.
When the stimulus is derived from an emotional
source, secretion of norepinephrine predominates; PINEAL GLAND
when the stimulus is physiological (e.g., pain), secretion
of epinephrine predominates. Catecholamines released The pineal gland is responsive to diurnal light and dark
by the suprarenal medulla exhibit a more generalized periods and is thought to influence gonadal activity.
overall effect than do the catecholamines released by
sympathetic neurons. However, these effects are not The pineal gland (or pineal body) is an endocrine
uniform for all tissues. Generally, they increase oxygen gland whose secretions are influenced by the light and
consumption, increase heat production, and mobilize fat dark periods of the day. It is a cone-shaped, midline pro-
for energy; in the cardiovascular system, they function in jection from the roof of the diencephalon, within a
controlling the heart rate and the arterial smooth muscles, recess of the third ventricle extending into the stalk that
thus increasing blood pressure. Additionally, cate- is attached to it. It is 5 to 8 mm long and 3 to 5 mm
cholamines regulate muscle contractions in some tissues wide; it weighs approximately 120 mg. The gland is
(e.g., bladder sphincters); in other organs, they influence covered by pia mater, forming a capsule from which
muscle relaxation (e.g., intestinal smooth muscle). septa extend, dividing the pineal gland into incomplete
In severe fear or stress, increased epinephrine is lobules. Blood vessels enter the gland via the connec-
released to prepare the body for “fight or flight.” The tive tissue septa. The parenchymal cells of the gland are
resulting plasma levels of epinephrine, up to 300 times composed primarily of pinealocytes and interstitial
the normal level, increase alertness, cardiac output, and cells (Fig. 13-15).
BS
Pi
Figure 13–15 Pineal gland (×132).

The large, darkly staining structures
are brain sand (BS) scattered among
the pinealocytes (Pi). Neuroglial cells
are present but difficult to distinguish
at this magnification.
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Pinealocytes Interstitial Cells

Pinealocytes are the parenchymal cells of the pineal Interstitial cells of the pineal gland are believed to be
gland that are responsible for secreting melatonin. astroglia-like cells.
Pinealocytes are slightly basophilic cells with one or two Interstitial cells, believed to be astrocyte-like neuroglial
long processes whose terminal dilations approximate cells, are scattered throughout the pinealocytes and are
capillaries and, occasionally, other parenchymal cells. particularly abundant in the pineal stalk that leads to
Their spherical nuclei have a single prominent nucleo- the diencephalon. These cells have deeply staining,
lus. The cytoplasm contains SER and RER, a small elongated nuclei and well-developed RER; some have
Golgi apparatus, numerous mitochondria, and small deposits of glycogen. Their long cellular processes
secretory vesicles, some with electron-dense cores. are rich in intermediate filaments, microtubules, and
Pinealocytes also contain a well-developed cytoskeleton microfilaments.
composed of microtubules, microfilaments, and dense The pineal gland also contains concretions of
tubular structures invested by spherical vesicular ele- calcium phosphates and carbonates, which are deposited
ments. These unusual structures, known as synaptic in concentric rings around an organic matrix. These
ribbons (also observed in the retina and inner ear), structures, called corpora arenacea (“brain sand”),
increase in number during the dark period of the appear in early childhood and increase in size throughout
diurnal cycle, but their function is not understood. life. Although it is unclear how they are formed or func-
Melatonin, synthesized from tryptophan by pinealo- tion, they increase during short photoperiods and are
cytes and released at night, inhibits the release of growth reduced when the pineal gland is actively secreting.
hormone and gonadotropin by the hypophysis and hypo-
thalamus, respectively. It has been suggested that mela- Histophysiology of the
tonin induces the feeling of sleepiness and, therefore, Pineal Gland
some individuals use it as a supplement to combat sleep
disorders, mood disorders, and depression. Although the pineal gland is connected to the midline
of the brain as a projection of the roof of the dien-
cephalon, no brain-derived, afferent or efferent nerve
fibers enter the gland. Instead, the pineal body is
CLINICAL CORRELATIONS innervated by postganglionic sympathetic nerves
from the superior cervical ganglion. As the axons enter
It has been suggested that melatonin may act to the gland, their myelin is lost and they synapse on
protect the central nervous system by its ability the pinealocytes. Norepinephrine, released at the
to scavenge and eliminate free radicals that are pinealocytes, controls production of melatonin (see
produced during oxidative stress. Additional Table 13-2). Synthesis of pineal hormones exhibits a
theory suggest that melatonin may alter human diurnal rhythm, in that it is increased during dark
moods, causing depression during shortened periods and is inhibited during light periods. Melatonin
daylight hours of winter months. It has been is released into the connective tissue spaces to be dis-
reported that exposure to bright artificial light tributed by blood vessels, whereas serotonin is taken up
may reduce the secretion of melatonin and may by presynaptic axon terminals. Continued research on
result in alleviation of depression. the pineal gland is focused on the pineal hormones and
their functions.
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14 䡲䡲䡲
Integument
The integument, composed of skin and its apparatus. Additional downgrowths of the epidermal
appendages—the sweat glands, sebaceous glands, derivatives (i.e., hair follicles, sweat glands, and seba-
hair, and nails—is the largest organ of the body, con- ceous glands) that come to lie in the dermis cause the
stituting 16% of body weight. It invests the entire body, interface to have an irregular contour.
becoming continuous with the mucous membranes of The hypodermis, a loose connective tissue contain-
the digestive system at the lips and the anus, the respi- ing varying amounts of fat, underlies the skin. The hypo-
ratory system in the nose, and the urogenital systems dermis is not part of the skin but is the superficial
where they surface. Additionally, the skin of the eyelids fascia of gross anatomical dissection that covers the
becomes continuous with the conjunctiva lining the entire body, immediately deep to the skin. Individuals
anterior portion of the orb. Skin also lines the external who are overnourished or who live in cold climates
auditory meatus and covers the external surface of the possess a large amount of fat deposited in the superfi-
tympanic membrane. cial fascia (hypodermis), named panniculus adiposus.
In certain regions of the body, the skin displays dif-
ferent textures and thicknesses. For example, skin of the
SKIN eyelid is soft, fine, and thin and has fine hairs, whereas
only a short distance away, on the eyebrow, the skin is
Skin, the largest organ of the body, is composed of an thicker and manifests coarse hair. Skin of the forehead
epidermis and the underlying dermis. produces oily secretions; the skin on the chin lacks oily
secretions but develops much hair.
Besides providing a cover for the underlying soft tissues,
The palms of the hands and soles of the feet are thick
skin performs many additional functions, including (1)
and do not produce hair but contain many sweat glands.
protection against injury, bacterial invasion, and desic-
Finger and toe pad surfaces have well-defined, alternat-
cation; (2) regulation of body temperature; (3)
ing ridges and grooves that form patterns of loops, curves,
reception of continual sensations from the environ-
arches, and whorls called dermatoglyphs (fingerprints),
ment (e.g., touch, temperature, and pain); (4) excretion
which develop in the fetus and remain unchanged
from sweat glands; and (5) absorption of ultraviolet
throughout life. Dermatoglyphs are so individualized that
radiation from the sun for the synthesis of vitamin D.
they are used for identification purposes in forensic med-
Skin consists of two layers: an outer epidermis and a
icine and in criminal investigations. Although fingerprints
deeper connective tissue layer, the dermis (Fig. 14-1).
are determined genetically, perhaps by multiple genes,
The epidermis is composed of an ectodermally
other grooves and flexure lines about the knees, elbows,
derived stratified squamous keratinized epithelium.
and hands are, for the most part, related to habitual use
Lying directly below and interdigitating with the epi-
and physical stresses in a person’s environment.
dermis is the dermis, derived from mesoderm and
composed of dense, irregular collagenous connective
tissue. The interface between the epidermis and dermis Epidermis
is formed by raised ridges of the dermis, the dermal
Epidermis, the surface layer of skin, is derived from
ridges (papillae), which interdigitate with invagina-
ectoderm and is composed of stratified squamous
tions of the epidermis called epidermal ridges. Col-
keratinized epithelium.
lectively, the two types of ridges are known as the rete
327
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328 䡲䡲䡲 Chapter 14 䡲 Integument
Hair shaft
Sweat pore
Stratum corneum
Stratum spinosum
Malpighian Epidermis
layer Stratum basale
Melanocyte
Stratum corneum Meissner’s

Stratum lucidum corpuscle
Stratum granulosum Dermis
Epidermis
Hypodermis
Dermis
Stratum Hair follicle
spinosum
Merkel cell Eccrine sweat
Langerhans cell gland
Hair root
Melanocyte Sebaceous gland Artery
Stratum basale Arrector pili muscle Vein
Nerve fiber Adipose tissue
Basement membrane
Blood vessel
THICK SKIN THIN SKIN
Figure 14–1 Comparison of thick skin and thin skin.
The epidermis is 0.07 to 0.12 mm in thickness over most constantly renewed. Renewal is accomplished through
of the body, with increased localized thickening on the mitotic activity of the keratinocytes in the basal layers
palms of the hands and the soles of the feet (where it of the epidermis. Keratinocytes undergo mitosis at
may be as much as 0.8 mm and 1.4 mm in thickness, night, and as the new cells are forming, the cells above
respectively). Thicker skin on the palms and soles is continue to be pushed toward the surface. Along their
evident in the fetus, but use, applied pressure, and fric- way to the surface, the cells differentiate and begin to
tion result in continued increases in skin thickness in accumulate keratin filaments in their cytoplasm.
these areas over time. Eventually, as they near the surface, the cells die and
The stratified squamous keratinized epithelium of are sloughed off, a process that takes 20 to 30 days.
skin is composed of four populations of cells: Because of the cytomorphosis of keratinocytes
during their migration from the basal layer of the epi-
䡲 Keratinocytes
dermis to its surface, five morphologically distinct zones
䡲 Langerhans cells
of the epidermis can be identified. From the inner to
䡲 Melanocytes
the outer layer, they are (1) stratum basale (germi-
䡲 Merkel cells
nativum), (2) stratum spinosum, (3) stratum gran-
ulosum, (4) stratum lucidum, and (5) stratum
Keratinocytes corneum. Skin is classified as thick or thin according to
Keratinocytes, which form the largest population of the thickness of the epidermis (see Fig. 14-1). However,
cells, are arranged in five recognizable layers; the these two classifications are also are distinguished by the
remaining three cell types are interspersed among ke- presence or absence of certain epidermal layers and the
ratinocytes in specific locations (see later). Because ke- presence or absence of hair.
ratinocytes are continually being sloughed from the Thick skin covers the the palms and soles (Table
surface of the epidermis, this cell population must be 14-1). The epidermis of thick skin (see Fig. 14-2), which
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Chapter 14 䡲 Integument ■ ■ ■ 329
TABLE 14–1 Strata and Histological Features of Thick Skin
Layer Histological Features
Epidermis Derived from ectoderm; composed of stratified squamous keratinized epithelium

(keratinocytes)
Stratum corneum Numerous layers of dead flattened keratinized cells, keratinocytes, without nuclei and
organelles (squames, or horny cells) that will be sloughed off
Stratum lucidum* Lightly stained thin layer of keratinocytes without nuclei and organelles; cells contain densely
packed keratin filaments and eleidin
Stratum granulosum* A layer three to five cell layers thick; these keratinocytes still retain nuclei; cells contain large,
coarse keratohyalin granules as well as membrane-coating granules
Stratum spinosum Thickest layer of epidermis, whose keratinocytes, known as prickle cells, interdigitate with
one another by forming intercellular bridges and a large number of desmosomes; prickle
cells have numerous tonofilaments and membrane-coating granules and are mitotically
active; this layer also houses Langerhans cells
Stratum basale This single layer of cuboidal to low columnar, mitotically active cells is separated from the
(germinativum) papillary layer of the dermis by a well-developed basement membrane; Merkel cells and
melanocytes are also present in this layer
Dermis Derived from mesoderm; composed mostly of type I collagen and elastic fibers, the dermis is
subdivided into two regions: the papillary layer and the reticular layer, a dense, irregular
collagenous connective tissue
Papillary layer Interdigitates with epidermis, forming the dermal papilla component of the rete apparatus;
type III collagen and elastic fibers in loose arrangement and anchoring fibrils (type VII
collagen); abundant capillary beds, connective tissue cells, and mechanoreceptors are
located in this layer; occasionally, melanocytes are also present in the papillary layer
Reticular layer Deepest layer of skin; type I collagen, thick elastic fibers, and connective tissue cells; contains
sweat glands and their ducts, hair follicles and arrector pili muscles, and sebaceous glands
as well as mechanoreceptors (such as pacinian corpuscles)
*Present only in thick skin. All layers are usually thinner in thin skin.
is 400 to 600 mm thick, is characterized by the presence The deepest layer of the epidermis, the stratum basale,
of all five layers. Thick skin lacks hair follicles, arrector is supported by a basement membrane and sits on the
pili muscles, and sebaceous glands but does possess dermis, forming an irregular interface. The stratum
sweat glands. basale consists of a single layer of mitotically active,
Thin skin covers most of the remainder of the body. cuboidal to low columnar cells containing basophilic
The epidermis of thin skin, which ranges from 75 to cytoplasm and a large nucleus (Fig. 14-3). Many desmo-
150 mm in thickness, has a thin stratum corneum and lacks somes are located on the lateral cell membrane attach-
a definite stratum lucidum and stratum granulosum, ing stratum basale cells to each other and to cells of the
although individual cells of these layers are present in their stratum spinosum. Basally located hemidesmosomes
proper locations. Thin skin has hair follicles, arrector attach the cells to the basal lamina. Electron micro-
pili muscles, sebaceous glands, and sweat glands. graphs reveal a few mitochondria, a small Golgi
complex, a few rough endoplasmic reticulum (RER)
profiles, and abundant free ribosomes. Numerous
Stratum Basale bundles and single (10-nm) intermediate filaments
(Stratum Germinativum) (tonofilaments) course through the plaques of the
laterally placed desmosomes and end in plaques of
Stratum basale, the germinal layer that undergoes
hemidesmosomes.
mitosis, forms interdigitations with the dermis and is
Mitotic figures should be common in the stratum
separated from it by a basement membrane.
basale because this layer is partially responsible for cell
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SS
SB
ER
D
DR
Figure 14–3 Light micrograph of thick skin demonstrating the

BV stratum basale (SB) and stratum spinosum (SS) (×540).
Figure 14–2 Light micrograph of thick skin (×132). Observe the richer in bundles of intermediate filaments (tonofila-
epidermis (E) and dermis (D) as well as the dermal ridges (DR) that
are interdigitating with epidermal ridges (ER). Several blood vessels ments), representing cytokeratin, than cells in the
(BV) are present. stratum basale. In the stratum spinosum cells, these
bundles radiate outward from the perinuclear region
toward highly interdigitated cellular processes, which
renewal in the epithelium. However, mitosis occurs attach adjacent cells to each other by desmosomes.
mostly during the night, and histological specimens are These processes, called “intercellular bridges” by early
procured during the day; thus, mitotic figures are rarely histologists, give cells of the stratum spinosum a “prickle
seen in histological slides of skin. When new cells are cell” appearance (see Fig. 14-3). As keratinocytes move
formed via mitosis, the previous layer of cells is pushed toward the surface through the stratum spinosum, they
surfaceward to join the next layer of the epidermis, the continue to produce tonofilaments, which become
stratum spinosum. grouped in bundles called tonofibrils, causing the
cytoplasm to become eosinophilic (Fig. 14-4). Cells
Stratum Spinosum of the stratum spinosum also contain cytoplasmic
secretory granules (0.1 to 0.4 µm in diameter) called
The stratum spinosum is composed of several layers of membrane-coating granules (lamellar granules).
mitotically active polymorphous cells whose numerous These flattened vesicles house lipid substance arranged
processes give this layer a prickly appearance. in a closely packed, lamellar configuration.
The thickest layer of the epidermis is the stratum spi- Stratum Granulosum
nosum, composed of polyhedral to flattened cells. The
basally located keratinocytes in the stratum spinosum The stratum granulosum is composed of three to five
also are mitotically active, and the two strata together, layers of cells housing keratohyalin granules.
frequently referred to as the malpighian layer, are
responsible for the turnover of epidermal keratinocytes. The stratum granulosum, consisting of three to five
Keratinocytes of the stratum spinosum have the same layers of flattened keratinocytes, is the most superficial
organelle population as described for the stratum layer of the epidermis in which cells still possess nuclei.
basale. However, the cells in the stratum spinosum are The cytoplasm of these keratinocytes contains large,
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graph of the stratum spinosum
(×6800). The tonofibrils (arrows)
and the cytoplasmic processes are
bridging the intercellular spaces.
(From Leeson TS, Leeson CR, and
Paparo AA: Text-Atlas of Histology.
irregularly shaped, coarse, basophilic keratohyalin Stratum Corneum

granules, which are not membrane-bound. Bundles of
keratin filaments pass through these granules. The stratum corneum is composed of several layers of
Cells of the stratum granulosum also contain mem- flattened, keratin-containing dead cells known as
brane-coating granules. The contents of these granules squames.
are released by exocytosis into the extracellular space,
forming sheets of lipid-rich substance that acts as a The most superficial layer of skin, the stratum corneum,
waterproof barrier, one of the functions of skin. This is composed of numerous layers of flattened, kerat-
impermeable layer prevents cells lying superficial to this inized cells with a thickened plasmalemma. These cells
region from being bathed in the nutrient-filled aqueous lack nuclei and organelles but are filled with keratin fil-
extracellular fluid, thus hastening their death. aments embedded in an amorphous matrix. Those cells
farther away from the skin surface display desmosomes,
Stratum Lucidum whereas cells near the surface of the skin, called
squames, or horny cells, lose their desmosomes and
Present only in thick skin, cells of the stratum lucidum become desquamated (sloughed off).
are devoid of nuclei and organelles but contain eleidin.
Nonkeratinocytes in the Epidermis
The clear, homogeneous, lightly staining, thin layer of
In addition to keratinocytes, the epidermis contains
cells immediately superficial to the stratum granulosum
three other cell types: Largerhans cells, merkel cells,
is the stratum lucidum. This layer is present only in
and melanocytes.
thick skin (i.e., palms of the hands and soles of the feet).
Although the flattened cells of the stratum lucidum lack Langerhans Cells
organelles and nuclei, they contain densely packed
keratin filaments oriented parallel to the skin surface Langerhans cells are antigen-presenting cells located
and eleidin, a transformation product of keratohyalin. among the cells of the stratum spinosum.
The cytoplasmic aspect of the plasma membrane of
these cells has a thickened appearance because of the Although they are scattered throughout the epidermis
deposition of a nonkeratin protein, known as involu- where they normally represent 2% to 4% of the epi-
crin, whose function is not known. dermal cell population, Langerhans cells, sometimes
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called dendritic cells because of their numerous long and in the processes, whose function is unclear, are the
processes, are located primarily in the stratum spino- distinguishing feature of Merkel cells.
sum. These cells also may be found in the dermis as well Myelinated sensory nerves traverse the basal lamina
as in the stratified squamous epithelia of the oral cavity, to approximate the Merkel cells, thus forming Merkel
esophagus, and vagina. However, they are most preva- cell–neurite complexes. These complexes may func-
lent in the epidermis, where their numbers may reach tion as mechanoreceptors. These cells exhibit a
800 per mm2. synaptophysin-like immunoreactivity, indicating that
Viewed with light microscopy, Langerhans cells Merkel cells may release neurocrine-like substances,
display a dense nucleus, pale cytoplasm, and long suggesting that the cells display diffuse neuroendocrine
slender processes that radiate out from the cell body system–related activity.
into the intercellular spaces between keratinocytes.
Electron micrographs reveal the nucleus to be poly- Melanocytes
morphous; the electron-lucent cytoplasm houses a few
mitochondria, sparse RER, and no intermediate fila- Melanocytes, derived from neural crest cells, produce
ments but contains lysosomes, multivesicular bodies, melanin pigment that imparts a brown coloration to
and small vesicles. Although the irregularly contoured skin.
nucleus and the absence of tonofilaments distinguish
Langerhans cells from surrounding keratinocytes, the Melanocytes, derived from the neural crest, are located
most unique feature of Langerhans cells are the among the cells of the stratum basale, although they
membrane-bound Birbeck granules (vermiform may also reside in the superficial portions of the dermis
granules), which in section resemble Ping-Pong (Fig. 14-6).
paddles (15 to 50 nm in length and 4 nm thick). These Melanocytes are round to columnar cells whose long,
granules form as a result of clathrin-assisted endocyto- undulating processes extend from the superficial sur-
sis; however, their function is not known. faces of the cells and penetrate the intercellular spaces
Langerhans cells, once thought to be derived from of the stratum spinosum (see Fig. 14-6). Tyrosinase pro-
neural crest cells, are now known to originate from pre- duced by the RER of the melanocyte is packaged by its
cursors in the bone marrow and are a part of the Golgi apparatus into oval granules known as melano-
mononuclear phagocyte system. Although they are somes (although the melanosomes of red-haired indi-
capable of mitosis, this activity is restricted; thus, they viduals are round instead of oval). The amino acid
are continually replaced by precursor cells leaving the tyrosine is preferentially transported into melanosomes,
bloodstream to migrate into the epidermis and differ- where tyrosinase converts it into melanin by means of
entiate into Langerhans cells. These cells function in a series of reactions progressing through 3,4-dihydroxy-
the immune response. and have cell-surface Fc (anti- phenylalanine (dopa, methyldopa) and dopaquinone. It
body) and C3 (complement) as well as other receptors, is interesting that the enzyme tyrosinase is activated by
and they phagocytose and process foreign antigens, ultraviolet light.
after which they migrate to lymph nodes in the vicinity,
where they present epitopes of processed foreign anti-
gens to T lymphocytes; thus, Langerhans cells are CLINICAL CORRELATIONS
antigen-presenting cells.
Ultraviolet light darkens the melanin and speeds
tyrosinase synthesis, thus increasing melanin
Merkel Cells production. Also, pituitary ACTH influences
pigmentation. In Addison’s disease there is
Merkel cells, scattered among cells of the stratum
insufficient production of cortisol by the adrenal
basale, may serve as mechanoreceptors.
cortex so excess ACTH is produced, which leads
Merkel cells, which are interspersed among the kerat- to hyperpigmentation.
inocytes of the stratum basale of the epidermis, are espe- Albinism is the absence of melanin produc-
cially abundant in the fingertips and oral mucosa and at tion resulting from a genetic defect in tyrosinase
the base of hair follicles. These cells are derived from the synthesis. Melanosomes are present but the
neural crest and are usually found as single cells oriented melanocytes fail to produce tyrosinase.
parallel to the basal lamina; however, they may extend
their processes between keratinocytes, to which they are
attached by desmosomes (Fig. 14-5). Merkel cell nuclei Melanosomes leave the cell body of the melanocytes
are deeply indented, and three types of cytokeratins and travel to the tips of their long processes. Once there,
within the cytoplasm make up the cytoskeletal filaments. the tips of the melanocyte processes penetrate the
Dense-cored granules located in the perinuclear zone cytoplasm of the stratum spinosum cells and become
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Figure 14–5 Electron micrograph of a Merkel

cell (M) and its nerve terminal (NT) in an adult rat.
(Scale bar = 0.5 µm). Note the spine-like processes
(asterisks) that project into the intercellular spaces of
the stratum spinosum. Merkel cells form desmo-
somes (d) with cells of the stratum spinosum and
share the basal lamina (bl) of cells of the stratum
basale. (From English KB, Wang ZZ, Stayner N,
et al: Serotonin-like immunoreactivity in Merkel’s
cells and their afferent neurons in touch domes from
hairy skin of rats. Anat Rec 232:112-120, 1991.)
pinched off via a special secretory process called of melanocytes but to an increase in their tyrosinase
cytocrine secretion. Each truncated melanocyte activity.
process elongates and receives more melanosomes, and Although limited exposure to ultraviolet radiation
the cycle is repeated. A particular melanocyte serves a increases the size and functional activity of melanocytes,
number of keratinocytes with which it is associated, con- their population remains the same. After continued
stituting an epidermal melanin unit. Within the cells exposure to ultraviolet radiation, however, there is also
of the stratum intermedium, the melanosomes are trans- an increase in the melanocyte population. In Blacks,
ported to the supranuclear region (that is, between the melanosomes are large, numerous, and dispersed
nucleus and the surfacemost region of the cell) so that throughout the cytoplasm of the keratinocytes, whereas
the melanosomes form a protective barrier between the in Caucasians, melanosomes are smaller and fewer and
nucleus and the impinging ultraviolet rays from the congregate in the vicinity of the nucleus. Also, melano-
sun. Eventually, the melanin pigment is attacked and somes are degraded and removed more rapidly in the
degraded by lysosomes of the keratinocyte. This process Caucasian population than in the Black population.
occurs over a period of several days.
The number of melanocytes per square millimeter
varies in different regions of skin of an individual, CLINICAL CORRELATIONS
ranging from 800 to 2300. For example, there are much
fewer melanocytes on the insides of the arms and thighs Ultraviolet rays exist as two types. Ultraviolet
than on the face. The difference in skin pigmentation is B (UVB) is the component in sunlight that pro-
related more to location of the melanin than to the total duces sunburn, whereas ultraviolet A (UVA) is
number of melanocytes in the skin, which is nearly the responsible for tanning. Until recently, it was
same for all races. For instance, there are more believed that UVA was relatively safe but it
melanocytes in the skin on the dorsum than on the appears that UVA radiation penetrates the skin
palmar surface of the hand; however, these numbers are and damages the deep layers, producing muta-
very similar among the various races. The reason for the tions that are implicated in tumor progression.
darker pigmentation is due not to the effective number
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Sunlight: Increases production and changes thicker in men than in women and on the dorsal rather
chemical characteristics of melanin. than on the ventral surfaces of the body.
Stratum Papillary Layer of the Dermis
spinosum
The most superficial layer of the dermis, the papillary
layer, interdigitates directly with the epidermis but is
separated from it by the basement membrane.
The superficial papillary layer of the dermis is uneven

where it interdigitates with the epidermis, forming the
dermal ridges (papillae) (see Fig. 14-2). It is composed
Pinched
of a loose connective tissue whose thin, type III colla-
off Melanin granule gen fibers (reticular fibers) and elastic fibers are
(no tyrosinase arranged in loose networks. Anchoring fibrils, com-
activity)
posed of type VII collagen, extend from the basal lamina
into the papillary layer, binding the epidermis to the
dermis (see Chapter 4, Figs. 4-13 and 4-14). The papil-
lary layer contains fibroblasts, macrophages, plasma cells,
Golgi Melanosome mast cells, and other cells common to connective tissue.
(tyrosinase The papillary layer also possesses many capillary
and melanin)
loops, which extend to the epidermis-dermis interface.
These capillaries regulate body temperature and nourish
the cells of the avascular epidermis. Located in some
dermal papillae are pear-shaped encapsulated Meissner
corpuscles, mechanoreceptors specialized to respond
to slight deformations of the epidermis. These receptors
are most common in areas of the skin that are especially
Melanocyte sensitive to tactile stimulation (e.g., lips, external geni-
Tyrosinase Stratum basale
is synthesized cell talia, and nipples). Another encapsulated mechanore-
in RER ceptor present in the papillary layer is the Krause end
bulb. Although this receptor was once thought to
Figure 14–6 Melanocytes and their function. RER, rough endo- respond to cold, its function is currently unclear.
plasmic reticulum.
Reticular Layer of the Dermis
The reticular layer of the dermis also contains
Dermis (Corium) epidermally derived structures, including sweat glands,
hair follicles, and sebaceous glands.
The dermis, the layer of skin immediately deep to the
epidermis, is derived from mesoderm and comprises a The interface between the papillary layer and reticular
loose papillary layer and a deeper, denser reticular layer. layer of the dermis is indistinguishable because the two
layers are continuous with each other. Characteristi-
The region of the skin lying directly beneath the epi- cally, the reticular layer is composed of dense, irregular
dermis, called the dermis, is derived from the meso- collagenous connective tissue, displaying thick type I
derm and is divided into two layers: the superficial, collagen fibers, which are closely packed into large
loosely woven papillary layer and the deeper, much bundles lying mostly parallel to the skin surface. Net-
denser reticular layer. The dermis is composed of works of thick elastic fibers are intermingled with the
dense, irregular collagenous connective tissue, contain- collagen fibers, appearing especially abundant near
ing mostly type I collagen fibers and networks of elastic sebaceous and sweat glands. Proteoglycans, rich in der-
fibers, which support the epidermis and bind the skin matan sulfate, fill the interstices of the reticular layer.
to the underlying hypodermis (superficial fascia). The Cells are more sparse in this layer than in the papillary
dermis ranges in thickness from 0.6 mm in the eyelids layer. They include fibroblasts, mast cells, lymphocytes,
to 3 mm or so on the palm of the hand and the sole of macrophages, and, frequently, fat cells in the deeper
the foot. However, there is not a sharp line of demar- aspects of the reticular layer.
cation at its interface with the underlying connective Sweat glands, sebaceous glands, and hair folli-
tissue of the superficial fascia. Normally, the dermis is cles, all derived from the epidermis, invade the dermis
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and hypodermis during embryogenesis, where they Epidermis-Dermis Interface

remain permanently (see Fig. 14-1). Groups of smooth
muscle cells are located in the deeper regions of the The interdigitation of the epidermal ridges with the
reticular layer at particular sites such as the skin of the dermal ridges is known as the rete apparatus.
penis and scrotum and the areola around the nipples;
contractions of these muscle groups wrinkle the skin in The interdigitations of the epidermal and dermal layers
these regions. Other smooth muscle fibers, called are translated through the epidermis and are apparent on
arrector pili muscles, are inserted into the hair folli- the surface of the skin, especially of the palms and soles,
cles; contractions of these muscles erect the hairs when where they are represented by whorls, arches, and loops
the body is cold or suddenly exposed to a cold environ- (dermatoglyphs or fingerprints). Because these interdig-
ment, giving the skin “goose bumps.” Additionally, a itations are not easily visualized from two-dimensional
particular group of striated muscles located in the face, histological sections, ethylenediaminetetraacetic acid
parts of the anterior neck, and scalp (muscles of facial (EDTA) can be used to chelate calcium ions (Ca2+) of
expression) originate in the superficial fascia and insert hemidesmosomes, permitting the dissociation of the epi-
into the dermis. dermis from the dermis. Once the epidermis and dermis
At least two types of encapsulated mechanoreceptors are dissociated, the three-dimensional surface of the
are located in the deeper portions of the dermis: (1) papillary layer of the dermis may be examined with scan-
pacinian corpuscles, which respond to pressure and ning electron microscopy.
vibrations, and (2) Ruffini corpuscles, which respond The papillary layer presents parallel primary
to tensile forces. The latter are most abundant in the dermal ridges on its surface separated by primary
dermis of the soles of the feet. grooves, which house projections of the epidermis (see
Freckles are hyperpigmented spots located on sun- the epidermis and usually is caused by exposure to
exposed areas of the skin, especially in fair-skinned ultraviolet radiation. Although basal cell carcinomas
individuals who sunburn easily. Freckles are usually do not usually metastasize, they are destructive to
exhibited by 3 years of age and are the result of local tissue. Of the several types of lesions that occur,
increased melanin production and accumulation in the most common is the nodular variety, character-
the basal area of the epidermis without an increase ized by a papule or nodule with a central depressed
in melanocytes. They tend to fade in the winter and “crater” that eventually ulcerates and crusts. These
darken with exposure to ultraviolet light. lesions are most common on the face, especially the
Psoriasis is a disease characterized by patchy nose. Surgery is the usual treatment, and up to 90%
lesions caused by greater keratinocyte proliferation of patients recover with no additional sequelae.
in the stratum basale and stratum spinosum and an Squamous cell carcinoma, the second most
accelerated cell cycle (turnover is increased as much common skin cancer, arises in the keratinocytes of
as seven times), resulting in accumulations of ker- the epidermis. It is locally invasive and may metas-
atinocytes and stratum corneum. The lesions are tasize. It is characterized by a hyperkeratotic scaly
common on the scalp, elbows, and knees, but they plaque or nodule that often bleeds or ulcerates. It
may occur almost anywhere on the body. In some invades deeply, resulting in fixation to the underly-
cases, the nails may also be involved. Psoriasis is an ing tissues. Several factors may cause this disease,
incurable but manageable chronic condition whose including ultraviolet radiation, x-irradiation, soot,
symptoms periodically escalate and then diminish chemical carcinogens, and arsenic. The lesions are
with no apparent cause. most common on the head and neck. Surgery is the
Warts are benign epidermal growths caused by usual treatment of choice.
infection of the keratinocytes with papillomavir- Malignant melanoma, a skin cancer, is most
uses. The resulting epidermal hyperplasia thickens prevalent in fair-skinned individuals and is increasing
the epidermis with scaling. Deeper ingrowth of the in incidence. It is usually associated with excessive
dermis brings capillaries closer to the surface. Warts exposure to the sun. Malignant melanoma is very inva-
are common in children, young adults, and immuno- sive because the malignant cells originate from trans-
suppressed patients. formed melanocytes; the melanocytes penetrate the
Basal cell carcinoma, the most common human dermis and enter lymphatic vessels as well as the blood-
malignancy, arises in the stratum basale cells of stream to gain wide distribution throughout the body.
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Fig. 14-2). In the center of each primary dermal ridge

is a secondary groove, which receives a downgrowth
of the epidermis known as an interpapillary peg. Along
this and other adjacent ridges are rows of round-topped
dermal papillae that project into concavities in the
epidermis, thus firmly interlocking the epidermis and
dermis at the interface. The epidermis-dermis interface
d
in thin skin is much less complex, lacking such deep and
widespread interlocking.
Histophysiology of Skin
The structural protein produced by the keratinocytes is
keratin, which forms 10-nm filaments within the cyto- L
plasm of keratinocytes. Approximately 10 different
species of keratin have been identified, and four of
these are present within the epidermis.
Stratum basale cells synthesize two of the four ker-
atins, whereas the cells of the stratum spinosum synthe-
size the other two, which tend to form coarser bundles of
filaments. Cells of the stratum spinosum also produce
and deposit the protein involucrin on the cytoplasmic
aspect of their plasmalemma. Moreover, cells of the
stratum spinosum also form the membrane-coating
granules, which later release their lipid-rich contents S
into the intercellular spaces, forming a permeability barrier.
The keratin-synthesizing machinery shuts down after
keratinocytes enter the stratum granulosum. The cells in S
this layer produce filaggrin, a protein thought to help
assemble keratin filaments into still coarser bundles.
Once keratinocytes reach this stratum they also become Figure 14–7 Light micrograph of sweat gland showing secretory
permeable to calcium ions, which assist in cross-linking units (S) and ducts (d), some displaying a lumen (L) (×132).
involucrin with other proteins, thereby forming a tough
layer beneath the plasmalemma. As keratinocytes
move through the stratum granulosum into the stratum
lucidum, enzymes released from lysosomes digest the
organelles and the nucleus. When the cells finally enter Eccrine sweat glands are about 0.4 mm in diameter and
the stratum corneum, they are nonliving, organelle-free, are located in the skin throughout most of the body.
tough shells filled with bundles of keratin filaments. Numbering as many as 3 to 4 million, they are impor-
Epidermal growth factor (EGF) and interleukin tant organs of thermoregulation. Eccrine sweat glands
(IL-1a) influence the growth and development of develop as invaginations of the epithelium of the dermal
keratinocytes, at least in tissue culture. In contrast, ridge that grows down into the dermis, with its deep
transforming growth factor (TGF) suppresses ker- aspect becoming the glandular portion of the sweat
atinocyte proliferation and differentiation. gland. These glands, which begin to function soon after
birth, excrete sweat and may secrete as much as 10 L
Glands of the Skin of sweat a day under extreme conditions in highly active
people engaged in vigorous exercise.
The glands of the skin include eccrine glands, apocrine Eccrine sweat glands are simple coiled tubular
sweat glands, sebaceous glands, and the mammary glands located deep in the dermis or in the underlying
gland (a modified and highly specialized type of sweat hypodermis (Figs. 14-7 and 14-8). Passing from the
gland). The mammary gland is described in Chapter 20. secretory portion of each gland is a slender, coiled duct
that traverses the dermis and epidermis to open on the
Eccrine Sweat Glands surface of the skin at a sweat pore. Eccrine sweat
glands are merocrine in their method of releasing their
Eccrine sweat glands are abundant throughout the skin.
secretory product. The eccrine glands are innervated by
They release their secretory product, sweat, via the
postganglionic fibers of the sympathetic nervous
merocrine method of secretion.
system.
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Sebaceous gland
cell (late stage)
Sebaceous gland cell

(early stage)
Myoepithelial Excretory duct

cell
Sebaceous gland
Dark cell
Eccrine sweat
Clear cell gland
Figure 14–8 An eccrine sweat gland and a sebaceous gland and their constituent cells.
Secretory Unit dense glycoprotein-containing secretory granules are

located in the apical cytoplasm of the dark cells, and the
The secretory portion of the gland is said to be a simple secretion released by these cells is mucous in nature.
cuboidal to low columnar epithelium composed of dark
cells and clear cells; however, some investigators con-
sider the secretory portion to be pseudostratified. CLEAR CELLS
DARK CELLS (MUCOID CELLS) Clear cells do not possess secretory granules; they
release a watery secretion.
Dark cells line the lumen of the secretory unit and
secrete a mucus-rich substance. Clear cells have a narrow apical area and a broader base
that extends to the basal lamina. Unlike dark cells, clear
Dark cells resemble an inverted cone, with the broad cells do not contain secretory granules but do contain
ends lining the lumen. The narrowed ends, which accumulations of glycogen; their organelles are similar
seldom reach the basal lamina, conform to fit between to those of dark cells, except that they have little RER.
adjacent clear cells. Electron micrographs reveal some The bases of the clear cells are tortuously infolded,
RER, numerous free ribosomes, elongated mitochon- similar to those of other cell types involved in transep-
dria, and a well-developed Golgi complex. Moderately ithelial transport. Clear cells have limited access to the
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lumen of the gland because of the dark cells; therefore, auditory canal and the glands of Moll in the eyelids.
their watery secretion enters intercellular canali- Apocrine sweat glands are much larger than eccrine
culi interposed between adjacent clear cells, where it sweat glands, up to 3 mm in diameter. These glands are
mixes with the mucous secretion of the dark cells. embedded in the deeper portions of the dermis and
hypodermis. Unlike the ducts of eccrine sweat glands,
MYOEPITHELIAL CELLS which open onto the skin surface, the ducts of apocrine
sweat glands open into canals of the hair follicles just
Myoepithelial cells surrounding the secretory portion of superficial to the entry of the sebaceous gland ducts.
the gland contain actin and myosin, imparting a The secretory cells of apocrine glands are simple
contractile ability to these cells. cuboidal to low columnar in profile. When the lumen of
the gland is filled with secretory product, these cells
Myoepithelial cells surrounding the secretory portion of may become squamous. The lumina of these glands are
the eccrine sweat glands are enveloped by the basal much larger than those of eccrine glands, and the secre-
lamina of the secretory cells. The cytoplasm of myoep- tory cells contain granules that are isolated from the
ithelial cells has myosin filaments as well as many apical membrane by a prominent terminal web. The
deeply acidophil-staining actin filaments, which give viscous secretory product of apocrine glands is odorless
the cell contractile capability. Contractions of the upon secretion, but when metabolized by bacteria, it
myoepithelial cells assist in expressing the fluid from the presents a distinctive odor. Myoepithelial cells surround
gland. the secretory portion of the apocrine sweat glands and
assist in expressing the secretory product into the duct
Duct of the gland.
The duct of eccrine sweat glands, composed of basal and
An apocrine sweat gland arises from the epithelium
luminal cells, is highly coiled and traverses the dermis
of the hair follicles as an epithelial bud that develops
and epidermis on its way to opening on the skin surface.
into a gland. Secretion by apocrine glands is under the
influence of hormones and does not begin until puberty.
The duct of an eccrine sweat gland is continuous with Their innervation is provided by fibers of the postgan-
the secretory unit at its base but narrows as it passes glionic sympathetic nervous system. Because of the sim-
through the dermis on its way to the epidermal surface. ilarity of their location, their histology, and the fact that
The duct is composed of a stratified cuboidal epithe- the odor is most likely due to the bacterial metabolism
lium made up of two layers (see Figs. 14-7 and 14-8). of 3-methyl-1,2-hexanoic acid (a volatile acid similar to
The cells of the basal layer have a large, heterochro- pheromone signals), it is speculated that apocrine sweat
matic nucleus and abundant mitochondria. The cells of glands evolved from glands that secrete sex attractants
the luminal layer have an irregularly shaped nucleus, in lower animals. As an interesting note, apocrine sweat
little cytoplasm, only a few organelles, and a terminal glands in women undergo cyclical changes that seem to
web immediately deep to the apical plasma membrane. be related to the menstrual cycle—that is, the secretory
The ducts follow a helical path through the dermis. cells and lumina enlarge before the premenstrual
As a duct reaches the epidermis, keratinocytes envelop period and diminish during menstruation.
the duct on its way to the sweat pore. The fluid secreted The term apocrine given to these special sweat
by the secretory portion of the gland is similar to blood glands implies that the secretion contains a portion of
plasma in regard to electrolyte balance, including potas- the cytoplasm of the secreting cells. Although some
sium and sodium chloride as well as ammonia and urea. researchers suggest that these cells release their secre-
However, most of the potassium, sodium, and chloride tion via the apocrine method, most investigators report
ions are reabsorbed by cells of the duct as the secretion that, despite their name, apocrine sweat glands release
travels through its lumen. Duct cells excrete ions, urea, their secretory product via the merocrine mode of
lactic acid, and some drugs into the lumen. secretion.
Apocrine Sweat Glands Sebaceous Glands

Apocrine sweat glands are found only in the axilla, Sebaceous glands secrete an oily substance known as
areola of the nipple, and anal region and may represent sebum, which maintains the suppleness of the skin.
vestigial scent glands.
Except for the palms of the hands, soles of the feet, and
Apocrine sweat glands are found only in certain loca- sides of the feet inferior to the hairline, sebaceous
tions: the axilla (arm pit), the areola of the nipple, and glands are found throughout the body, embedded in the
the anal region. Modified apocrine sweat glands consti- dermis and hypodermis. These glands are most abun-
tute the ceruminous (wax) glands of the external dant on the face, scalp, and the forehead. The secretory
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product of the sebaceous glands, sebum, is a wax-like, basal cells and larger round cells. The larger cells have
oily mixture of cholesterol, triglycerides, and secretory abundant SER and cytoplasm filled with lipid droplets.
cellular debris. Sebum is believed to facilitate the main- The central region of the acinus is filled with cells in dif-
tenance of proper skin texture and hair flexibility. ferent stages of degeneration. These pale-staining cells
Like apocrine sweat glands, sebaceous glands are display only strands of cytoplasm, deeply staining
appendages of hair follicles. The ducts of the sebaceous pyknotic nuclei, ruptured plasmalemmae, and coalesc-
glands open into the upper third of the follicular canal, ing lipid droplets. Lipid synthesis continues for a short
where they discharge their secretory product to coat the time, followed by necrosis of the cells and the ultimate
hair shaft and, eventually, the skin surface (see Fig. 14- release of lipid and cellular debris, which form the
8). The ducts of sebaceous glands in certain regions of secretory product (holocrine secretion). The secretory
the body lacking hair follicles (i.e., the lips, glans penis, product is released into a duct lined with a stratified
areola of the nipples, labia minora, and mucous surface squamous epithelium that is continuous with the follic-
of the prepuce) open onto the surface of the skin to ular canal at the hair follicle.
empty their secretions. Sebaceous glands are under the
influence of sex hormones and increase their activity
greatly after puberty.
Sebaceous glands are lobular with clusters of acini CLINICAL CORRELATIONS
opening into single short ducts. Each acinus is com- Acne, the most common disease seen by der-
posed of peripherally located small basal cells (resting matologists, is a chronic inflammatory disease
on the basal lamina), which surround larger round cells involving the sebaceous glands and hair follicles.
that fill the remainder of the acinus (Fig. 14-9). The Obstructions resulting from impaction of sebum
basal cells have a spherical nucleus, both smooth endo- and keratinous debris within hair follicles is one
plasmic reticulum (SER) and RER, glycogen, and lipid cause of acne lesions. Anaerobic bacteria near
droplets. These cells undergo cell division to form more these obstructions may contribute to develop-
ment of acne, although the role of bacteria is not
clear. However, the efficacy of antibiotic treat-
ment for acne supports the idea of bacterial
involvement in its pathogenesis. The disease is
most severe in boys, with onset commonly from
age 9 to 11 years, when increasing levels of sex
hormones begin to stimulate the sebaceous
glands. Acne usually subsides through the later
AP teen years, but it may not resolve until the fourth
decade of life. In some people, acne does not
begin until adulthood.
Hair
Hairs are filamentous, keratinized structures that
project from the epidermal surface of the skin (see Fig.
N
14-1). Hair grows over most of the body except on the
vermilion zone of the lips, palms and sides of the palms,
soles and sides of the feet, dorsum of the distal pha-
langes of the fingers and toes, glans penis, glans clitoris,
labia minora, and vestibular aspect of the labia majora.
Two types of hairs are present on the human body.
Hairs that are soft, fine, short, and pale (e.g., those cov-
SG ering the eyelids) are called vellus hairs; those that are
hard, large, coarse, long, and dark (e.g., those of the
scalp and eyebrows) are called terminal hairs. Addi-
tionally, very fine hair, called lanugo, is present on the
Figure 14–9 Light micrograph showing human sebaceous fetus.
glands (SG) and the nuclei (N) of their cells (×132). AP, arrector pili The number of hairs on humans is essentially the
muscle. same as on other primates, but most human hair is of
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the vellus type, whereas terminal hairs predominate on the shape of the dermal papilla occupying it. The hair
other primates. Human hair does not provide thermal root and the dermal papilla together are known as the
insulation, as does the fur of animals. Instead, human hair bulb. The dermal papilla contains a rich supply of
hairs serve in tactile sensation, such that any stimulus capillaries that provide nutrients and oxygen for the
that deforms a hair is translated down the shaft to cells of the hair follicle. The dermal papilla also acts as
sensory nerves that surround the hair follicle. an inductive force controlling the physiological activi-
Hair growth is optimal from about 16 to 46 years of ties of the hair follicle.
age; after age 50, hair growth begins to diminish. The bulk of the cells composing the hair root is called
During pregnancy, hair growth is normal; after parturi- the matrix. Proliferation of these matrix cells accounts
tion, the cycle of hair growth subsides and hair loss is for the growth of hair; thus, they are homologous to the
temporarily increased. stratum basale of the epidermis. The outer layers of fol-
licular epithelium form the external root sheath,
Hair Follicles which is composed of a single layer of cells at the hair
bulb and several layers of cells near the surface of the
Hair follicles develop from the epidermis and invade the skin (Fig. 14-12).
dermis and hypodermis. The external root sheath surrounds several layers of
epidermally derived cells, the internal root sheath,
Hair follicles, the organs from which hairs develop, arise which consists of three components: (1) an outer single
from invaginations of the epidermis that invade the row of cuboidal cells, Henle’s layer, which contacts the
dermis, hypodermis, or both. Hair follicles are sur- innermost layer of cells of the external root sheath; (2)
rounded by dense accumulations of fibrous connective one or two layers of flattened cells forming Huxley’s
tissue belonging to the dermis (Fig. 14-10). A thickened layer; and (3) the cuticle of the internal root sheath,
basement membrane, the glassy membrane, separates formed by overlapping scale-like cells whose free ends
the dermis from the epithelium of the hair follicle (Fig. project toward the base of the hair follicle. The internal
14-11). The expanded terminus of the hair follicle, the root sheath ends where the duct of the sebaceous gland
hair root, is indented, and the concavity conforms to attaches to the hair follicle (see Fig. 14-12).
HR
E
C I
P
Figure 14–10 Light micrograph of a longitudinal section of a Figure 14–11 Light micrograph of hair follicles in cross section
hair follicle with its hair root (HR) and papilla (P) (×132). The dark (×132). Observe the external root sheath (E), the internal root sheath
areas (arrow) are pigment. (I), and the cortex (C).
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Medulla
Cortex Hair
Cuticle
Cuticle
Huxley’s layer Internal root
Henle’s layer sheath
External root
sheath
Glassy membrane
Hair follicle
Figure 14–12 The hair follicle.
The hair shaft is a long slender filament that extends chohyalin granules (resembling keratohyalin granules
to and through the surface of the epidermis (Fig. of the epidermis). These granules coalesce, forming an
14-13). It consists of three regions: medulla, cortex, and amorphous substance in which the keratin filaments are
the cuticle of the hair. As the cells of the matrix within embedded. Scattered among the cells of the matrix
the hair root proliferate and differentiate, they move nearest to the dermal papilla are large melanocytes,
toward the surface of the skin, eventually developing into with long dendritic processes that transfer melano-
the hair shaft. The cells in the center of the matrix are somes to the cells of the cortex. The melanosomes
closest to the underlying dermal papilla and thus are most remain in these cells, imparting to the hair a color based
influenced by it; cells lying more and more peripheral on the amount of melanin present. With age, the
to the matrix center are progressively less influenced by melanocytes gradually lose their ability to produce
the dermal papilla. The distinctive layers of the follicle tyrosinase, which is essential for the production of
develop from different matrix cells as follows: melanin, and the hair becomes gray.
䡲 The most central matrix cells give rise to large vac-
uolated cells that form the core of the hair shaft (the Arrector Pili Muscles
medulla). This layer is present only in thick hair.
䡲 Matrix cells slightly peripheral to the center become Arrector pili muscles are smooth muscle cells extending
the cortex of the hair shaft. from midshaft of the hair follicle to the papillary layer
䡲 More peripheral matrix cells become the cuticle of of the dermis.
the hair.
Attached to the connective tissue sheath surrounding
䡲 The most peripheral matrix cells develop into the
the hair follicles and to the papillary layer of the dermis
cells of the internal root sheath.
are the arrector pili muscles (see Fig. 14-1). These
As the cells of the cortex are displaced surfaceward, smooth muscles attach to the hair follicle above its
they synthesize abundant keratin filaments and tri- middle at an oblique angle. Contractions of these
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monkey scalp that shows three hair shafts and their
sebaceous glands surrounded by the dense, irregular,
collagenous connective tissue of the dermis (×235). (From
Leeson TS, Leeson, CR, and Paparo AA: Text/Atlas of
Histology. Philadelphia, WB Saunders, 1998.)
muscles depress the skin over their attachment and an axillary hair is roughly 4 months, whereas scalp hair
elevate the hair shaft and the skin around the hair shaft, may remain in the anagen phase for as long as 6 years
forming tiny “goose bumps” on the surface of the skin. and in the telogen phase for 4 months.
These are easily observed when a person is chilled or Hair follicles in certain regions of the body respond
suddenly frightened. to male sex hormones. For this reason, men begin to
develop more dark-pigmented terminal hairs about the
chin, cheeks, and upper lip at puberty. Although women
Histophysiology of Hair possess the same number of hair follicles in these
Hair grows at an average rate of about 1 cm/month, but regions, these hairs remain the fine, pale, vellus type. In
hair growth is not continuous. The hair growth cycle both sexes at puberty, however, heavily pigmented,
consists of three successive phases: (1) the growth coarse terminal hairs begin to grow in the axillary and
period, the anagen phase; (2) a brief period of involu- pubic regions.
tion, the catagen phase; and (3) the final phase of rest, The keratinization processes in hair and in skin,
the telogen phase, in which the mature, aged hair is although generally similar, differ in some respects. The
shed (falls out or is pulled out). Hairs shed in this fashion superficial cell layers of the epidermis of the skin form
are called club hairs because they retain their club- a soft keratin, consisting of keratin filaments embed-
shaped root. Soon afterward, a new hair is formed by the ded in filaggrin; the keratinized cells are sloughed con-
hair follicle and the hair growth cycle begins again. tinuously. In contrast, not only does keratinization of
The duration of the hair growth cycle varies in dif- hair form a hard keratin, consisting of keratin fila-
ferent areas of the body. For example, the life span of ments embedded in trichohyalin, but the keratinizing
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Figure 14–14 Scanning electron micro-

graph of a hair from a monkey’s scalp (×1115).
(From Leeson TS, Leeson CR, Paparo AA:
Text/Atlas of Histology. Philadelphia, WB
Saunders, 1988.)
cells are not shed; instead they accumulate, becoming

compressed and hard. Dermis
The arrangement of cells composing the cuticle of Nail root
the hair and cuticle of the internal root sheath interlocks
the apposing free edges of these cells, making it diffi- Lunula
cult to pull the hair shaft out of its follicle (Fig. 14-14).
Cuticle
Nails Nail body
Nails represent keratinized epithelial cells arranged in

plates of hard keratin.
Nails, located on the distal phalanx of each finger and

toe, are composed of plates of heavily compacted,
highly keratinized epithelial cells that form the nail Capillaries
plate, lying on the epidermis, known as the nail bed
(Figs. 14-15 and 14-16). The nails develop from cells of Epidermal
the nail matrix that proliferate and become kera- ridges
tinized. The nail matrix, a region of the nail root, is
located beneath the proximal nail fold. The stratum Dermal papillae
corneum of the proximal nail fold forms the eponych-
ium (cuticle), which extends from the proximal end up Figure 14–15 Structure of the thumbnail.
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on the nail for about 0.5 to 1 mm. Laterally, the skin

turns under as lateral nail folds, forming the lateral
nail grooves; the epidermis continues beneath the nail
plate as the nail bed, and the nail plate occupies the
D position (and function) of the stratum corneum.
The white crescent observed at the proximal end of
Hy the nail is called the lunula. The distal end of the nail
NB
plate is not attached to the nail bed, which becomes
continuous with the skin of the fingertip (or end of the
toe). Near this junction is an accumulation of stratum
corneum called the hyponychium.
Fingernails grow continuously at the rate of about
0.5 mm/week; toenails grow somewhat more slowly. The
translucency of the fingernails provides a quick indica-
tion of the health of an individual; pinkness indicates a
well-oxygenated blood supply.
Figure 14–16 Light micrograph of a longitudinal section

through a fingernail (×14). Observes the dermis (D), hyponychium
(Hy) and the nail bed (NB).
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15 䡲䡲䡲
Respiratory System
The respiratory system, comprising the lungs and a composed of the nasal cavity, mouth, nasopharynx,
sequence of airways leading to the external environ- pharynx, larynx, trachea, primary bronchi, secondary
ment, functions in providing oxygen (O2) to and elimi- bronchi (lobar bronchi), tertiary bronchi (segmental
nating carbon dioxide (CO2) from the cells of the body. bronchi), bronchioles, and terminal bronchioles. These
The realization of this goal requires the fulfillment of structures not only transport but also filter, moisten, and
the following four discrete events, collectively known as warm the inspired air before it reaches the respiratory
respiration: portion of the lungs.
The patency of the conducting airways is maintained
䡲 Movement of air in and out of the lungs (breathing
by a combination of bone, cartilage, and fibrous ele-
or ventilation)
ments. As the air progresses along the airway during
䡲 Exchange of O2 in the inspired air for carbon dioxide
inspiration, it encounters a branching system of tubules.
in the blood (external respiration)
Although the luminal diameter of each succeeding
䡲 Conveyance of O2 and CO2 to and from the cells
tubule continues to decrease, the total cross-sectional
(transport of gases)
diameter of the various branches increases at each level
䡲 Exchange of CO2 for O2 in the vicinity of the cells
of branching. As a result, the velocity of air flow for a
(internal respiration)
given volume of inhaled air decreases as the air pro-
The first two of these events, ventilation and exter- ceeds toward the respiratory portion.
nal respiration, occur within the confines of the respi-
ratory system, whereas the transport of gases is Nasal Cavity
performed by the circulatory system and internal respi-
ration occurs in the tissues throughout the body. The nasal cavity is divided into right and left halves
The respiratory system is subdivided into two major by the cartilaginous and bony nasal septum. Each half
components: the conducting portion and the respiratory of the nasal cavity is bounded laterally by a bony wall
portion (Table 15-1). The conducting portion, situ- and a cartilaginous ala (wing) of the nose; it com-
ated both outside and within the lungs, conveys air from municates with the outside, anteriorly, via the naris
the external milieu to the lungs. The respiratory (nostril) and with the nasopharynx by way of the
portion, located strictly within the lungs, functions in choana. Projecting from the bony lateral wall are
the actual exchange of oxygen for carbon dioxide (exter- three thin scroll-like bony shelves, situated one above
nal respiration). the other: the superior, middle, and inferior nasal
conchae.
CONDUCTING PORTION OF THE Anterior Portion of the
RESPIRATORY SYSTEM Nasal Cavity
The conducting portion of the respiratory system The anterior portion of the nasal cavity, in the vicinity
conveys air to and from the respiratory portion of the of the nares, is dilated and is known as the vestibule.
respiratory system. This region is lined with thin skin and has vibrissae—
short, stiff hairs that prevent larger dust particles from
The conducting portion of the respiratory system, listed entering the nasal cavity. The dermis of the vestibule
in order from the exterior to the inside of the lung, is houses numerous sebaceous and sweat glands. The
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346 䡲䡲䡲 Chapter 15 䡲 Respiratory System
TABLE 15–1 Divisions and Characteristic Features of the Respiratory System
Region Support Glands Epithelium Cell Types Additional Features
Extrapulmonary Conducting Division
Nasal vestibule Hyaline cartilage Sebaceous Stratified Epidermal Vibrissae

and sweat squamous
glands keratinized
Nasal cavity: Hyaline cartilage Seromucous Respiratory Basal, goblet, Erectile-like tissue
respiratory and bone glands ciliated, brush,
serous, and DNES
Nasal cavity: Bone Bowman’s Olfactory Olfactory, Olfactory vesicle

olfactory glands sustentacular, and
(serous) basal
Nasopharynx Skeletal muscle Seromucous Respiratory Basal, goblet, Pharyngeal tonsils

glands ciliated, brush, and eustachian tubes
serous, and DNES
Larynx Hyaline and elastic Mucous and Respiratory Basal, goblet, Epiglottis, vocal folds,
cartilages seromucous stratified ciliated, brush, and vestibular folds
glands squamous serous, and DNES
nonkeratinized
Trachea and Hyaline cartilage Mucous and Respiratory Basal, goblet, C-rings and trachealis
primary bronchi and dense, irregular, seromucous ciliated, brush, muscle (smooth
collagenous, glands serous, and DNES muscle) in adventitia
connective tissue
Intrapulmonary Conducting Division
Secondary Hyaline cartilage Seromucous Respiratory Basal, goblet, Plates of hyaline

(intrapulmonary) and smooth muscle glands ciliated, brush, cartilage and two
bronchi serous, and DNES ribbons of helically
oriented smooth muscle
(Primary) Smooth muscle No glands Simple columnar Ciliated cells and Less than 1 mm in
bronchioles to simple Clara cells (and diameter; supply air to
cuboidal occasional goblet lobules; two ribbons
cells in larger of helically oriented
bronchioles) smooth muscle
Terminal Smooth muscle No glands Simple cuboidal Some ciliated cells Less than 0.5 mm in
bronchioles and many Clara diameter; supply air to
cells (no goblet lung acini; some
cells) smooth muscle
Respiratory Division
Respiratory Some smooth No glands Simple cuboidal Some ciliated Alveoli in walls; alveoli
bronchioles muscle and and highly cuboidal cells, have smooth muscle
collagen fibers attenuated Clara cells, and sphincters in their
simple squamous types I and II openings
pneumocytes
Alveolar ducts Type III collagen No glands Highly attenuated Type I and type II No walls of their
(reticular) fibers simple squamous pneumocytes own; only a linear
and smooth muscle of alveoli sequence of alveoli
sphincters of alveoli
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Chapter 15 䡲 Respiratory System ■ ■ ■ 347
TABLE 15–1 Divisions and Characteristic Features of the Respiratory System—cont’d
Region Support Glands Epithlium Cell Types Additional Features
Alveolar sacs Type III collagen No glands Highly attenuated Type I and type II Clusters of alveoli
and elastic fibers simple squamous pneumocytes
Alveoli Type III collagen No glands Highly attenuated Type I and type II 200 µm in diameter;
and elastic fibers simple squamous pneumocytes have alveolar
macrophages
DNES, diffuse neuroendocrine system.
dermis is anchored by numerous collagen bundles to

the perichondria of the hyaline cartilage segments that
form the supporting skeleton of the ala. Ci
Posterior Aspect of the OC

Nasal Cavity
BC
Except for the vestibule and the olfactory region, the
nasal cavity is lined by pseudostratified ciliated colum-
nar epithelium, frequently called the respiratory LP
epithelium (see discussion of the trachea later), which
is well endowed with goblet cells in the more posterior
regions of the nasal cavity. The subepithelial connective
tissue (lamina propria) is richly vascularized, espe-
cially in the region of the conchae and the anterior
aspect of the nasal septum, housing large arterial
plexuses and venous sinuses. The lamina propria has
many seromucous glands and abundant lymphoid ele-
ments, including occasional lymphoid nodules, mast
cells, and plasma cells. Antibodies produced by plasma
cells (immunoglobulins IgA, IgE, and IgG) protect the
nasal mucosa against inhaled antigens as well as against
microbial invasion.
Figure 15–1 Light micrograph of the human olfactory mucosa

(×540). Observe that the olfactory cilia (Ci) are well represented and
CLINICAL CORRELATIONS that the connective tissue displays the presence of Bowman’s glands.
Nasal bleeding usually occurs from Kiessel- BC, basal cell; OC, olfactory cell; LP, lamina propria.
bach’s area, the anteroinferior region of the
nasal septum, which is the site of anastomosis of The roof of the nasal cavity, the superior aspect of the
the arterial supply of the nasal mucosa. The nasal septum, and the superior concha are covered by
bleeding may be arrested by applying pressure an olfactory epithelium 60 µm thick. The underlying
on the region or by packing the nasal cavity with lamina propria houses serous fluid–secreting Bowman’s
cotton. glands, a rich vascular plexus, and collections of axons
that arise from the olfactory cells of the olfactory
epithelium. The olfactory epithelium, which is yellow
in the living person, is composed of three types of cells:
Olfactory Region of the Nasal Cavity olfactory, sustentacular, and basal (Fig. 15-1).
The olfactory region comprises the olfactory epithelium OLFACTORY CELLS

and the underlying lamina propria that houses
Olfactory cells are bipolar neurons whose apical aspect,
Bowman’s glands and a rich vascular plexus.
the distal terminus of its slender dendrite, is modified
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Bowman's
Schwann cell gland
Connective
tissue
Basal cell
Olfactory
receptor cell
Sustentacular
cell
Dendrite
Olfactory vesicle
Olfactory cilia Microvilli

Duct of Bowman's gland
Figure 15–2 The olfactory epithelium, displaying basal, olfactory, and sustentacular cells. (Compare with Fig. 15-1.)
to form a bulb, the olfactory vesicle, which projects SUSTENTACULAR AND BASAL CELLS
above the surface of the sustentacular cells (Figs. 15-2
and 15-3). The nucleus of the cell is spherical and is Sustentacular cells are columnar cells, 50 to 60 µm
closer to the basal lamina than to the olfactory vesicle. tall, whose apical aspects have a striated border com-
Most of the organelles of the cell are in the vicinity of posed of microvilli. Their oval nuclei are in the apical
the nucleus. third of the cell, somewhat superficial to the location of
Scanning electron micrographs demonstrate that six the olfactory cell nuclei. The apical cytoplasm of these
to eight long, nonmotile olfactory cilia extend from the cells has secretory granules housing a yellow pigment
olfactory vesicle and lie on the free surface of the whose color is characteristic of the olfactory mucosa.
epithelium. Transmission electron micrographs of these Electron micrographs of sustentacular cells demon-
cilia display an unusual axoneme pattern that begins as strate that they form junctional complexes with the
a typical peripheral ring of nine doublet microtubules olfactory vesicle regions of olfactory cells as well as with
surrounding two central singlets (9 + 2 configuration) contiguous sustentacular cells. The morphology of sus-
but without the characteristic dynein arms. The tentacular cells is not remarkable, although they do
axoneme changes distally so that it is composed of nine display a prominent terminal web of actin microfila-
singlets surrounding the two central singlets, and near ments. These cells are believed to provide physical
the end of the cilium only the central singlets are support, nourishment, and electrical insulation for the
present. olfactory cells.
The basal region of the olfactory cell is its axon, Basal cells are of two types, horizontal and globose.
which penetrates the basal lamina and joins similar Horizontal cells are flat and lie against the basement
axons to form bundles of nerve fibers. Each axon, membrane, whereas globose cells are short, basophilic,
although unmyelinated, has a sheath composed of pyramid-shaped cells whose apical aspects do not reach
Schwann cell–like olfactory ensheathing (glial) cells. the epithelial surface. Their nuclei are centrally located,
The nerve fibers pass through the cribriform plate in but because these are short cells, the nuclei occupy the
the roof of the nasal cavity to synapse with secondary basal third of the epithelium. The globose type of basal
neurons in the olfactory bulb. cells have considerable proliferative capacity and can
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Figure 15–3 Transmission electron micrograph

of the apical region of the rat olfactory epithelium
(×8260). Note the olfactory vesicles and the cilia pro-
jecting from them. (Compare with the Figs. 15-1 and
15-2.) (From Mendoza AS, Kühnel W: Postnatal
changes in the ultrastructure of the rat olfactory
epithelium: The supranuclear region of supporting
cells. Cell Tissue Res 265:193-196, 1991.)
replace both sustentacular and olfactory cells. In a cous glands of the lamina propria. The serous fluid, pro-
healthy person, the olfactory cells live for less than three duced by the seromucous glands, is situated between
months and sustentacular cells have a life span of less the mucus and the apical plasmalemmae of the respi-
than a year. The horizontal basal cells replicate to ratory epithelial cells. Because the cilia of the ciliated
replace the globose basal cells. columnar cells do not reach the mucous layer, their
movement is restricted to the serous fluid layer. As the
LAMINA PROPRIA cilia move within that watery fluid, the mucus is swept
The lamina propria of the olfactory mucosa is composed along (“hydroplaned”) at the interface of the two fluids.
of a richly vascularized, loose to dense, irregular col- The particulate matter trapped in mucus is thus deliv-
lagenous connective tissue that is firmly attached to the ered, by ciliary action, to the pharynx to be swallowed
underlying periosteum. It houses numerous lymphoid or expectorated.
elements as well as the collection of axons of the olfac- In addition to being filtered, the air is also warmed
tory cells, which form fascicles of unmyelinated nerve and humidified by being passed over the mucosa, which
fibers. Bowman’s glands (olfactory glands), which is kept warm and moist by its rich blood supply.
produce a serous secretory product, are also present Warming of the inspired air is facilitated by the pres-
and are indicative of the olfactory mucosa. These glands ence of an extensive network of rows of arched vessels
release IgA, lactoferrin, lysozyme, and odorant-binding grouped in an anteroposterior arrangement. Capillary
protein, a molecule that prevents the odorant from beds arising from these vessels lie just beneath the
leaving the region of the olfactory epithelium, thus epithelium and the flow of blood into this vascular
enhancing a person’s ability to detect odors. network is directed from posterior to anterior, opposite
to the flow of air; thus, heat is continuously being
Histophysiology of the Nasal Cavity transferred to the inspired air by a countercurrent
mechanism.
The nasal mucosa filters, warms, and humidifies the Antigens and allergens carried by the air are com-
inhaled air and also is responsible for the perception bated by lymphoid elements of the lamina propria.
of odors. Secretory immunoglobulin (IgA), produced by plasma
cells, is transported across the epithelium into the nasal
The moist nasal mucosa filters inhaled air. Particulate cavity by ciliated columnar cells and by the acinar
matter, such as dust, is trapped by the mucus produced cells of the seromucous glands. IgE, which is also pro-
by the goblet cells of the epithelium and the seromu- duced by plasma cells, binds to IgE receptors (FcεRI
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receptors) of mast cell and basophil plasmalemmae. input to several glomeruli. Although there are only
Subsequent binding of a specific antigen or allergen to about 1000 glomeruli, each receiving information con-
the bound IgE causes the mast cell (and basophil) to cerning a single odor receptor molecule, the olfactory
release various mediators of inflammation. These, in cortex has the ability to distinguish about 10,000 differ-
turn, act on the nasal mucosa, inducing the symptoms ent scents. It does so by recognizing information arising
associated with colds and hay fever. from a particular combination of glomeruli as a single
scent. Thus, a particular glomerulus may be active in
the recognition of several scents.
To ensure that a single stimulus does not produce
CLINICAL CORRELATIONS repeated responses, the continuous flow of serous fluid
The nasal mucosa is protected from dehydration from Bowman’s glands provides a constant refreshment
by alternating blood flow to the venous sinuses of the olfactory cilia.
of the lamina propria overlying the conchae of
the right and left nasal cavities. The erectile Paranasal Sinuses
tissue-like region (swell bodies) of one side The ethmoid, sphenoid, frontal, and maxilla bones of
expands when its venous sinuses become the skull house large, mucoperiosteum-lined spaces, the
engorged with blood, reducing the flow of air paranasal sinuses (named after their location), which
through that side. Seepage of plasma from the communicate with the nasal cavity. The mucosa of each
sinuses and seromucous secretions from the sinus comprises a vascular connective tissue lamina
glands thus rehydrate the mucosa approximately propria fused with the periosteum. The thin lamina
every half hour. propria resembles that of the nasal cavity, in that it
Chemical irritants and particulate matter are houses seromucous glands as well as lymphoid ele-
removed from the nasal cavity by the sneeze ments. The respiratory epithelial lining of the paranasal
reflex. The sudden explosive expulsion of air sinuses, similar to that of the nasal cavity, has numerous
usually clears the nasal passage of the irritant. ciliated columnar cells whose cilia sweep the mucus
layer toward the nasal cavity.
The olfactory epithelium is responsible for the per- Nasopharynx

ception of odors, which also makes a major contribution The pharynx begins at the choana and extends to the
to the sense of taste discrimination. The mechanism of opening of the larynx. This continuous cavity is subdi-
odor discernment is poorly understood, although it is vided into three regions: (1) the superior nasopharynx,
known that the plasmalemma of the olfactory cilia of a (2) the middle oral pharynx, and (3) the inferior laryn-
particular olfactory cell has numerous copies of one par- geal pharynx. The nasopharynx is lined by a respiratory
ticular odor receptor molecule. Molecules of an epithelium, whereas the oral and laryngeal regions are
odoriferous substance dissolved in the serous fluid bind lined by a stratified squamous epithelium. The lamina
to its specific receptor. When a threshold number of propria is composed of a loose to dense, irregular type
odor receptors are occupied, the olfactory cell becomes of vascularized connective tissue housing seromucous
stimulated, an action potential is generated, and the glands and lymphoid elements. It is fused with the
information is transmitted via its axon to the olfactory epimysium of the skeletal muscle components of the
bulb, a projection of the central nervous system, for pro- pharynx. The lamina propria of the posterior aspect of
cessing. Axons of olfactory cells synapse with the den- the nasopharynx houses the pharyngeal tonsil, an
drites of 1 of 30 mitral cells within small spherical unencapsulated collection of lymphoid tissue described
regions of the olfactory bulb known as glomeruli. If a in Chapter 12.
threshold level of impulses reaches a mitral cell, it
becomes depolarized and relays the signal to the olfac- Larynx
tory cortex for further processing.
Each glomerulus receives input (information) from The larynx, or voice box, is responsible for phonation
approximately 2000 olfactory neurons, each specific for and for preventing the entry of food and fluids into the
the same odoriferous substance. Similar to antigens, respiratory system.
which may have several epitopes, each of which binds
a specific antibody, odoriferous substances possess The larynx, situated between the pharynx and the
several small regions, each of which binds to a specific trachea, is a rigid, short, cylindrical tube 4 cm in length
odor receptor molecule. Thus, a particular odoriferous and approximately 4 cm in diameter. It is responsible
substance may bind to several odor receptor molecules, for phonation and prevents the entry of solids or liquids
activating a number of olfactory neurons and providing into the respiratory system during swallowing. The wall
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of the larynx is reinforced by several hyaline cartilages

(the unpaired thyroid and cricoid cartilages and the CLINICAL CORRELATIONS
inferior aspect of the paired arytenoids) and elastic car-
tilages (the unpaired epiglottis, the paired corniculate Laryngitis (inflammation of the laryngeal
and cuneiform cartilages, and the superior aspect of the tissues, including the vocal folds) prevents the
arytenoids). These cartilages are connected to one vocal folds from vibrating freely. Persons suffer-
another by ligaments, and their movements with ing from laryngitis sound hoarse or can only
respect to one another are controlled by intrinsic and whisper.
extrinsic skeletal muscles. The presence of chemical irritants or particu-
The thyroid and cricoid cartilages form the cylindri- late matter in the upper air passages, including
cal support for the larynx, whereas the epiglottis pro- the trachea or bronchi, elicits the cough reflex,
vides a cover over the laryngeal aditus (opening). producing an explosive rush of air in an effort to
During respiration, the epiglottis is in the vertical posi- remove the irritant. The cough reflex begins with
tion, permitting the flow of air. During swallowing of the inhalation of a large volume of air and the
food, fluids, or saliva, however, it is positioned horizon- closure of the epiglottis and glottis (abduction
tally, closing the laryngeal aditus; yet normally, even in of the vocal folds), followed by powerful con-
the absence of an epiglottis, swallowed material traction of the muscles responsible for forced
bypasses the laryngeal opening. The arytenoid and cor- expiration (intercostal and abdominal muscles).
niculate cartilages are occasionally fused to each other, Sudden opening of the glottis and epiglottis
and most of the intrinsic muscles of the larynx move the generates a rush of air whose velocity can exceed
two arytenoids with respect to each other and to the 100 miles per hour, removing the irritant with an
cricoid cartilage. enormous force.
The lumen of the larynx is characterized by two pairs
of shelf-like folds, the superiorly positioned vestibular
folds and the inferiorly placed vocal folds. The vestibu-
lar folds are immovable. Their lamina propria, com- Trachea
posed of loose connective tissue, houses seromucous
glands, adipose cells, and lymphoid elements. The free The trachea has three layers: mucosa, submucosa, and
edge of each vocal fold is reinforced by dense, regular adventitia. C-rings are located in the adventitia.
elastic connective tissue, the vocal ligament. The
vocalis muscle, attached to the vocal ligament, assists The trachea is a tube, 12 cm in length and 2 cm in diam-
the other intrinsic muscles of the larynx in altering the eter, that begins at the cricoid cartilage of the larynx and
tension on the vocal folds. These muscles also regulate ends when it bifurcates to form the primary bronchi.
the width of the space between the vocal folds (the The wall of the trachea is reinforced by 10 to 12 horse-
rima glottidis), thus permitting precisely regulated shoe-shaped hyaline cartilage rings (C-rings). The
vibrations of their free edges by the exhaled air. open ends of these rings face posteriorly and are con-
During silent respiration, the vocal folds are partly nected to each other by smooth muscle, the trachealis
abducted (pulled apart), and during forced inspiration, muscle. Because of this arrangement of the C-rings, the
they are fully abducted. During phonation, however, the trachea is rounded anteriorly but flattened posteriorly.
vocal folds are strongly adducted (drawn together), The perichondrium of each C-ring is connected to the
forming a narrow interval between them. The move- perichondria lying directly above and below it by fibro-
ment of air against the edges of the strongly adducted elastic connective tissue, which provides flexibility to
vocal folds produces and modulates sound (but not the trachea and permits its elongation during inspira-
speech, which is formed by movements of the pharynx, tion. Contraction of the trachealis muscle decreases the
soft palate, tongue, and lips). The longer and more diameter of the tracheal lumen, resulting in faster air
relaxed the vocal folds, the deeper the pitch of the flow, which assists in the dislodging of foreign material
sound. Because the larynx of a postpubescent male is (or mucus or other irritants) from the larynx by
larger than that of a female, men tend to have deeper coughing.
voices than women. The trachea has three layers: mucosa, submucosa,
The larynx is lined by pseudostratified ciliated and adventitia (Fig. 15-4).
columnar epithelium, except on the superior surfaces
of the epiglottis and vocal folds, which are covered Mucosa
by stratified squamous nonkeratinized epithelium. The
cilia of the larynx beat toward the pharynx, transporting The mucosal lining of the trachea is composed of pseu-
mucus and trapped particulate matter toward the dostratified ciliated columnar (respiratory) epithelium,
mouth to be expectorated or swallowed. the subepithelial connective tissue (lamina propria), and
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Ci
MG
HC
GC
PC
L
Figure 15–4 Light photomi-
crograph of the trachea in a monkey
(×270). There are numerous cilia
(Ci) as well as goblet cells (GC) in
the epithelium. Also observe the
mucous glands (MG) in the sub-
epithelial connective tissue and the
hyaline C-ring (HC) in the adventi-
tia. L, lumen; PC, perichondrium.
a relatively thick bundle of elastic fibers separating the

mucosa from the submucosa.
Respiratory Epithelium
The respiratory epithelium is a pseudostratified ciliated
columnar epithelium composed of six cell types; goblet
cells, ciliated columnar cells, and basal cells constitute
90% of the cell population.
The respiratory epithelium, a pseudostratified ciliated

columnar epithelium, is separated from the lamina
propria by a thick basement membrane. The epithelium
is composed of six cell types: goblet cells, ciliated colum-
nar cells, basal cells, brush cells, serous cells, and cells of
the diffuse neuroendocrine system (DNES). All of these
cells come into contact with the basement membrane,
but they do not all reach the lumen (Fig. 15-5).
Goblet cells constitute about 30% of the total cell
population of the respiratory epithelium. They produce
mucinogen, which becomes hydrated and is known as
mucin when released into an aqueous environment. Figure 15–5 Transmission electron micrograph of monkey res-
Like goblet cells elsewhere, goblet cells in the respira- piratory epithelium from the anterior nasal septum. Note the pres-
tory epithelium have a narrow, basally positioned stem ence of goblet cells (gc), ciliated cells (c), basal cells (bc), and small
and an expanded theca containing secretory granules. granule mucous cells (smg). (From Harkema JR, Plopper CG, Hyde
DM, et al: Nonolfactory surface epithelium of the nasal cavity of the
Electron micrography demonstrates that the nucleus bonnet monkey: A morphologic and morphometric study of the tran-
and most organelles are located in the stem. This region sitional and respiratory epithelium. Am J Anat 180:266-279, 1987.)
displays a rich network of rough endoplasmic reticulum
(RER), a well-developed Golgi complex, numerous
mitochondria, and an abundance of ribosomes. The
theca is filled with numerous mucinogen-containing
secretory granules of varied diameters. The apical
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columnar cells with tall microvilli. Their function is

unknown, but they have been associated with nerve
endings; thus, some investigators suggest that they may
have a sensory role. Other investigators believe that
brush cells are merely goblet cells that have released
their mucinogen.
Serous cells, which make up about 3% of the total
cell population of the respiratory epithelium, are colum-
nar cells. They have apical microvilli and apical granules
containing an electron-dense secretory product, a
serous fluid of unknown composition.
DNES cells, also known as small-granule cells or
Kulchitsky cells, constitute about 3% to 4% of the
total cell population. Many of these cells possess long,
slender processes that extend into the lumen, and it is
believed that they have the ability to monitor the oxygen
and carbon dioxide levels in the lumen of the airway.
These cells are closely associated with naked sensory
nerve endings with which they make synaptic contact,
and together with these nerve fibers they are referred
to as pulmonary neuroepithelial bodies. DNES cells
contain numerous granules in their basal cytoplasm
that house pharmacological agents such as amines, pep-
tides, acetylcholine, and adenosine triphosphate. Under
hypoxic conditions, these agents are released not only
into the synaptic clefts but also into the connective
tissue spaces of the lamina propria, where they act as
paracrine hormones or may enter the vascular supply to
act as hormones. Therefore, it has been suggested that
these pulmonary neuroepithelial bodies can exert local
Figure 15–6 Scanning electron micrograph of the human effects to alleviate localized hypoxic conditions by
fetal trachea displaying ciliated and nonciliated cells (×5500). (From
Montgomery PQ, Stafford ND, Stolinski C: Ultrastructure of the
regulating perfusion and ventilation in their vicinity or
human fetal trachea: A morphologic study of the luminal and glan- they may have generalized effects via the efferent nerve
dular epithelia at the mid-trimester. J Anat 173:43-59, 1990.) fibers that relay information about hypoxic conditions to
the respiratory regulators located in the medulla
oblongata.
plasmalemma has a few short, blunt microvilli (see
Fig. 15-5). Lamina Propria and Elastic Fibers
Ciliated columnar cells constitute approximately
The lamina propria of the trachea is composed of a
30% of the total cell population. These tall, slender cells
loose, fibroelastic connective tissue. It contains lym-
have a basally located nucleus and possess cilia and
phoid elements (e.g., lymphoid nodules, lymphocytes,
microvilli on their apical cell membrane (Fig. 15-6).
and neutrophils) as well as mucous and seromucous
The cytoplasm just below these structures is rich in
glands, whose ducts open onto the epithelial surface. A
mitochondria and has a Golgi complex. The remainder
dense layer of elastic fibers, the elastic lamina, separates
of the cytoplasm possesses some RER and a few ribo-
the lamina propria from the underlying submucosa.
somes. These cells move the mucus and its trapped
particulate matter, via ciliary action, toward the Submucosa
nasopharynx for elimination.
The short basal cells constitute about 30% of the The tracheal submucosa is composed of a dense, irreg-
total cell population. They are located on the basement ular fibroelastic connective tissue housing numerous
membrane, but their apical surfaces do not reach the mucous and seromucous glands. The short ducts of
lumen (see Fig. 15-5). These relatively undifferentiated these glands pierce the elastic lamina and the lamina
cells are considered to be stem cells that proliferate to propria to open onto the epithelial surface. Lymphoid
replace defunct goblet, ciliated columnar, and brush cells. elements are also present in the submucosa. Moreover,
Brush cells (small-granule mucous cells) constitute this region has a rich blood and lymph supply, the
about 3% of the total cell population. They are narrow, smaller branches of which reach the lamina propria.
Ch015-X2945.qxd 15/8/06 2:50 PM Page 354
Adventitia veins, and lymph vessels, pierces the root of the lung.
The right bronchus is straighter than the left bronchus.
The adventitia of the trachea is composed of a fibro- The right bronchus trifurcates to lead to the three lobes
elastic connective tissue (see Fig. 15-4). The most of the right lung, and the left bronchus bifurcates,
prominent features of the adventitia are the hyaline car- sending branches to the two lobes of the left lung. These
tilage C-rings and the intervening fibrous connective branches then enter the substance of the lungs as intra-
tissue. The adventitia also is responsible for anchoring pulmonary bronchi.
the trachea to the adjacent structures (i.e., esophagus
and connective tissues of the neck).
Secondary and Tertiary
(Intrapulmonary) Bronchi
Each intrapulmonary bronchus serves a lobe of the lung;
The respiratory epithelium of people chronically tertiary bronchi serve bronchopulmonary segments.
exposed to irritants such as cigarette smoke and
coal dust undergoes reversible alterations known Each intrapulmonary bronchus is the airway to a lobe
as metaplasia, associated with an increase in the of the lung. These airways are similar to primary
number of goblet cells relative to ciliated cells. bronchi, with the following exceptions. The cartilage
The increased number of goblet cells produces a C-rings are replaced by irregular plates of hyaline
thicker layer of mucus to remove the irritants, cartilage that completely surround the lumina of the
but the reduced number of cilia retards the rate intrapulmonary bronchi; thus, these airways do not have
of mucus elimination, resulting in congestion. a flattened region but are completely round. The
Moreover, the seromucous glands of the lamina smooth muscle is located at the interface of the fibro-
propria and submucosa increase in size, forming elastic lamina propria and submucosa as two distinct
a more copious secretion. A few months after smooth muscle layers spiraling in opposite directions.
elimination of the pollutants, the cell ratio Elastic fibers, which radiate from the adventitia,
returns to normal (1:1) and the seromucous connect to elastic fibers arising from the adventitia of
glands revert to their previous size. other parts of the bronchial tree.
As in the primary bronchi and in the trachea, sero-
mucous glands and lymphoid elements are present in
the lamina propria and the submucosa of the intrapul-
Bronchial Tree monary bronchi. Ducts of these glands deliver their
secretory products onto the surface of the pseudostrat-
The bronchial tree begins at the bifurcation of the
ified, ciliated epithelial lining of the lumen. Lymphoid
trachea, as the right and left primary bronchi, which
nodules are particularly evident where these airways
arborize (form branches that gradually decrease in
branch to form increasingly smaller intrapulmonary
size). The bronchial tree is composed of airways
bronchi. The smaller intrapulmonary bronchi have
located outside the lungs (primary bronchi, extrapul-
thinner walls, decreasing amounts of hyaline cartilage
monary bronchi) and airways located inside the lungs:
plates, and shorter epithelium-lining cells.
intrapulmonary bronchi (secondary and tertiary
Secondary bronchi, direct branches of the primary
bronchi), bronchioles, terminal bronchioles, and respi-
bronchi leading to the lobes of the lung, are also known
ratory bronchioles (Fig. 15-7). The bronchial tree
as lobar bronchi. The left lung has two lobes and thus
divides 15 to 20 times before reaching the level of the
has two secondary bronchi; the right lung has three
terminal bronchioles. As the airways progressively
lobes and thus has three secondary bronchi.
decrease in size, several trends are observed, includ-
As secondary bronchi enter the lobes of the lung,
ing a decrease in the amount of cartilage, the
they subdivide into smaller branches, tertiary (segmen-
numbers of glands and goblet cells, and the height
tal) bronchi. Each tertiary bronchus arborizes but leads
of epithelial cells and an increase in smooth muscle
to a discrete section of lung tissue known as a bron-
and elastic tissue (with respect to the thickness of
chopulmonary segment. Each lung has 10 bron-
the wall).
chopulmonary segments that are completely separated
from one another by connective tissue elements and are
Primary (Extrapulmonary) Bronchi clinically important in surgical procedures involving the
The structure of the primary bronchi is identical to that lungs.
of the trachea, except that primary bronchi are smaller As the arborized branches of intrapulmonary bron-
in diameter and their walls are thinner. Each primary chi decrease in diameter, they eventually lead to
bronchus, accompanied by the pulmonary arteries, bronchioles.
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Smooth muscle
fibers
Pulmonary
artery (carrying
deoxygenated
Intra-alveolar blood)
septum
Respiratory
bronchiole
Respiratory
bronchiole
Pulmonary vein
(carrying
oxygenated Alveolar duct
blood)
Alveolar Alveoli Alveolar elastin

pore network
Figure 15–7 The respiratory

system, displaying bronchioles, termi-
nal bronchioles, respiratory bron-
chioles, alveolar ducts, alveolar pores,
and alveoli. Alveolar capillary network
Bronchioles (but should not be regarded as a reason to complicate

the life of the student).
Bronchioles possess no cartilage in their walls, are less The epithelial lining of bronchioles ranges from cil-
than 1 mm in diameter, and have Clara cells in their iated simple columnar with occasional goblet cells in
epithelial lining. larger bronchioles to simple cuboidal (many with cilia)
with occasional Clara cells and no goblet cells in smaller
Each bronchiole (or primary bronchiole) supplies air bronchioles.
to a pulmonary lobule. Bronchioles are considered the Clara cells are columnar cells with dome-shaped
10th to 15th generation of dichotomous branching apices that have short, blunt microvilli (Fig. 15-8). Their
of the bronchial tree. Their diameter commonly is apical cytoplasm houses numerous secretory granules
described as less than 1 mm, although this number containing glycoproteins manufactured on their abun-
varies among authors from 5 mm to 0.3 mm. This dis- dant RER. Clara cells are believed to protect the bron-
agreement concerning the diameter of bronchioles may chiolar epithelium by lining it with their secretory
lead to confusion in the descriptions of their structure product. Additionally, these cells degrade toxins in the
Ch015-X2945.qxd 15/8/06 2:50 PM Page 356

micrograph of Clara cells and cili-
ated cuboidal cells of rat terminal
bronchioles (×1817). (From Peao
MND, Aguas AP, De Sa CM,
Grande NR: Anatomy of Clara cell
secretion: Surface changes observed
by scanning electron microscopy. J
Anat 183:377-388, 1993.)
inhaled air via cytochrome P-450 enzymes in their

smooth endoplasmic reticulum. Some investigators
suggest that Clara cells produce a surfactant-like mate-
rial that reduces the surface tension of bronchioles
and facilitates the maintenance of their patency. More-
over, Clara cells divide to regenerate the bronchiolar A
epithelium.
The lamina propria of bronchioles has no glands; it
is surrounded by a loose meshwork of helically oriented E
smooth muscle layers (Fig. 15-9). The walls of bronchi-
SM
oles and their branches have no cartilage. Elastic fibers
radiate from the fibroelastic connective tissue that sur-
L
rounds the smooth muscle coats of bronchioles. These
elastic fibers connect to elastic fibers ramifying from
other branches of the bronchial tree. During inhalation,
as the lung expands in volume, the elastic fibers exert
tension on the bronchiolar walls; by pulling uniformly
in all directions, the elastic fibers help maintain the
patency of the bronchioles.
CLINICAL CORRELATIONS Figure 15–9 Light photomicrograph of a bronchiole (×117).

Note the presence of smooth muscle (SM) and the absence of carti-
The smooth muscle layers of bronchioles are lage in its wall. Observe that the entire structure is intrapulmonary
controlled by the parasympathetic nervous and is surrounded by lung tissue. A, alveolus; E, epithelium; L, lumen.
system. Normally, the smooth muscle coats con-
tract at the end of expiration and relax during
inspiration. In persons with asthma, however, Terminal Bronchioles
the smooth muscle coat undergoes prolonged
Terminal bronchioles form the smallest and most distal
contraction during expiration; thus, these indi-
region of the conducting portion of the respiratory
viduals have difficulty in expelling air from their
system.
lungs. Steroids and β2-agonists relax bronchiolar
smooth muscle and are frequently used to relieve Each bronchiole subdivides to form several smaller ter-
asthmatic attacks. minal bronchioles, which are less than 0.5 mm in diam-
eter and constitute the terminus of the conducting
Ch015-X2945.qxd 15/8/06 2:50 PM Page 357
portion of the respiratory system. These structures

supply air to lung acini, subdivisions of the lung lobule.
The epithelium of terminal bronchioles is composed of
Clara cells and cuboidal cells, some with cilia. The R
narrow lamina propria consists of fibroelastic connec-
tive tissue and is surrounded by one or two layers of
smooth muscle cells. Elastic fibers radiate from the
adventitia and, as with bronchioles, bind to elastic fibers
radiating from other members of the bronchial tree.
Terminal bronchioles branch to give rise to respiratory
bronchioles.
RESPIRATORY PORTION OF THE

RESPIRATORY SYSTEM
The respiratory portion of the respiratory system is
A
composed of respiratory bronchioles, alveolar ducts,
alveolar sacs, and alveoli.
Respiratory Bronchioles
Respiratory bronchioles are the first region of the
respiratory system where exchange of gases can occur.
Respiratory bronchioles are similar in structure to ter-

minal bronchioles, but their wall is interrupted by the
presence of thin-walled, pouch-like structures known as
alveoli, where gaseous exchange (O2 for CO2) can
occur. As respiratory bronchioles branch, they become
narrower in diameter and their population of alveoli Figure 15–10 Light micrograph of a human respiratory bron-
increases. Subsequent to several branchings, each chiole (R) giving rise to an alveolar duct (A). Respiratory bronchioles
respiratory bronchiole terminates in an alveolar duct have definite walls with alveoli interjected. Alveolar ducts have no
(Fig. 15-10). walls of their own; the ducts are created by neighboring alveoli.
Alveolar Duct, Atrium, and

Alveolar Sac Fine elastic fibers ramify from the periphery of
alveolar ducts and sacs to intermingle with elastic
Alveolar ducts, atria, and alveoli are supplied by a rich fibers radiating from other intrapulmonary elements.
capillary network. This network of elastic fibers not only maintains the
patency of these delicate structures during inhalation
Alveolar ducts do not have walls of their own; they are but also protects them against damage during distention
merely linear arrangements of alveoli (Figs. 15-11 and and is responsible for nonforced exhalation.
15-12). An alveolar duct that arises from a respiratory
bronchiole branches, and each of the resultant alveolar Alveoli
ducts usually ends as a blind outpouching composed of
two or more small clusters of alveoli, in which each Alveoli are small air sacs composed of highly attenuated
cluster is known as an alveolar sac. These alveolar sacs type I pneumocytes and larger type II pneumocytes.
thus open into a common space, which some investiga-
tors call the atrium. Each alveolus is a small outpouching, about 200 µm
Slender connective tissue elements between alveoli, in diameter, of respiratory bronchioles, alveolar ducts,
the interalveolar septa, reinforce the alveolar duct, and alveolar sacs (Fig. 15-13; also see Figs. 15-11A and
stabilizing it somewhat. Additionally, the opening of B and 15-12). Alveoli form the primary structural and
each alveolus to the alveolar duct is controlled by a functional unit of the respiratory system, because their
single smooth muscle cell (smooth muscle “knob”), thin walls permit exchange of CO2 for O2 between the
embedded in type III collagen, which forms a delicate air in their lumina and blood in adjacent capillaries.
sphincter regulating the diameter of the opening. Although each alveolus is a small structure, about
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Alveolar pore Interior of alveolus

Respiratory
Cell of
bronchiole O2
CO2 alveolus
Plasma
Alveolar duct Red
blood
cell
Deoxygenated
Alveolar capillary blood from
heart
B
Oxygenated
blood to heart
Alveolus
Diffusion of CO2 into blood and conversion to HCO3– Diffusion of CO2 out of blood into alveolus
CO2
Produced Cl–
by tissue CO2
cells
Hb HCO3–+H+
–
CO2+H2O HCO3 +H+ Hb
H2CO3 Alveolus
Carbonic CO2+H2O
anhydrase H2CO3 Carbonic
HCO3– anhydrase
Cl– CO2
CO2
Body tissue Capillary C D Capillary Alveolus

of lung
Figure 15–11 A, A respiratory bronchiole, alveolar sac, alveolar pore, and alveoli. B, Interalveolar septum. C, Carbon dioxide uptake from
body tissues by erythrocytes and plasma. D, Carbon dioxide release by erythrocytes and plasma in the lung. (Compare A with the alveolar duct
shown in Fig. 15-10.)
Ch015-X2945.qxd 15/8/06 2:50 PM Page 359

a rat lung displaying a bronchiole (b), small artery (v),
and alveoli (d), some of which present alveolar pores.
(From Leeson TS, Leeson CR, and Paparo AA:
Text/Atlas of Histology. Philadelphia, WB Saunders,
1988.)
Figure 15–13 Transmission electron micro-

graph of the interalveolar septum in a monkey.
Note the presence of alveoli (a), erythrocytes (e)
within capillaries (c), and alveolar macrophages
(m). Filopodia (arrows) and alveolar pores (aster-
isks) are evident. (From Maina JN: Morphology
and morphometry of the normal lung of the adult
vervet monkey (Cercopithecus aethiops). Am J
Anat 183:258-267, 1988.)
Ch015-X2945.qxd 15/8/06 2:50 PM Page 360
0.002 mm3, their total number approximates 300 wider, and it houses much of the cell’s organelle popu-
million, conferring on the lung its sponge-like consis- lation, composed of a small number of mitochondria, a
tency. It has been estimated that the total surface area of few profiles of RER, and a modest Golgi apparatus.
all the alveoli available for gas exchange exceeds 140 m2 Type I pneumocytes form occluding junctions with
(the approximate floor space of an average-sized two- each other, thus preventing the seepage of extracellular
bedroom apartment or the size of a singles tennis court). fluid (tissue fluid) into the alveolar lumen. The adlumi-
Because of their large number, alveoli are frequently nal aspect of these cells is covered by a well-developed
pressed against each other, eliminating the connective basal lamina, which extends almost to the rim of the
tissue interstitium between them. In such areas of alveolar pores. The rim of each alveolar pore is formed
contact, the air spaces of the two alveoli may commu- by the fusion of the cell membranes of two closely
nicate with each other through an alveolar pore (pore apposed type I pneumocytes that belong to two discrete
of Kohn), whose diameter varies from 8 to 60 µm alveoli. The luminal aspect of type I pneumocytes is
(see Fig. 15-12). These pores presumably function to lined by surfactant as detailed below.
equilibrate air pressure within pulmonary segments.
The region between adjacent alveoli is known as the Type II Pneumocytes
interalveolar septum. It is occupied by an extensive
Although type II pneumocytes (also known as great
capillary bed composed of continuous capillaries,
alveolar cells, septal cells, and type II alveolar
supplied by the pulmonary artery and drained by the
cells) are more numerous than type I pneumocytes,
pulmonary vein. The connective tissue of the inter-
they occupy only about 5% of the alveolar surface.
alveolar septum is rich in elastic fibers and type III
These cuboidal cells are interspersed among, and form
collagen (reticular) fibers.
occluding junctions with, type I pneumocytes. Their
Because alveoli and capillaries are composed of
dome-shaped apical surface juts into the lumen of the
epithelial cells, they are invested by a prominent basal
alveolus (Figs. 15-15 and 15-16). Type II pneumocytes
lamina. The openings of alveoli associated with alveolar
are usually located in regions where adjacent alveoli are
sacs, unlike those of respiratory bronchioles and alveo-
separated from each other by a septum (hence the name
lar ducts, are devoid of smooth muscle cells. Instead,
septal cells), and their adluminal surface is covered by
their orifices are circumscribed by elastic and, espe-
basal lamina.
cially, reticular fibers. Walls of alveoli are composed
Electron micrographs of type II pneumocytes display
of two types of cells: type I pneumocytes and type II
short, apical microvilli. They have a centrally placed
pneumocytes.
nucleus, an abundance of RER profiles, a well-developed
Golgi apparatus, and mitochondria. The most distin-
Type I Pneumocytes guishing feature of these cells is the presence of
Approximately 95% of the alveolar surface is composed membrane-bound lamellar bodies that contain pulmo-
of simple squamous epithelium, whose cells are known nary surfactant, the secretory product of these cells.
as type I pneumocytes (also called type I alveolar Pulmonary surfactant, synthesized on the RER of
cells and squamous alveolar cells). Because the cells type II pneumocytes, is composed primarily of two
of this epithelium are highly attenuated, their cytoplasm phospholipids, dipalmitoyl phosphatidylcholine and
may be as thin as 80 nm in width (Fig. 15-14; also see phosphatidylglycerol; neutral lipid; and four unique
Fig. 15-12). The region of the nucleus is, as expected, proteins, surfactant apoproteins SP-A, SP-B, SP-C,
r
p
en
ep
b a
Figure 15–14 Transmission electron micrograph of the blood-gas barrier (×71,250). Note the presence of the alveolus (a), attenuated type
I pneumocytes (ep), fused basal laminae (b), attenuated endothelial cell of the capillary (en) with pinocytotic vesicles (arrows), plasma (p), and
an erythrocyte (r) within the capillary lumen. (From Maina JN: Morphology and morphometry of the normal lung of the adult vervet monkey
(Cercopithecus aethiops). Am J Anat 183:258-267, 1988.)
Ch015-X2945.qxd 15/8/06 2:50 PM Page 361
Surfactant extruded from The surfactant is released by exocytosis into the

lipoprotein vesicle
Aqueous hypophase lumen of the alveolus. Here it forms a broad, lattice-like
Small
Surfactant network known as tubular myelin, which becomes
Lipid monolayer separated into lipid and protein portions. The lipid is
lamellar body
(phospholipid) inserted into a monomolecular phospholipid film,
forming an interface with air, and the protein enters an
Small lamellar
aqueous layer between the pneumocytes and the phos-
body fusing to pholipid film. The surfactant decreases surface tension,
lipoprotein vesicle thus preventing atelectasis, namely the collapse of the
alveolus. It is continuously manufactured by type II
pneumocytes and is phagocytosed and recycled by type
II pneumocytes and, less frequently, by alveolar
Multivesicular macrophages.
body In addition to producing and phagocytosing surfac-
tant, type II pneumocytes undergo mito-sis to regener-
Protein ate themselves as well as type I pneumocytes.
synthesis
Golgi
Alveolar Macrophages (Dust Cells)
Alveolar macrophages phagocytose particulate matter in
the lumen of the alveolus as well as in the interalveolar
spaces.
Monocytes gain access to the pulmonary interstitium,

become alveolar macrophages (dust cells), migrate
Phosphatidylcholine synthesis between type I pneumocytes, and enter the lumen of the
Choline
alveolus. These cells phagocytose particulate matter, such
Amino acids
as dust and bacteria, and thus maintain a sterile environ-
ment within the lungs (Fig. 15-17; also see Fig. 15-13).
Figure 15–15 A type II pneumocyte. (Compare with the type Dust cells also assist type II pneumocytes in the uptake of
II pneumocyte shown in Fig. 15-16.) surfactant. Approximately 100 million macrophages
migrate to the bronchi each day and are transported from
there by ciliary action to the pharynx to be eliminated
and SP-D. The surfactant is modified in the Golgi appa- by being swallowed or expectorated. Some alveolar
ratus and is then released from the trans Golgi network macrophages, however, reenter the pulmonary intersti-
into secretory vesicles, known as composite bodies, tium and migrate into lymph vessels to exit the lungs.
the immediate precursors of lamellar bodies.
Alveolar macrophages of patients with pul-
At birth, the infant’s lungs expand upon the first monary congestion and congestive heart failure
intake of breath, and the presence of pulmonary contain phagocytosed, extravasated red blood
surfactant permits the alveoli to remain patent. cells. These macrophages are frequently called
Immature infants (those born before 7 months of heart failure cells.
gestation) who have not as yet produced surfac- Emphysema is a disease usually associated
tant (or who have produced an inadequate with the sequelae of long-term exposure to ciga-
supply of surfactant) suffer from the potentially rette smoke and other inhibitors of the protein
fatal respiratory distress of the newborn. α1-antitrypsin. This protein safeguards the lungs
These newborns are treated with a combination against the destruction of elastic fibers by elas-
of synthetic surfactant and glucocorticoid tase synthesized by dust cells. In such patients,
therapy. The synthetic surfactant acts immedi- elasticity of the lung tissue is reduced and large,
ately to reduce surface tension, and the gluco- fluid-filled sacs are present that decrease the gas-
corticoids stimulate type II pneumocytes to exchange capability of the respiratory portion of
produce surfactant. the respiratory system.
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Figure 15–16 Transmission electron micrograph of a type II pneumocyte. Observe the centrally placed nucleus (N) flanked by several
lamellar bodies. a, alveolus; c, capillaries; e, elastic fibers; En, nucleus of endothelial cell; f, collagen fibers. Arrows mark the blood-gas barrier;
asterisk indicates a platelet. (From Leeson TS, Leeson CR, and Paparo AA: Text/Atlas of Histology. Philadelphia, WB Saunders, 1988.)
DC
Figure 15–17 Alveolar macro-

phages (dust cells) in the human
lung (×270). Dust cells (DC) appear
as black spots on the image because
they have phagocytosed dust parti-
cles that were present in the air
spaces of the lung. A, alveolus.
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Interalveolar Septum rich air is exhaled. The passage of O2 and CO2 across
the blood-gas barrier is due to passive diffusion in
The region between two adjacent alveoli, known as an response to the partial pressures of these gases within
interalveolar septum, is lined on both sides by alveolar the blood and alveolar lumina.
epithelium (see Fig. 15-13). The interalveolar septum Approximately 200 mL of CO2 is formed by the cells
may be extremely narrow, housing only a continuous of the body per minute. CO2 enters the bloodstream
capillary and its basal lamina, or it may be somewhat and is transported in three forms: (1) as a dissolved gas
wider, including connective tissue elements, such as in plasma (20 mL), (2) bound to hemoglobin (40 mL),
type III collagen and elastic fibers, macrophages, and (3) as plasma bicarbonate ion (140 mL). The fol-
fibroblasts (and myofibroblasts), mast cells, and lym- lowing sequence of events occurs (see Fig. 15-11C):
phoid elements.
1 Most of the CO2 dissolved in the plasma diffuses into
Blood-Gas Barrier the cytosol of the erythrocytes.
2 Some of the CO2 binds to the globin moiety of hemo-
The blood-gas barrier is that region of the interalveolar globin. Although CO2 is carried in a different region
septum that is traversed by O2 and CO2 as these gases of the hemoglobin molecule, its binding capacity is
go from the lumen of the blood vessel to the lumen of greater in the absence than in the presence of O2 in
the alveolus, and vice versa. the heme portion.
3 Within the cytosol of the erythrocyte, most of the
The thinnest regions of the interalveolar septum where CO2 combines with water, a reaction catalyzed by the
gases can be exchanged are called the blood-gas barri- enzyme carbonic anhydrase, to form carbonic acid,
ers (see Fig. 15-14). The narrowest blood-gas barrier, which dissociates into hydrogen ion (H+) and bicar-
where type I pneumocytes are in intimate contact with bonate ion (HCO3−). The hydrogen ion binds to
the endothelial lining of the capillary and where the hemoglobin and the bicarbonate ion leaves the eryth-
basal laminae of the two epithelia become fused, is most rocyte to enter the plasma. To maintain ionic equi-
efficient for the exchange of O2 (in the alveolar lumen) librium, chloride ion (Cl−) enters the erythrocyte
for CO2 (in the blood). These regions are composed of from the plasma; this exchange of bicarbonate for
the following structures: chloride ions is known as the chloride shift.
䡲 Surfactant and type I pneumocytes The bicarbonate-rich blood is delivered to the lungs
䡲 Fused basal laminae of type I pneumocytes and by the pulmonary arteries. Because the level of CO2 is
endothelial cells of the capillary greater in the blood than in the lumina of the alveoli,
䡲 Endothelial cells of the continuous capillary CO2 is released (following the concentration gradient).
The mechanism of release is the reverse of the previ-
Exchange of Gases between the ous reactions. The following sequence of events occurs
Tissues and Lungs (see Fig. 15-11D):
1 Bicarbonate ions enter the erythrocytes (with a con-
In the lungs, O2 is exchanged for CO2 carried by blood; sequent release of Cl− from the red blood cells into
in the tissues of the body, CO2 is exchanged for O2 the plasma, known as the chloride shift).
carried by blood. 2 Bicarbonate ions and hydrogen ions within the eryth-
rocyte cytosol combine to form carbonic acid.
During inspiration, oxygen-containing air enters the 3 In the lung, the combining of O2 with hemoglobin
alveolar spaces of the lung. Because the total surface makes the hemoglobin more acidic and reduces its
area of all the alveoli exceeds 140 m2 and the total blood ability to bind CO2. Additionally, the excess hydrogen
volume in all of the capillaries in the lungs at any one ions released because of the greater acidity of hemo-
time is no more than 140 mL, the space available for globin become bound to bicarbonate ions, forming
diffusion of gases is enormous. Moreover, the diameter carbonic acid.
of the capillaries is small enough so that red blood cells 4 Carbonic anhydrase catalyzes the cleavage of car-
may travel only in single file; thus, oxygen can reach bonic acid to form water and CO2.
each erythrocyte from all around, utilizing all the 5 CO2 dissolved in the plasma, bound to hemoglobin,
surface area of the red blood cells available for gas and cleaved from carbonic acid follows the concen-
exchange. Oxygen diffuses through the blood-gas tration gradient to diffuse across the blood-gas
barrier to enter the lumina of the capillaries and binds barrier to enter the lumina of the alveoli.
to the heme portion of the erythrocyte hemoglobin,
forming oxyhemoglobin. CO2 leaves the blood, dif- Hemoglobin also has two types of binding sites for
fuses through the blood-gas barrier into the lumina of nitric oxide (NO), a neurotransmitter substance that,
the alveolus, and exits the alveolar spaces as the CO2- when released by endothelial cells of blood vessels,
Ch015-X2945.qxd 15/8/06 2:50 PM Page 364
causes relaxation of the vascular smooth muscle cells For exhalation to occur, the respiratory (and acces-
with a resultant dilation of the blood vessels. Hemoglo- sory respiratory) muscles relax, decreasing the volume
bin, S-nitrosylated (binding site 1) by nitric oxide man- of the pleural cavities, with a consequent increase in the
ufactured by blood vessels of the lung, ferries bound pressure within the pleural cavities. Additionally, the
nitric oxide to arterioles and metarterioles of the tissues, stretched elastic fibers return to their resting length,
where NO is released and causes vasodilation. In this driving air out of the lungs. Thus, normal expiration
fashion, hemoglobin not only contributes to the modu- does not require energy. In forced expiration, the inter-
lation of blood pressure but also facilitates the more nal intercostal and abdominal muscles also contract,
efficient exchange of O2 for CO2. Moreover, once O2 further decreasing the volume of the pleural cavity,
leaves the heme portion of hemoglobin to oxygenate the forcing additional air to leave the lungs.
tissues, NO takes its place on the iron atoms (binding
site 2) and is transported into the lungs, where it is
released into the alveoli to be exhaled along with CO2.
Pleural Cavities and the In persons afflicted with poliomyelitis, the
Mechanism of Ventilation muscles of respiration may become so weakened
that the accessory muscles hypertrophy because
Alteration of the volume of the pleural cavities by they become responsible for the elevation of the
muscle action is responsible for the movement of gases thoracic cage. In other diseases, such as myas-
into and out of the respiratory system. thenia gravis and Guillain-Barré syndrome,
the weakness of the respiratory and accessory
The thoracic cage is separated into three regions: the respiratory muscles may lead to respiratory
left and right thoracic cavities and the centrally located failure and consequent death even though the
mediastinum. Each thoracic cavity is lined by a serous lungs function normally.
membrane, the pleura, composed of simple squamous
epithelium and subserous connective tissue. The pleura
may be imagined as an inflated balloon; as the lung
develops, it pushes against the serous membrane, as if
a fist were pushing against the outer surface of a Gross Structure of the Lungs
balloon. In this fashion, a portion of the pleura, the vis- The left lung has two lobes; the right lung has three
ceral pleura, covers and adheres to the lung, and the lobes.
remainder of the pleura, the parietal pleura, lines and
adheres to the walls of the thoracic cavity. Each lung has a medial indentation, the hilum, where
The space between the visceral and parietal pleura the primary bronchi, bronchiolar arteries, and pul-
(inside the balloon) is known as the pleural cavity. This monary arteries enter and the bronchiolar veins, pul-
space contains a slight amount of serous fluid (produced monary veins, and lymph vessels leave the lung. This
by the serous membranes) that permits a nearly fric- group of vessels and the airway that enter the hilum
tionless movement of the lungs during ventilation make up the root of the lung.
(breathing), which involves air moving into the lungs Each lobe is subdivided into several bronchopul-
(inhalation) and out of the lungs (exhalation). monary segments supplied by a tertiary intrapulmonary
Inhalation is an energy-requiring process because it (segmental) bronchus. In turn, bronchopulmonary seg-
involves contraction of the diaphragm, intercostal, and ments are subdivided into many lobules, each served by
scalenus muscles, as well as accessory respiratory a bronchiole. Lobules are separated from one another
muscles. As these muscles contract, the volume of the by connective tissue septa, in which lymph vessels and
thoracic cage expands. Because the parietal pleura is tributaries of pulmonary veins travel. Branches of
firmly attached to the walls of the thoracic cage, the bronchial and pulmonary arteries follow bronchioles in
pleural cavities also increase in volume, and conse- their passage through the center of the lobule.
quently, the pressure within the pleural cavities
decreases. The pressure differential between the atmos- Pulmonary Vascular and
pheric pressure outside the body and the pressure
within the pleural cavities drives air into the lungs. With
Lymphatic Supply
the influx of air the lungs expand, stretching the elastic The pulmonary arteries supply deoxygenated blood to
fiber network of the pleural interstitium, and the vis- the lungs from the right side of the heart at a rate of
ceral pleura is brought closer to the parietal pleura, 5 L per minute. Branches of these vessels follow the
reducing the volume of the pleural cavities and thus bronchial tubes into the lobules of the lung (see Fig.
increasing the pressure inside the pleural cavities. 15-7). When they reach the respiratory bronchioles,
Ch015-X2945.qxd 15/8/06 2:50 PM Page 365
these vessels form an extensive pulmonary capillary lymph nodes at the root of each lung. The deep network
network composed strictly of continuous capillaries. is organized into three groups following the pulmonary
Because these capillaries are only 8 µm in diameter, arteries, pulmonary veins, and bronchial tree down to
erythrocytes, as indicated above, follow each other in the levels of the respiratory bronchioles. All of these
single file through them, reducing the space that gases networks drain into the hilar lymph nodes at the root of
have to traverse and maximally exposing the erythro- each lung. Efferent lymph vessels from these lymph
cytes to oxygen. nodes deliver their lymph to the thoracic duct or the
The blood in the capillary bed becomes oxygenated right lymphatic duct, which returns the lymph to the
and then drains into veins of increasing diameter. These junction of the internal jugular and subclavian veins of
tributaries of the pulmonary vein carry oxygenated the left or right side, respectively.
blood and travel in the septa between lobules of the
lung. Thus, the veins follow a path that is different from Pulmonary Nerve Supply
that of the arteries, until they reach the apex of the
lobule, where they accompany the bronchial tubes to The thoracic sympathetic chain ganglia provide sympa-
the hilum of the lung to deliver oxygenated blood to the thetic fibers and the vagus nerve supplies parasympa-
left side of the heart. thetic fibers to the smooth muscles of the bronchial
Bronchial arteries, which are branches of the tho- tree. Sympathetic fibers (β-adrenergic) cause relax-
racic aorta, bring nutrient-laden and oxygen-laden ation of bronchial smooth muscles and thus bronchodi-
blood to the bronchial tree, interlobular septa, and lation (while causing constriction of pulmonary blood
pleura of the lungs. Many of the small branches anas- vessels: “paradoxical response”); parasympathetic
tomose with those of the pulmonary system. Others are fibers are cholinergic; they elicit contraction of
drained by tributaries of the bronchial veins, which bronchial smooth muscles, causing bronchoconstric-
return the blood to the azygos system of veins. tion. Additionally, nonadrenergic, noncholinergic fibers,
The lung has dual-lymph drainage, a superficial also traveling with the vagus nerve, cause bronchodila-
system of vessels in the visceral pleura and a deep tion by releasing NO near bronchial smooth muscle,
network of vessels in the pulmonary interstitium, but effecting their relaxation.
these systems have numerous interconnections. The Synapses occasionally involve type II pneumocytes,
superficial system of lymph vessels forms several larger suggesting the possibility of some neural control over
vessels, which drain into the hilar (bronchopulmonary) the production of pulmonary surfactant.
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16 䡲䡲䡲
Digestive System:
Oral Cavity
The digestive system, composed of the oral cavity, ali- remainder of the oral cavity is lined or covered by a
mentary tract, and associated glands, functions in the lining mucosa, composed of a nonkeratinized stratified
ingestion, mastication, deglutition (swallowing), diges- squamous epithelium overlying a looser type of dense
tion, and absorption of food as well as in the elimina- irregular collagenous connective tissue. Moreover, the
tion of its indigestible remnants. Regions of the aspects of the oral mucosa that bear taste buds (dorsal
digestive system are modified and have specialized surface of the tongue and patches of the soft palate and
structures to be able to perform these varied tasks. pharynx) are covered by specialized mucosa (spe-
This and the following two chapters detail the his- cialized to perceive taste).
tology and function of the component parts of the Ducts of the three pairs of major salivary glands
digestive system. The current chapter discusses the (parotid, submandibular, and sublingual) open into the
oral cavity; Chapter 17 describes the alimentary tract oral cavity, delivering saliva to moisten the mouth.
(esophagus, stomach, small and large intestines, rectum, These glands also manufacture and release the enzyme
and anus); and Chapter 18 considers the glands of the salivary amylase to break down carbohydrates, lacto-
digestive system (major salivary glands, pancreas, liver, ferrin and lysozymes, antibacterial agents, and secre-
and gallbladder). tory immunoglobulin (IgA). In addition, minor
salivary glands, located in the connective tissue ele-
ments of the oral mucosa, add to the flow of saliva into
ORAL MUCOSA: OVERVIEW the oral cavity. It is in the oral cavity that food is mois-
tened with saliva, chewed, and isolated by the tongue,
The oral mucosa, composed of a wet stratified squamous ultimately forming spherical masses about 2 cm in
epithelium (nonkeratinized, parakeratinized, or diameter. These spherical masses, each known as a
orthokeratinized) and an underlying dense irregular bolus, are forced by the tongue into the pharynx to be
collagenous connective tissue, may be divided into three swallowed.
classifications: lining mucosa, masticatory mucosa, and The lips form the anterior boundary, and the
specialized mucosa. palatoglossal folds form the posterior boundary of the
oral cavity. The structures of interest in and about
The oral cavity is lined by the oral mucosa, composed the oral cavity are the lips, the teeth and their associ-
of a wet stratified squamous keratinized, nonkera- ated structures, the palate, and the tongue.
tinized, or parakeratinized epithelium and an
underlying connective tissue. Regions of the oral cavity Lips
that are exposed to considerable frictional and shearing
forces (gingiva, dorsal surface of the tongue, and hard The lip has three regions: the skin aspect, the vermilion
palate) are lined or covered by a masticatory mucosa zone, and the mucous (internal) aspect.
composed of parakeratinized to completely keratinized
stratified squamous epithelium with an underlying The upper and lower lips are usually in contact with one
dense irregular collagenous connective tissue. The another and thus resemble a drawstring, in that they
367
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368 䡲䡲䡲 Chapter 16 䡲 Digestive System: Oral Cavity
guard the entrance into the oral cavity. The core of Lower lip
the lips is composed of skeletal muscle fibers that are M. orbicularis oris
Labial glands in connective tissue
responsible for lip mobility. Each lip may be subdivided
Vestibule
into three regions: the external aspect, the vermilion Enamel
zone, and the mucous (internal, wet) aspect. Dentin
The external aspect of the lip is covered with thin
skin and is associated with sweat glands, hair follicles, Crown
and sebaceous glands. This region is continuous with Gingiva
the vermilion zone, the pink region of the lip, which
is also covered by thin skin. However, the vermilion
zone is devoid of sweat glands and hair follicles, Alveolus
although occasional, nonfunctional sebaceous glands Root of tooth
are present there. The interdigitation between the Pulp
epithelial and connective tissue components of the oral
mucosa (the rete apparatus) is highly developed, so Cementum
that the capillary loops of the dermal papillae are close Periodontal
to the surface of the skin, imparting a pink color to the ligament
vermilion zone. The absence of functional glands in this Root canal
region necessitates the occasional moistening of the ver-
milion zone by the tongue. Apical foramen
Mandible
The mucous (internal) aspect of the lip is always
wet and is lined by stratified squamous nonkeratinized
epithelium. The subepithelial connective tissue is of the
dense, irregular collagenous type and houses numerous, Figure 16–1 A tooth in the oral cavity. Note the location of the
vestibule between the lip and the labial aspect of the tooth enamel
mostly mucous, minor salivary glands. and the gingiva, as well as the oral cavity on the buccal aspect of the
teeth and gingiva.
Teeth
Each tooth, whether deciduous or permanent, has a
crown, a cervix, and a root. subdivided into the pulp chamber and root canal. The
root canal communicates with the periodontal ligament
Humans have two sets of teeth: 20 deciduous (milk) space via a small opening, the apical foramen, at the tip
teeth, which are replaced by 32 permanent (adult) of each root. It is through this opening that blood and
teeth composed of 20 succedaneous teeth and 12 lymph vessels as well as nerves enter and leave the pulp
molars (accessional teeth). Both the deciduous and (Fig. 16-2).
permanent dentitions are evenly distributed between
the maxillary and mandibular arches. Mineralized Components
The various teeth have different morphologic fea- The mineralized structures of the tooth are enamel,
tures, numbers of roots, and functions, such as seizing dentin, and cementum. Dentin surrounds the pulp
prey, cutting smaller pieces from large chunks, and chamber and root canal and is covered on the crown by
macerating the chunks to form a bolus. Only the general enamel and on the root by cementum. Thus, the bulk
structure of teeth is discussed here. of the hard substance of the tooth is composed of
Each tooth is suspended in its bony socket, the alve- dentin. Enamel and cementum meet each other at the
olus, by a dense, irregular collagenous connective cervix of the tooth.
tissue, the periodontal ligament. The gingiva also
supports the tooth, and its epithelium seals the oral Enamel
cavity from the subepithelial connective tissue spaces
(Fig. 16-1). Enamel overlies dentin of the crown; it is composed of
The portion of the tooth that is visible in the oral 96% calcium hydroxyapatite and is the hardest
cavity is called the clinical crown, whereas the region substance in the body.
housed within the alveolus is known as the root. The
portion between the crown and the root is the cervix. Enamel is the hardest substance in the body. It is
The entire tooth is composed of three mineralized sub- translucent, and its coloration is due to the color of the
stances, which enclose a soft, gelatinous connective underlying dentin. Enamel consists of 96% calcium
tissue known as the pulp, located in a continuous space hydroxyapatite and 4% organic material and water. The
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Chapter 16 䡲 Digestive System: Oral Cavity ■ ■ ■ 369
Striae of Retzius ameloblasts die before the tooth erupts into the oral
in enamel cavity, the body cannot repair enamel.
Dentin
Clinical
crown CLINICAL CORRELATIONS
Gingival sulcus
Caries (cavities) usually result from the accu-
Anatomical mulation of microorganisms in and on slight
crown Free gingiva defects of the enamel surface. As these bacteria
Cervix
metabolize nutrients in the saliva and on the
tooth surface, they produce acids that begin
Gingival to decalcify the enamel. As the bacteria prolifer-
epithelium ate in the cavity that they have “excavated,” they
Pulp and the toxins that they release enlarge the
chamber caries.
Fluoride increases the hardness of enamel,
Cementum especially in young individuals, making the
enamel more resistant to caries. The incidence
of cavities has been greatly reduced by the addi-
tion of fluoride to the public water supply and to
toothpastes and by its topical application in the
Root Periodontal
ligament
dental office. As an individual ages, the enamel
crystals enlarge in size and there is less space
Alveolus available for the exchange of hydroxyl ions for
fluoride ions. Therefore, the use of fluoride treat-
Root canal ments in adults is not nearly as effective as for
young children.
Apical foramen
During its formation, enamel is elaborated in daily

segments; because of this, the quality of the enamel pro-
duced varies with the health of the mother during pre-
Figure 16–2 A tooth and its surrounding structures. Note that natal stages and with the health of the child after birth.
the clinical crown is that portion of the crown that is visible in the oral The enamel rod then reflects the metabolic state of the
cavity, whereas the anatomical crown extends from the cemento- person during the time of enamel formation, resulting
enamel junction to the occlusal surface of the tooth.
in successive rod segment sequences of hypocalcified
and normally calcified enamel. These alternating
sequences, analogous to growth rings in a tree trunk,
are evident histologically and are called striae of
calcified portion of enamel is composed of large crys- Retzius.
tals coated with a thin layer of organic matrix. The The free surface of a newly erupted tooth is covered
organic constituents of enamel are the keratin-like, high by a basal lamina-like substance, the primary enamel
molecular weight glycoproteins, tyrosine-rich enam- cuticle, manufactured by the same cells that elaborated
elins as well as a related protein, tuftleins. enamel. This cuticle wears away shortly after the tooth’s
Enamel is produced by cells known as ameloblasts, emergence into the oral cavity.
which elaborate enamel daily in 4- to 8-µm segments
known as rod segments. Successive rod segments Dentin
adhere to one another, forming keyhole-shaped enamel
rods (prisms), which extend over the complete width Dentin forms the bulk of the tooth; it is composed of
of the enamel from the dentinoenamel junction to the 70% calcium hydroxyapatite and is the second hardest
enamel surface. The calcium hydroxyapatite crystal ori- substance in the body.
entation within rods varies, permitting a subdivision of
the enamel rod into a cylindrical head to which a tail Dentin is the second hardest tissue in the body (Fig. 16-
(interrod enamel), in the shape of a rectangular solid, is 3; also see Fig. 16-2). It is yellowish in color, and its high
attached. Enamel is a nonvital substance; because the degree of elasticity protects the overlying brittle enamel
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Because odontoblasts remain functional, dentin has

the capability of self-repair, and reparative dentin is
elaborated on the surface of preexisting dentin within
the pulp chamber, thus reducing the size of the pulp
chamber with age.
E
Dentin sensitivity is mediated by sensory nerve
fibers that are closely associated with odonto-
blasts, their processes, and the dentinal tubules.
D Disturbance of the tissue fluid within dentinal
tubules is thought to depolarize the nerve fibers
somehow, sending a signal to the brain, where
the signal is interpreted as pain.
Cementum
P
Cementum overlies dentin of the roots. It is composed of
about 50% calcium hydroxyapatite and 50% organic
matrix and bound water; therefore, it is approximately
as hard as bone.
Figure 16–3 Light micrograph of the crown and neck of a tooth The third mineralized tissue of the tooth is cementum,
(×14). Observe that this is a ground section (nondecalcified) and that
the enamel (E) appears brown and the dentin (D) appears grayish
a substance that is restricted to the root (see Figs. 16-2
in this preparation. The pulp (P) cavity occupies the center of the and 16-3). Cementum is composed of 45% to 50%
tooth. calcium hydroxyapatite and 50% to 55% organic mate-
rial and bound water. Most of the organic material is
composed of type I collagen with associated proteo-
glycans and glycoproteins.
from becoming fractured. Dentin is composed of 65% The apical region of cementum is similar to bone in
to 70% calcium hydroxyapatite, 20% to 25% organic that it houses cells, cementocytes within lenticular
materials, and about 10% bound water. Most of the spaces, known as lacunae. Processes of cementocytes
organic substance is type I collagen associated with extend from lacunae within narrow canaliculi that
proteoglycans and glycoproteins. extend toward the vascular periodontal ligament.
The cells that produce dentin are known as odonto- Because of the presence of cementocytes, this type of
blasts. Unlike ameloblasts, they maintain their associa- cementum is called cellular cementum. The coronal
tion with dentin for the life of the tooth. These cells are region of cementum is without cementocytes, and thus
located at the periphery of the pulp, and their cyto- this type of cementum is called acellular cementum.
plasmic extensions, odontoblastic processes, occupy Both cellular cementum and acellular cementum have
tunnel-like spaces within dentin. These extracellular cementoblasts. These cells, which are responsible for
fluid–filled spaces, known as dentinal tubules, extend the formation of cementum, cover cementum at its
from the pulp to the dentinoenamel (in the crown) and interface with the periodontal ligament and continue to
to the dentinocemental (in the root) junctions. elaborate cementum for the life of the tooth.
During dentinogenesis, odontoblasts manufacture Collagen fibers of the periodontal ligament, known
about 4 to 8 µm of dentin every day. The quality of as Sharpey’s fibers, are embedded in cementum and
dentin, as of enamel, varies with the health of the in the alveolus, and in this fashion the ligament sus-
mother prenatally and of the child postnatally. Thus, pends the tooth in its bony socket.
along the length of the dentinal tubule, dentin displays Cementum can be resorbed by osteoclast-like cells
alternating regions of normal calcification and hypo- known as odontoclasts. During exfoliation, the replace-
calcification. These are recognizable histologically as ment of deciduous teeth by their succedaneous coun-
lines of Owen, analogous to the striae of Retzius in terparts, odontoclasts resorb cementum (and dentin) of
enamel. the root.
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It is customary to subdivide the pulp into three con-

CLINICAL CORRELATIONS centric zones around a central core:
䡲 The outermost odontoblastic zone of the pulp is
Cementum does not resorb as readily as does
bone, a property that orthodontists use to their composed of a single layer of odontoblasts, whose
advantage in moving improperly positioned processes extend into the adjacent dentinal tubules of
teeth. By placing the correct force on a tooth, the dentin.
䡲 The cell-free zone forms the layer deep to the odon-
orthodontist reshapes the bony socket and con-
sequently causes the tooth to be moved into its toblastic zone, and as its name implies, it is devoid of
correct position. cells.
䡲 The cell-rich zone, consisting of fibroblasts and
mesenchymal cells, is the deepest zone of the pulp,
immediately surrounding the pulp core.
Pulp The core of the pulp resembles most other loose
connective tissues but lacks adipose cells. Another
Pulp, a richly vascularized and innervated loose notable difference is that the pulp core is highly vascu-
connective tissue, is surrounded by dentin and larized and occasionally houses calcified elements called
communicates with the periodontal ligament via the pulp stones (denticles).
apical foramen. The nerve fibers of the pulp are of two types: (1)
sympathetic (vasomotor) fibers control the luminal
The pulp of the tooth is composed of a loose, gelatinous diameters of blood vessels, and (2) sensory fibers are
connective tissue that is rich in proteoglycans and gly- responsible for the transmission of pain sensation. Pain
cosaminoglycans, has an extensive vascular and nerve fibers are thin myelinated fibers that form the
supply, and has some lymph circulatory elements (Fig. Raschkow plexus, just deep to the cell-rich zone. As
16-4; also see Fig. 16-2). The pulp communicates with nerve fibers continue through this plexus, they lose their
the periodontal ligament through the apical foramen, a myelin sheath, pass through the cell-free zone, and pen-
small opening at the tip of each root. Vessels and nerves etrate the space between odontoblasts to enter the
enter and leave the pulp through these openings. dentinal tubule. Some nerve fibers synapse on the odon-
toblasts or their processes instead of entering the denti-
nal tubules.
Hemorrhage of the pulp is evident clinically as
dark discoloration of the tooth. Because the pulp
O
may recover, however, hemorrhage should not be
the sole indicator for root canal treatment.
CF Odontogenesis
CR
Odontogenesis begins with the appearance of the
dental lamina.
The first sign of odontogenesis (tooth development)

C occurs between the 6th and 7th weeks of gestation,
when the ectodermally derived oral epithelium pro-
liferates (Fig. 16-5). The result of this mitotic activity is
the formation of a horseshoe-shaped band of epithelial
cells, the dental lamina, surrounded by neural
crest–derived ectomesenchyme of the mandibular
Figure 16–4 Light micrograph of the pulp of a tooth (×132). and maxillary arches. The dental lamina is separated
Note the three layers-odontoblastic zone (O), cell-poor (cell-free) from the ectomesenchyme by a well-defined basal
zone (CF), cell-rich zone (CR)-and the core of the pulp (C). lamina.
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Oral Enamel Dental Enamel

epithelium organ lamina Dentin
Dental lamina Condensed Bony Bone
Bud mesenchyme crypt
A Bud stage B Cap stage C Bell stage D Apposition
Enamel Pulp
Dentin
Alveolar bone
Cementum
E Early root formation F Late root formation G Eruption Figure 16–5 Odontogenesis.
Bud Stage layers—the convex simple squamous outer enamel

epithelium and the concave simple squamous inner
Shortly after the appearance of the dental lamina, enamel epithelium—are continuous with each other
mitotic activity increases on the inferior aspect of this at a rim-like region, the cervical loop. They enclose a
epithelial band of each arch. This activity is responsible third layer, the stellate reticulum, whose cells have
for the formation of 10 discrete epithelial structures, numerous processes that are in contact with one
known as buds, initiating the bud stage of tooth devel- another. These epithelially derived layers, constituting
opment. These buds presage the 10 deciduous teeth of the “plump” enamel organ, are separated from the
both the maxillary and the mandibular arches. At the surrounding ectomesenchyme by a basal lamina. The
inferior tip of each bud, ectomesenchymal cells con- concavity of the cap is occupied by a congregation of
gregate to form the presumptive dental papilla. ectomesenchymal cells, the dental papilla. The dental
Further development, although similar for each bud, is papilla becomes vascularized and innervated during the
asynchronous, corresponding to the order of emergence cap stage of tooth development.
of the various teeth of the child. The process of morphodifferentiation is responsible
Cap Stage for the establishment of the template of the presump-
tive tooth; that is, the enamel organ assumes the shape
The cap stage of tooth development is recognized by of an incisiform, caniniform, or molariform tooth. This
the three-layered enamel organ. The three layers are: event is controlled by the enamel knot, a dense clump
outer enamel epithelium, stellate reticulum, and inner of cells located adjacent to the inner enamel epithelium
enamel epithelium. within the substance of the enamel organ. It appears
that the ectomesenchymal cells of the dental papilla
As cells of the bud proliferate, this structure not only induce the cells of the enamel knot to begin to express
increases in size but also alters its shape to form a three- signalling molecules, thus transforming the enamel
layered configuration, known as the cap, initiating the knot into one of the principal signaling centers of tooth
cap stage of tooth development. Two of the three morphogenesis.
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Cells of the enamel knot synthesize and release bone Proliferation of the cells of the tooth germ increases its
morphogenic proteins BMP-2, BMP-4, BMP-7, size, and the accumulation of fluid within the enamel
sonic hedgehog, and fibroblast growth factor-4 organ increases its plump appearance. In addition, its
(FGF-4) at specific time intervals, thus establishing a concavity deepens and another layer of cells develops
pattern of inductive events resulting in the formation of between the stellate reticulum and inner enamel
teeth with cusps. However, the cells of the enamel knot epithelium of the enamel organ. This new layer of cells
require the presence of epidermal growth factor is the stratum intermedium, and its appearance char-
(EGF) and FGF-4; otherwise, the cells undergo apop- acterizes the bell stage of tooth development. Because
tosis and die. Therefore, the enamel knot is responsible of changes in the morphology of the enamel organ and
for cusp formation; however, once the cusp pattern is changes in the shape of certain cells of the tooth germ,
established, EGF and FGF-4 are removed, the cells of this stage of odontogenesis is also called the stage of
the enamel knot die, and that structure can no longer morphodifferentiation and histodifferentiation.
exert any influence on odontogenesis. Moreover, the As most of the fluid within the enamel organ is
enamel knot of presumptive teeth, such as incisors that resorbed, much of the outer enamel epithelium col-
do not develop cusps, never becomes a principal sig- lapses over the stratum intermedium, bringing the
naling center; instead, its cells undergo apoptosis and vascularized dental sac close to that new layer. The
die during the cap stage. proximity of blood vessels apparently causes the stratum
The dental papilla and the enamel organ are col- intermedium to induce the simple squamous cells of
lectively called the tooth germ. The dental papilla, the inner enamel epithelium to differentiate into pre-
whose most peripheral layer of cells is separated from ameloblasts that will mature into enamel-producing
the inner enamel epithelium by the basal lamina, is columnar cells, known as ameloblasts (Fig. 16-6). In
responsible for the formation of the pulp and dentin of response to the histodifferentiation of the inner enamel
the tooth. Ectomesenchymal cells surrounding the
tooth germ form a vascularized membranous capsule,
the dental sac, which gives rise to the cementum, peri-
odontal ligament, connective tissue of the gingiva, and
alveolus. Cells of the inner enamel epithelium differ-
entiate into preameloblasts, which mature into amelo-
blasts to form enamel. Therefore, except for enamel,
the tooth and its associated structures are derived from
cells of neural crest origin.
During the cap stage of tooth development, a solid
cord of epithelial cells, the succedaneous lamina,
derived from the dental lamina, grows deep into the
ectomesenchyme. The cells at the tip of the succeda-
neous lamina proliferate to form a bud, the precursor
of the succedaneous tooth that eventually replaces
the deciduous tooth being developed. Because there
are only 20 deciduous teeth, only the same number of
succedaneous teeth are formed. The remaining 12 per-
manent teeth, known as accessional teeth (three per-
manent molars in each quadrant) because they do not
replace existing deciduous dentition, arise from the pos-
terior extensions of the maxillary and mandibular dental
laminae. The formation of the posteriorly directed
extension of the original dental laminae begins in the
5th month of gestation.
Bell Stage and Appositional Stage Ameloblast Odontoblast
The bell stage is recognized by the four-layered enamel Figure 16–6 An ameloblast and an odontoblast. Note that the
organ. The four layers are the outer enamel epithelium, odontoblastic process is very long and a large section of it has been
stellate reticulum, stratum intermedium, and inner cut out (white space). (From Lentz TL: Cell Fine Structure: An Atlas
enamel epithelium. of Drawings of Whole-Cell Structure. Philadelphia, WB Saunders,
1971.)
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As the ameloblasts secrete the enamel matrix, their

apical region becomes constricted by the matrix,
forming Tomes’ process. The ameloblasts then move
away from the newly elaborated enamel, and the con-
stricted region expands to its previous size, and
ameloblasts secrete more enamel matrix to fill the space
that the Tomes’ process previously occupied. This block
of new enamel matrix is known as a rod segment. The
cyclic nature of the Tomes’ process formation continues
until enamel formation ceases. As dentin matrix
becomes calcified to form dentin, the process of calci-
fication spreads into the enamel matrix, which becomes
known as enamel.
Root Formation
Root formation begins after the completion of the crown
and is organized by the Hertwig epithelial root sheath.
When all of the enamel and coronal dentin (dentin of

the crown) have been manufactured, the tooth germ
enters the next stage of odontogenesis, root formation.
The outer and inner enamel epithelia of the cervical
loop elongate, forming a sleeve-like structure known as
the Hertwig epithelial root sheath (HERS), which
encompasses ectomesenchymal cells located deep to
the developing crown, forming an elongation of the
dental papilla.
The absence of the stratum intermedium prevents
the cells of the inner enamel epithelium from differen-
tiating into ameloblasts; thus, enamel is not formed on
Figure 16–7 Electron micrograph of rat incisor odontoblasts the developing root surface. However, the most periph-
(×3416). (From Ohshima H, Yoshida S: The relationship between eral cells of the root dental papilla differentiate into
odontoblasts and pulp capillaries in the process of enamel-related
cementum-related dentin formation in rat incisors. Cell Tissue Res odontoblasts and begin to elaborate root dentin. As the
268:51-63, 1992.) HERS elongates, more and more of the root continues
to be manufactured and the region of HERS closer to
the cervical loop begins to disintegrate, forming perfo-
rations in this sleeve-like structure. Ectomesenchymal
epithelial cells, the most peripheral cells of the dental
cells from the dental sac migrate through the openings
papilla, those in contact with the basal lamina, also dif-
in the HERS, approximate the newly formed dentin,
ferentiate to become preodontoblasts that will mature
and differentiate into cementoblasts. These newly
into dentin-producing columnar cells, known as odon-
differentiated cells manufacture cementum matrix,
toblasts (Fig. 16-7; also see Fig. 16-6).
which subsequently calcifies and is referred to as
Shortly after the odontoblasts begin to elaborate the
cementum.
matrix of dentin into the basal lamina, the ameloblasts
The elongation of the root is a consequence of the
also begin to manufacture the matrix of enamel. The
lengthening of the HERS. As the root becomes longer,
dentin and enamel adjoin each other, and the junction
the crown approaches and eventually erupts into the
between them is called the dentinoenamel junction
oral cavity. Although the two processes are simultane-
(DEJ) (see Fig. 16-3). The tooth germ is now said to be
ous, the root is not “pushing” on the tissue apical to it;
in the appositional stage of odontogenesis.
instead, it is believed that specialized fibroblasts, myofi-
During the formation of dentin, as the odontoblasts
broblasts, of the dental sac pull the forming tooth into
move away from the DEJ, the distal tip of their process
the proper position.
remains at that junction and the process continues to
elongate. This cytoplasmic extension, known as the odon- Structures Associated with Teeth
toblastic process, is surrounded by dentin. The space
occupied by the odontoblastic process is the dentinal The structures associated with teeth are the periodon-
tubule. tal ligament, alveolus, and gingiva.
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Periodontal Ligament
The periodontal ligament is a dense, irregular
collagenous connective tissue whose principal fiber Proprioceptive fibers in the periodontal ligament
groups, composed of type I collagen, suspend the tooth are responsible for the jaw-jerk reflex, an invol-
in its alveolus. untary opening of the jaw when one unexpect-
edly bites down on something hard. This reflex
The periodontal ligament (PDL) is located in the PDL causes relaxation of the muscles of mastication
space, defined as the region between the cementum of and contraction of muscles responsible for
the root and the bony alveolus (see Figs. 16-1 and 16- opening the jaw, thus protecting the teeth from
2). The PDL space is less than 0.5 mm wide. Although fracture.
this richly vascularized connective tissue is classified as
dense irregular collagenous connective tissue, it has
principal fiber groups, composed of type I collagen
fibers, that are arranged in specific, predetermined pat- Alveolus
terns to absorb and counteract masticatory forces. The
ends of the principal fiber groups are embedded in the The alveolus is the bony socket in which the tooth
alveolus and cementum as Sharpey’s fibers, which is suspended by fibers of the periodontal
permit the periodontal ligament to suspend the tooth in ligament.
its socket (Fig. 16-8).
Fibroblasts are the most populous cells of the peri- The alveolar process, a bony continuation of the
odontal ligament. These cells not only manufacture the mandible and maxilla, is divided into compartments,
collagen and amorphous intercellular components of the each known as an alveolus, that house the root or, in the
PDL but also help to resorb collagen fibers, thus being case of multirooted teeth, roots of a tooth. Adjacent
responsible for the high turnover of collagen in the alveoli are separated from each other by a bony inter-
PDL. In addition, mast cells, macrophages, plasma cells, alveolar septum. The alveolus has three regions (see
and leukocytes are also present in the PDL. Figs. 16-1 and 16-2). The cortical plates, disposed
Nerves of the PDL include: (1) autonomic fibers, lingually and labially, form a firm supporting ledge of
which regulate the luminal diameter of the arterioles; compact bone, lined by cancellous bone, the spon-
(2) pain fibers, which mediate pain sensation; and (3) giosa. The spongiosa surrounds a thin layer of compact
proprioceptive fibers, which are responsible for the bone, the alveolar bone proper, whose shape mirrors
perception of spatial orientation. that of the root suspended in it.

of tooth socket (bony alveolus). The
periodontal ligament (L) is a dense,
irregular, collagenous connective
tissue located between the cemen-
tum (C) of the root and the bony
alveolus (A) (×132).
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Nutrient arteries travel in canals (referred to as is occupied by skeletal muscle responsible for its
nutrient canals) within the spongiosa, supplying the movements.
bony alveolus. The alveolar bone proper, said to be sup- The masticatory mucosa on the oral aspect of the
ported by the cortical plate and the spongiosa, has hard palate is composed of a wet stratified squamous
numerous perforations. Branches of the nutrient artery, keratinized (or parakeratinized) epithelium underlain
named perforating arteries, pass from the spongiosa by dense, irregular collagenous connective tissue. The
into the periodontal ligament, contributing to its vascu- connective tissue of the anterior lateral region of the
larization. hard palate displays clusters of adipose tissue, whereas
its posterior lateral aspect exhibits acini of mucous
minor salivary glands. The nasal aspect of the hard
Gingiva (Gums) palate is covered by respiratory epithelium with occa-
sional patches of stratified squamous nonkeratinized
The gingiva is attached to the enamel surface by
epithelium.
a thin, wedge-shaped, stratified squamous
The oral surface of the soft palate is covered by a
nonkeratinized epithelium, known as the junctional
lining mucosa, composed of a wet stratified squamous
epithelium.
nonkeratinized epithelium and a subjacent dense,
Since the gingiva is exposed to strenuous frictional irregular collagenous connective tissue housing mucous
forces, its stratified squamous epithelium is either fully minor salivary glands that are continuous with those
keratinized (orthokeratinized) or partially keratinized of the hard palate. The epithelium of its nasal aspect,
(parakeratinized) (see Figs. 16-1 and 16-2). Deep to like that of the hard palate, is of the pseudostratified cil-
the epithelium is a dense, irregular collagenous con- iated columnar type. The most posterior extension of
nective tissue whose type I collagen fibers form princi- the soft palate is the uvula, whose histological appear-
pal fiber groups that resemble those of the periodontal ance is similar to that of the soft palate, but its epithe-
ligament. lium is composed solely of stratified squamous
As the epithelium of the gingiva approaches the nonkeratinized epithelium. The connective tissue of
tooth, it forms a hairpin turn, proceeds apically (toward the uvula is also a dense irregular collagenous type and
the root tip) for 1 to 2 mm, and then attaches to the possesses mucous minor salivary glands and its core is
enamel surface by the formation of hemidesmosomes. composed of skeletal muscle that is responsible for its
The 1- to 2-mm-deep space between the gingiva and movement.
the tooth is the gingival sulcus.
The region of the gingival epithelium that attaches
to the enamel surface is known as the junctional Tongue
epithelium, which forms a collar around the neck of
the tooth. The junctional epithelium forms a robust The tongue has three regions: the anterior two-thirds,
barrier between the bacteria-laden oral cavity and the the posterior one-third, and a root.
sterile environment of the gingival connective tissue.
The principal fiber groups of the gingiva assist in the The tongue is the largest structure in the oral cavity. Its
adherence of the junctional epithelium to the tooth extreme mobility is due to the large intertwined mass
surface, maintaining the integrity of the epithelial of skeletal muscle fibers that compose its bulk (Fig.
barrier. This barrier is a wedge-shaped structure, about 16-9). The muscle fibers may be classified into two
1 mm long, and is only about 35 to 50 cells wide coro- groups: those that originate outside the tongue, the
nally and 5 to 7 cells wide apically. extrinsic muscles, and those that originate within and
insert into the tongue, the intrinsic muscles. The
extrinsic muscles are responsible for moving the tongue
Palate in and out of the mouth as well as from side to side,
whereas the intrinsic muscles alter the shape of the
The palate, comprising the hard palate, the soft palate, tongue. The intrinsic muscles are arranged in four
and the uvula, separates the oral cavity from the nasal groups: superior and inferior longitudinal, vertical, and
cavity. transverse.
The tongue has a dorsal surface, a ventral surface,
The oral and nasal cavities are separated from each and two lateral surfaces. The dorsal surface is observed
other by the hard palate and the soft palate. The to have two unequal regions, the larger anterior two-
hard palate, positioned anteriorly, is immovable and thirds and the smaller posterior one-third. The two
receives its name from the bony shelf contained within regions are separated from one another by a shallow, V-
it. In contrast, the soft palate is movable, and its core shaped groove, the sulcus terminalis, whose apex
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Geniohyoid muscle Uvula
Palatoglossal fold
Genioglossus muscle
Palatine tonsil
Foramen cecum
Lingual tonsil
Epiglottis
Hyoid bone
Fungiform
papilla
Circumvallate papilla
Filiform papillae
Taste buds
Intrinsic muscle
Taste buds
on circumvallate
Figure 16–9 The tongue and papilla
its lingual papillae. Serous glands
points posteriorly and contains a deep concavity, the The numerous filiform papillae are slender struc-
foramen cecum. tures that impart a velvety appearance to the dorsal
The dorsal surface of the posterior one third of surface (see Figs. 16-9 and 16-10). These papillae are
the tongue is uneven because of the presence of the covered by stratified squamous keratinized epithelium
lingual tonsil (see Chapter 12). The most posterior and help to scrape food off a surface. The high degree
portion of the tongue is known as the root of the of keratinization is especially apparent in the sandpa-
tongue. Lingual papillae, most of which project above per-like quality of the cat tongue. Filiform papillae do
the surface, cover the anterior two thirds of the tongue’s not have taste buds.
dorsal surface. Each fungiform papilla resembles a mushroom
whose slender stalk connects a broad cap to the tongue
surface (see Figs. 16-9 and 16-10). The epithelial cov-
Lingual Papillae ering of these papillae is stratified squamous non-
keratinized; thus, the blood coursing through the
There are four types of lingual papillae: filiform, subepithelial capillary loops is evident as red dots dis-
fungiform, foliate, and circumvallate. tributed randomly among the filiform papillae on the
dorsum of the tongue. Fungiform papillae have taste
On the basis of their structure and function, the lingual buds on the dorsal aspect of their cap.
papillae are of four types: filiform, fungiform, foliate, Foliate papillae are located along the posterolateral
and circumvallate (Fig. 16-10; also see Fig. 16-9). They aspect of the tongue. They appear as vertical furrows,
are all located anterior to the sulcus terminalis on the reminiscent of pages of a book. These papillae have
dorsal or lateral aspect of the tongue. functional taste buds in the neonate, but these taste
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Serous gland
Fungiform papilla B
Connective tissue
Taste pore
Microvilli
Wall of
taste pore Figure 16–11 Light micrograph of monkey taste buds (×497).
The taste bud (B) is completely within the epithelium and appears to
Sensory
Nerve be composed of several types of cells; however, these are the same
nerve
cells at various times of their life cycle.
Type I cell fiber
Basal cell
(Type IV)
Four types of cells constitute the taste bud:
Figure 16–10 Lingual papillae and a taste bud.
䡲 Basal cells (type IV cells)
䡲 Dark cells (type I cells)
䡲 Light cells (type II cells)
buds degenerate by the second or third year of life. 䡲 Intermediate cells (type III cells)
Slender ducts of serous minor salivary glands of von
The relationship among the various cell types is not
Ebner, located in the core of the tongue, empty into
clear, although researchers agree that basal cells func-
the base of the furrows.
tion as reserve cells and regenerate the cells of the taste
There are 8 to 12 large circumvallate papillae in
buds, which have an average life span of 10 days. Most
a V-shaped arrangement just anterior to the sulcus
investigators believe in the following progression: Basal
terminalis. These papillae are submerged into the
cells give rise to dark cells, which mature into light cells,
surface of the tongue so that they are surrounded by
which become intermediate cells and die.
an epithelially lined groove, whose base is pierced by
Nerve fibers enter the taste bud and form synaptic
slender ducts of glands of von Ebner (see Figs. 16-9
junctions with type I, type II, and type III cells, indi-
and 16-10). The epithelial lining of the groove and the
cating that all three cell types probably function in the
side (but not the dorsum) of these papillae have taste
discernment of taste. Each of these cell types has long,
buds.
slender microvilli that protrude from the taste pore (see
Fig. 16-12). In the past, these microvilli were noted with
TASTE BUDS
the light microscope and were called taste hairs.
Taste buds are intraepithelial sensory organs that func- Tastants, chemicals from food dissolved in saliva,
tion in the perception of taste. The surface of the tongue interact either with ion channels or with receptors
and the posterior aspect of the oral cavity have approx- located on the microvilli of the taste cells, effecting elec-
imately 3000 taste buds. Each taste bud, composed of trical alterations in the resting potentials of these cells
60 to 80 spindle-shaped cells, is an oval structure, 70 to resulting in depolarization of the cell and initiating an
80 µm long and 30 to 40 µm wide, and is distinctly paler action potential that is transmitted to the brain where
than the epithelium surrounding it (Figs. 16-11 and 16- the signals are interpreted as specific taste sensations.
12; see Fig. 16-10). The narrow end of the taste bud, There are five primary taste sensations: salty, sweet,
located at the free surface of the epithelium, projects sour, bitter, and umami (a savory taste sensed via gluta-
into an opening, the taste pore, formed by the squa- mate receptors). It is believed that although every taste
mous epithelial cells that overlie the taste bud (see Fig. bud can discern each of the five sensations, each taste
16-12). bud specializes in two of the five tastes. The reaction to
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Figure 16–12 Low-power electron micrograph

of a taste bud from the lamb epiglottis (×2353). B,
basal cell; I, type I cell; II, type II cell; P, taste pore;
Pg, perigemmal cell. Arrowheads represent nerve
fibers; arrow represents synapse-like structure
between a type I cell and a nerve fiber. (From Sweazy
RD, Edwards CA, Kapp BM: Fine structure of taste
buds located on the lamb epiglottis. Anat Rec
238:517-527, 1994.)
these taste modalities is due to the presence of to detect fat and some individuals prefer foods that are
specific ion channels (salty and sour) and G protein- fatty.
coupled membrane receptors (bitter, sweet, and The process of complex taste perception is due more
umami) in the plasmalemma of the cells of the taste to the olfactory apparatus than to the taste buds, as evi-
bud. Recently, another receptor was localized on taste denced by the decreased taste ability of people with
buds, CD36, a fatty acid transporter, that has the ability nasal congestion from colds.
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17 䡲䡲䡲
Digestive System:
Alimentary Canal
The alimentary canal, the continuation of the oral cavity, Mucosa

is the tubular portion of the digestive tract. It is here
that food is churned, liquefied, and digested; its nutri- The lumen of the alimentary canal is lined by an
tional elements and water are absorbed; and its indi- epithelium, deep to which is a loose connective tissue
gestible components are eliminated. The alimentary known as the lamina propria. This richly vascularized
canal, which is about 9 meters long, is subdivided into connective tissue houses glands as well as lymph vessels
morphologically recognizable regions: the esophagus, and occasional lymphoid nodules, members of the
stomach, small intestine (duodenum, jejunum, and mucosa-associated lymphoid tissue (MALT) system.
ileum), and large intestine (cecum, colon, rectum, anal Certain cells of the lamina propria are responsible for
canal, and appendix). the synthesis and release of growth factors that control
Before a discussion of the individual regions of the the cell cycle of the overlying epithelium. Surrounding
alimentary canal is presented, it is reasonable and this connective tissue coat is the muscularis mucosae,
preferable to describe the general plan of the digestive composed of an inner circular layer and an outer longi-
tract. Once the conceptual design of the alimentary tudinal layer of smooth muscle. The epithelium, lamina
canal is understood, variations on that common theme propria, and muscularis mucosae are collectively called
are easier to assimilate. the mucosa.
Submucosa
GENERAL PLAN OF THE
ALIMENTARY CANAL The mucosa is surrounded by a dense, irregular fibro-
elastic connective tissue layer, the submucosa (see Fig.
17-1); this layer houses no glands except in the esophagus
The alimentary canal comprises four concentric layers:
and duodenum. The submucosa also contains blood and
mucosa, submucosa, muscularis externa, and serosa (or
lymph vessels as well as a component of the enteric
adventitia).
nervous system known as Meissner’s submucosal
The alimentary canal is composed of several histologi- plexus. This plexus, which also houses postganglionic
cal layers (Fig. 17-1). These layers are innervated by the parasympathetic nerve cell bodies, controls the motility
enteric nervous system and modulated by parasympa- of the mucosa (and, to a limited extent, motility of the
thetic and sympathetic nerves; they are also served by submucosa) and the secretory activities of its glands.
sensory fibers.
Muscularis Externa
Alimentary Canal Histology
The muscularis externa is usually composed of inner
The histology of the alimentary canal often is discussed in circular and outer longitudinal smooth muscle layers.
terms of four broad layers: the mucosa, submucosa, mus-
cularis externa, and serosa (or adventitia). These layers The submucosa is invested by a thick muscular layer,
are similar throughout the length of the digestive tract the muscularis externa, responsible for peristaltic
but display regional modifications and specializations. activity, which moves the contents of the lumen along
381
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382 䡲䡲䡲 Chapter 17 䡲 Digestive System: Alimentary Canal
Stomach
Mesentery Common bile duct
Submucosal blood vessels
Lamina propria
Intestinal villi
with epithelial
Gland in lining
submucosa
Gland in
Serosa
lamina propria
Outer longitudinal
muscle layer
Muscularis
externa Inner circular
muscle layer
Submucosa
Muscularis
mucosae
Lymphoid nodule
Figure 17–1 Alimentary tract. Layer contents are generalized.
the alimentary tract. The muscularis externa is com- covering is known as the serosa. If the organ is
posed of smooth muscle (except in the esophagus) and retroperitoneal, it adheres to the body wall by its dense
is usually organized in an inner circular layer and an irregular connective tissue component and is known as
outer longitudinal layer. Certain smooth muscle-like the adventitia.
cells, the interstitial cells of Cajal, undergo rhythmic
contractions and, therefore, are considered to be the Innervation of the Digestive Tract
pacemakers for the contraction of the muscularis
externa. A second component of the enteric nervous The enteric nervous system, innervating the alimentary
system, known as Auerbach’s myenteric plexus, is canal, is modulated by sympathetic and parasympathetic
situated between these two muscle layers and regulates nervous systems.
the activity of the muscularis externa (and, to a limited
extent, the activity of the mucosa). Auerbach’s plexus The innervation of the alimentary canal is composed of
also houses postganglionic parasympathetic nerve cell two parts: the enteric nervous system and the sympa-
bodies. thetic and parasympathetic components. The major
Three-dimensional reconstruction of the muscularis controlling factor resides in the enteric nervous system,
mucosae and of the muscularis externa shows that both which is self-sufficient; however, its functions are nor-
the inner circular layer and the outer longitudinal layer mally modified by the sympathetic and parasympathetic
are arranged helically. The pitch of the helices differs, components. In fact, if the sympathetic and parasym-
however; the inner circular layer displays a tight helix, pathetic connections to the entire gut are severed, the
whereas the outer longitudinal layer presents a loose alimentary canal can perform all of its functions without
helix. any major problems.
Serosa and Adventitia Enteric Nervous System

The muscularis externa is enveloped by a thin connec-
The enteric nervous system is self-contained and
tive tissue layer that may or may not be surrounded by
comprises numerous repeating ganglia known as
the simple squamous epithelium of the visceral peri-
Meissner’s submucosal plexus and Auerbach’s myenteric
toneum. If the region of the alimentary canal is
plexus.
intraperitoneal, it is invested by peritoneum, and the
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Chapter 17 䡲 Digestive System: Alimentary Canal ■ ■ ■ 383
The digestive tract has its own self-contained nervous colon and rectum, which are innervated by the sacral
system (the enteric nervous system), which extends the (spinal) outflow. Most of the fibers of the vagus nerve
entire length of the alimentary canal from the esopha- are sensory and deliver information from receptors in
gus to the anus. The enteric nervous system is thus ded- the mucosa and muscularis of the alimentary canal
icated to controlling the secretory and motile functions to the central nervous system. Frequently, responses to
of the alimentary canal. The 100 million or so neurons the information are then conveyed by the vagal fibers
of the enteric nervous system are distributed in a large to the alimentary canal. This process is known as the
number of small clusters of nerve cell bodies and asso- vagovasal reflex. The parasympathetic fibers synapse
ciated nerve fibers, in Auerbach’s myenteric plexus with postganglionic parasympathetic nerve cell bodies
and in Meissner’s submucosal plexus. It is interest- as well as with nerve cell bodies of the enteric nervous
ing that the number of neurons associated with the system in both plexuses. The parasympathetic innerva-
enteric nervous system approximates the total number tion is responsible for inducing secretions from the
of neurons contained within the spinal cord, suggesting glands of the digestive tract as well as for smooth muscle
that the enteric nervous system is an exceptionally contraction.
important entity. Some investigators have proposed that The sympathetic innervation is derived from the
it should be considered the third component of the splanchnic nerves. Sympathetic fibers are vasomotor,
autonomic nervous system (sympathetic, parasympa- controlling blood flow to the alimentary canal.
thetic, and enteric nervous systems). As a generalization, it may be stated that parasym-
Although the two plexuses have numerous intercon- pathetic innervation stimulates peristalsis, inhibits
nections, they serve different functions. Generally sphincter muscles, and triggers secretory activity,
speaking, the peristaltic motility of the digestive tract is whereas sympathetic innervation inhibits peristalsis
under the direction of the myenteric plexus, whereas its and activates sphincter muscles.
secretory function and mucosal movement as well as the The remainder of this chapter discusses the various
regulation of localized blood flow are governed by the regions of the alimentary canal and examines how they
submucosal plexus. Moreover, the myenteric plexus is differ from the general plan.
concerned not only with local conditions but also with
conditions along much of the digestive tract, whereas
the submucosal plexus is attentive primarily to local ESOPHAGUS
conditions in the vicinity of the particular cluster of The esophagus is a muscular tube, approximately 25 cm
nerve cells in question. As with all generalizations, there in length, that conveys the bolus (masticated food) from
are exceptions to the rules; therefore, it must be appre- the oral pharynx to the stomach. Along its entire length,
ciated that there is a great deal of interaction between its mucosa presents numerous longitudinal folds with
the two sets of plexuses, and the possibility of cross- intervening grooves that cause the lumen to appear to be
controls has been suggested. obstructed; however, when the esophagus is distended
Sensory components have also been described in the folds disappear and the lumen becomes patent.
the wall of the alimentary canal. They convey informa-
tion concerning the luminal contents, muscular status,
and secretory status of the gut to the plexuses in the Esophageal Histology
vicinity of the information as well as to plexuses at con- Mucosa
siderable distances from the location of the source of
the information. In fact, some of the information is The esophageal mucosa is composed of a stratified
transmitted to sensory ganglia as well as to the central squamous epithelium, fibroelastic lamina propria, and a
nervous system by nerve fibers that accompany fibers of smooth muscle layer that is the longitudinally disposed
the sympathetic and parasympathetic nerve supplies of muscularis mucosae.
the gut.
The mucosa of the esophagus is composed of three
Parasympathetic and Sympathetic layers: epithelium, lamina propria, and muscularis
Supply to the Gut mucosae (Fig. 17-2).
The lumen of the esophagus, lined by a 0.5-mm-
Parasympathetic innervation stimulates peristalsis, thick, stratified squamous nonkeratinized epithe-
inhibits sphincter muscles, and triggers secretory activity; lium, is usually collapsed and opens only during the
sympathetic nerves inhibit peristalsis and activate process of swallowing. The epithelium presents a well-
sphincter muscles. developed rete apparatus as it interdigitates with the
underlying connective tissue. The epithelium is regen-
The digestive tract receives its parasympathetic nerve erated at a much slower rate than the remainder of the
supply from the vagus nerve, except for the descending gastrointestinal tract; the newly formed cell in the basal
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LP
S
IC
Figure 17-2 Light micrograph

of the esophagus (×17). Note that
the lumen is lined by a relatively
OL
thick stratified squamous epithelium
(E) that forms a well-developed rete
apparatus with the underlying
lamina propria (LP). The submucosa
(S) is surrounded by a thick muscu-
laris externa, composed of inner cir-
cular (IC) and outer longitudinal
(OL) muscle layers.
layer of the epithelium reaches the free surface in about The submucosa of the esophagus is composed of a
3 weeks after formation. Interspersed within the ker- dense, fibroelastic connective tissue, which houses the
atinocytes of the epithelium are antigen-presenting esophageal glands proper. The esophagus and the
cells, known as Langerhans cells, which phagocytose duodenum are the only two regions of the alimentary
and degrade antigens into small polypeptides known as canal with glands in the submucosa. Electron micro-
epitopes. These cells also synthesize major histocom- graphs of these tubuloacinar glands indicate that their
patibility complex (MHC) II molecules, attach the secretory units are composed of two types of cells,
epitopes to these molecules, and place the MHC mucous cells and serous cells.
II–epitope complex on the external aspect of their plas- Mucous cells have basally located, flattened nuclei
malemmae. Langerhans cells then migrate to lymph and apical accumulations of mucus-filled secretory
nodes, where they present the MHC II–epitope granules. The second cell type is serous cells, with
complex to lymphocytes (see Chapter 12). round, centrally placed nuclei. The secretory granules
The lamina propria is unremarkable. It houses of these cells contain the proenzyme pepsinogen and
esophageal cardiac glands, which are located in two the antibacterial agent lysozyme. The ducts of these
regions of the esophagus, one cluster near the pharynx glands deliver their secretions into the lumen of the
and the other near its juncture with the stomach. It also esophagus.
houses occasional lymphoid nodules, members of the The submucosal plexus is in its customary location
MALT system. The muscularis mucosae is unusual in within the submucosa, in the vicinity of the inner cir-
that it consists only of a single layer of longitudinally ori- cular layer of the muscularis externa.
ented smooth muscle fibers that become thicker in the
vicinity of the stomach.
The esophageal cardiac glands produce mucus that Muscularis Externa and Adventitia
coats the lining of the esophagus, lubricating it to
The muscularis externa of the esophagus is composed of
protect the epithelium as the bolus is passed into the
both skeletal and smooth muscle cells.
stomach. Because these glands resemble glands from
the cardiac region of the stomach, some investigators The muscularis externa of the esophagus is arranged
suggest that they are ectopic patches of gastric tissue. in two layers, inner circular and outer longitudinal.
However, these muscle layers are unusual in that they
Submucosa are composed of both skeletal and smooth muscle
fibers. The muscularis externa of the upper third of the
The submucosa of the esophagus houses mucous glands
esophagus has mostly skeletal muscle; the middle third
known as the esophageal glands proper.
has both skeletal and smooth muscle; and the lowest
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third has only smooth muscle fibers. Auerbach’s plexus

occupies its usual position between the inner circular STOMACH
and outer longitudinal smooth muscle layers of the mus-
cularis externa. The stomach is responsible for the formation and
The esophagus is covered by an adventitia until it processing of the ingested food into a thick acidic fluid
pierces the diaphragm, after which it is covered by a known as chyme.
serosa.
The stomach, the most dilated region of the alimentary
canal, is a sac-like structure that, in the resting state, in
Esophageal Histophysiology the average adult has a volume of only 50 mL; however,
it can accommodate approximately 1500 mL of food and
The esophagus does not have an anatomical sphincter
gastric juices at maximal distention. As the stomach
but does have two physiological sphincters—the
expands, its intraluminal pressure remains relatively
pharyngoesophageal sphincter and the internal
constant due to the hormone ghrelin, which not only
and external gastroesophageal sphincters—which
induces the sensation of hunger but also modulates
prevent reflux into the pharynx from the esophagus
receptive relaxation of the smooth muscle fibers of
and into the esophagus from the stomach, respectively.
the muscularis externa. The bolus passes from the
The internal gastroesophageal sphincter, composed of
esophagus through the gastroesophageal junction into
smooth muscle fibers, is located at the region where the
the stomach, where it is churned into a viscous fluid
esophagus pierces the diaphragm and joins the
known as chyme. Intermittently, the stomach empties
stomach. The muscle fibers of this sphincter are always
small aliquots of its contents through the pyloric
in tonus except at those times when a bolus is about
valve into the duodenum. The stomach liquefies the
to pass into the stomach or if a person is vomiting.
food, continuing its digestion via the production of
Additionally, skeletal muscle fibers from the diap-
hydrochloric acid and the enzymes pepsin, rennin,
hragm encircle the esophagus and close it during in-
and gastric lipase and via production of paracrine
spiration and during elevation of the intra-abdominal
hormones.
pressure (as during defecation). A bolus entering the
Anatomically, the stomach has a concave lesser cur-
esophagus is conveyed, via peristaltic action of the
vature and a convex greater curvature. Gross observa-
muscularis externa, into the stomach at a rate of about
tions disclose that the stomach has four regions:
50 mm/sec.
䡲 Cardia: a narrow region at the gastroesophageal
junction, 2 to 3 cm wide
䡲 Fundus: a dome-shaped region to the left of the
CLINICAL CORRELATIONS esophagus, frequently filled with gas
䡲 Body (corpus): the largest portion, responsible for
As the esophagus passes through the diaphragm, the formation of chyme
it is reinforced by fibers of that muscular struc- 䡲 Pylorus (pyloric antrum): a funnel-shaped, con-
ture. In some people, development is abnormal, stricted portion equipped with a thick pyloric sphinc-
causing a gap in the diaphragm around the wall ter that controls the intermittent release of chyme
of the esophagus that permits herniation of the into the duodenum
stomach into the thoracic cage. This condition,
known as hiatal hernia, weakens the gastro- Histologically, the fundus and body are identical. All
esophageal sphincter, allowing reflux of the the gastric regions display rugae, longitudinal folds of
stomach contents into the esophagus. the mucosa and submucosa (but transverse in the
Barrett’s syndrome is probably a premalig- antrum), which disappear in the distended stomach.
nant condition due, initially, to gastroesophageal Rugae permit expansion of the stomach as it fills with
reflux. Part of the stratified squamous non- food and gastric juices. Additionally, the epithelial lining
keratinized epithelium of the esophagus, usually of the stomach invaginates into the mucosa, forming
in the lowest region, is replaced by a simple gastric pits (foveolae), which are shallowest in the
columnar epithelium that resembles the lining cardiac region and deepest in the pyloric region. Gastric
of the stomach. Endoscopically, this metaplastic pits increase the surface area of the gastric lining. Five
area is reddish in color, and at least 3 cm of to seven gastric glands of the lamina propria empty
the esophagus must be involved to be considered into the bottom of each gastric pit.
as Barrett’s syndrome. If there are numerous red
patches in the lower esophagus, esophageal Gastric Histology
resection may be necessary. The ensuing discussion of the stomach details the
fundic region (Fig. 17-3), because the microscopic
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Stomach
Surface lining cell
Regenerative cell
Pit
Mucosa Isthmus
Mucous neck cell
Neck
Gland
Base Oxyntic (parietal) cell
Gastric
Muscularis mucosae gland
Submucosa
Zymogenic (chief) cell
Enteroendocrine cell
(DNES cell; APUD cell)
Figure 17–3 Cellular composition of the fundic stomach and fundic gland. The fundic glands open into the bottom of the gastric pits, and
each gland is subdivided into an isthmus, a neck, and a base.
anatomy of each of the remaining regions is a variation The lumen of the fundic stomach is lined by a simple
of that of the fundic region. columnar epithelium composed of surface-lining
cells, which manufacture a thick layer of mucus, known
Fundic Mucosa as visible mucus (Fig. 17-4A), a gel-like substance
The mucosa of the fundic stomach is composed of the that adheres to the lining of the stomach and protects it
usual three components: (1) an epithelium lining the from autodigestion. Moreover, bicarbonate ions trapped
lumen; (2) an underlying connective tissue, the lamina in this layer of mucus are able to maintain a relatively
propria; and (3) the smooth muscle layers forming the neutral pH at its interface with the surface-lining cell
muscularis mucosae. membrane, despite the low (acidic) pH of the luminal
contents. Surface-lining cells continue into the gastric
Epithelium of the Stomach pits, forming their epithelial lining. Regenerative cells
are also present in the base of these pits, but because
The epithelial lining of the stomach secretes visible
they are more numerous in the neck of the gastric
mucus that adheres to and protects the stomach lining.
glands, they are discussed along with the glands.
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LP E M
Figure 17–4 A, Light micrograph

of the mucosa of the fundic stomach
(×132). The mucosa is composed of the
simple columnar epithelium (E), the con-
nective tissue lamina propria (LP), and C
the muscularis mucosae (MM). A little
section of the submucosa (S) is evident at
the bottom left hand corner of the light
micrograph. B, Light micrograph of
fundic glands (×270). Note that the MM
glands are very tightly packed, and much
of the connective tissue is compressed
into thin wafers occupied by capillaries.
C, chief cell; M, mucous neck cell; P, S
parietal cell.
Electron micrographs of surface-lining cells display into three regions: the isthmus, the neck, and the base,
glycocalyx-covered, short, stubby microvilli on their of which the base is the longest (see Fig. 17-3). The
apical surfaces. Their apical cytoplasm houses secretory simple columnar epithelium constituting the fundic
granules containing a homogeneous substance, the pre- gland is composed of six cell types: (1) surface-lining
cursor of visible mucus (Fig. 17-5). The lateral cell cells, (2) mucous neck cells, (3) regenerative (stem) cells,
membranes of these surface lining cells form intricate (4) parietal (oxyntic) cells, (5) chief (zymogenic) cells,
zonulae occludentes and zonulae adherentes with those and (6) diffuse neuroendocrine system (DNES) cells (also
of neighboring cells. The cytoplasm between their known as amine precursor uptake and decarboxylation
basally placed nuclei and apical secretory granules is [APUD] and enteroendocrine cells). The distribution of
occupied chiefly by mitochondria and the protein syn- these cells within the three regions of the gland is pre-
thesis and packaging apparatus of the cell. sented in Table 17-1.
The surface-lining cells in the isthmus region are
Lamina Propria of the Stomach similar to those in the epithelium described earlier. The
structure and function of the five other cell types are
The loose, highly vascularized connective tissue, the
discussed next.
lamina propria, has a rich population of plasma cells, lym-
phocytes, mast cells, fibroblasts, and occasional smooth
muscle cells. Much of the lamina propria is occupied by Mucous Neck Cells
the 15 million closely packed gastric glands, known as
Mucous neck cells produce soluble mucus that is mixed
fundic (oxyntic) glands in the fundic region (Fig. 17-4B).
with and lubricates the chyme, reducing friction as it
FUNDIC GLANDS moves along the digestive tract.
Each fundic gland extends from the muscularis Mucous neck cells are columnar and resemble surface-
mucosae to the base of the gastric pit and is subdivided lining cells, but they are distorted by pressures from
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mv
rER
Figure 17–5 Electron micrograph of a surface

P lining cell from the body of a mouse stomach
(×11,632). G, Golgi apparatus; J, junctional complex;
L, lumen; m, mitochondria exhibiting large spherical
densities known as nodules (n); mv, microvillus; N,
nucleus; ov, oval secretory granules; P, intercellular
projections; rER, rough endoplasmic reticulum; sp,
spherical granules. (From Karam SF, Leblond CP:
Identifying and counting epithelial cell types in the
“corpus” of the mouse stomach. Anat Rec 232:231-
246, 1992.)
surface-lining cells; this mucus is soluble and functions

TABLE 17–1 Distribution of Cell Types in to lubricate the gastric contents. The lateral membranes
Fundic Glands of mucous neck cells form zonulae occludentes and
zonulae adherentes with the surrounding cells.
Region Cell Types
Regenerative (Stem) Cells
Isthmus Surface lining cells and few DNES cells
A relatively few, thin regenerative cells are interspersed
Neck Mucous neck cells, regenerative cells, among the mucous neck cells of fundic glands (see Fig.
parietal cells, and few DNES cells 17-3). These columnar stem cells do not have many
Base Chief cells, occasional parietal cells, and organelles but do have a rich supply of ribosomes. Their
few DNES cells nuclei are basally located, have little heterochromatin,
and display a large nucleolus. The lateral cell mem-
DNES, diffuse neuroendocrine system. branes of these cells also form zonulae occludentes and
zonulae adherentes with those of neighboring cells.
Regenerative cells proliferate to replace all of the
neighboring cells. Thus, they have short microvilli, specialized cells lining the fundic glands, gastric pits,
basally located nuclei, and a well-developed Golgi appa- and luminal surface. Newly formed cells migrate to
ratus and rough endoplasmic reticulum (RER) (Fig. 17- their new locations either deep into the gland or up into
6). Their mitochondria are located mainly in the basal the gastric pit and gastric lining. Surface-lining cells,
region of the cell. The apical cytoplasm is filled with DNES cells, and mucous neck cells are replaced every
secretory granules containing a homogeneous secretory 5 to 7 days; thus, regenerative cells have a high prolif-
product, which differs from the mucus synthesized by erative rate.
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graph of a mucous neck cell from
the body of a mouse stomach. Inset:
Secretory granule, (c). c, dense-
cored granule; D, desmosome;
G, Golgi apparatus; J, junctional
complex; L, lumen; m, mitochon-
dria; mg, mucous granules; mv,
microvillus; N, nucleus; rER, rough
endoplasmic reticulum. (From
Karam SF, Leblond CP: Identifying
and counting epithelial cell types in
the “corpus” of the mouse stomach.
Anat Rec 232:231-246, 1992.)
Parietal (Oxyntic) Cells Parietal cells have round, basally located nuclei, and
their cytoplasm is eosinophilic. Their most remarkable
Parietal cells manufacture hydrochloric acid and gastric characteristic is the invaginations of their apical plas-
intrinsic factor; both products are released into the malemma to form deep intracellular canaliculi lined
lumen of the stomach. by microvilli (Figs. 17-7 and 17-8). The cytoplasm bor-
dering these canaliculi is richly endowed by round and
Large, round to pyramid–shaped parietal cells are tubular vesicles, the tubulovesicular system. Addi-
located mainly in the upper half of the fundic glands tionally, parietal cells are rich in mitochondria, whose
and only occasionally in the base (see Figs. 17-3 and combined volume constitutes almost half that of the
17-4). They are about 20 to 25 µm in diameter and are cytoplasm. The protein synthetic apparatus, the RER
situated at the periphery of the gland. These cells and the Golgi apparatus, are present but only to a
produce hydrochloric acid (HCl) and gastric intrin- limited extent.
sic factor. The number of microvilli and the abundance of vesi-
cles of the tubulovesicular system are indirectly related
to each other and vary with the HCl secretory activity
CLINICAL CORRELATIONS of parietal cells. During active HCl production, the
number of microvilli increases and the tubulovesicular
Gastric intrinsic factor, a glycoprotein secreted system decreases. Thus, the membrane, being stored as
into the lumen of the stomach, is necessary for tubules and vesicles, is probably used for microvillar
vitamin B12 absorption from the ileum. Absence assembly, increasing the surface area of the cell by four
of this factor results in deficiency of vitamin B12 to five times in preparation for HCl production.
with the consequent development of pernicious The process of microvillus formation requires energy
anemia. Because the liver stores high quantities and involves polymerization of soluble forms of actin
of vitamin B12, a deficiency of this vitamin may and myosin into filaments, which then interact to trans-
take several months to develop after production port membranes from the tubulovesicular system to
of gastric intrinsic factor ceases. that of the intracellular canaliculus. The stored mem-
branes have a high content of H+,K+-ATPase (a protein
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Figure 17–7 Electron micrograph of a parietal cell from the

body of a mouse stomach (×14,000). Go, Golgi apparatus; Mi, mito-
chondria; Ox, nucleus of oxyphil cell; Ve, tubulovesicular apparatus;
Figure 17–8 Scanning electron microscopy of the fractured
Vi, microvilli. (From Rhodin JAG.: An Atlas of Ultrastructure.
surface of a resting parietal cell (×50,000). The cytoplasmic matrix is
removed by the aldehyde-osmium-DMSO-osmium method (or A-
ODO method), exposing the cytoplasmic membranes. The tubulocis-
ternal network (TC) is connected to the intracellular canaliculus (IC)
that pumps protons from the cytoplasm into the intra- lined with microvilli (MV). Inset: A higher magnification of the area
cellular canaliculus). The formation of hydrochloric acid indicated by the arrow (×100,000). (From Ogata T, Yamasaki Y: Scan-
ning EM of the resting gastric parietal cells reveals a network of cyto-
is detailed later. plasmic tubules and cisternae connected to the intracellular
canaliculus. Anat Rec 258:15-24, 2000.)
Chief (Zymogenic) Cells
Chief cells manufacture the enzymes pepsinogen, rennin, ulation by the vagus nerve is the main contributor to
and gastric lipase and release them into the lumen of pepsinogen release. Binding of secretin to receptors in
the stomach. the basal plasma membrane of chief cells triggers a
second messenger system that also leads to exocytosis
Most of the cells in the base of fundic glands are chief of pepsinogen.
cells (see Figs. 17-3 and 17-4). These columnar cells
display a basophilic cytoplasm, basally located nuclei, DNES Cells (APUD or
and apically situated secretory granules that house the Enteroendocrine Cells)
proenzyme pepsinogen (as well as rennin and gastric
lipase). Electron micrographs of chief cells exhibit a rich DNES cells may be open or closed. They manufacture
supply of RER, an extensive Golgi apparatus, and endocrine, paracrine, and neurocrine hormones.
numerous apical secretory granules interspersed with a
A group of small cells that are individually dispersed
few lysosomes (Fig. 17-9). Short, blunt, glycocalyx-
among the other epithelial cells of the gastric mucosa
covered microvilli project from the apical aspect of the
are known collectively by several names:
cell into the lumen of the gland.
Exocytosis of pepsinogen from chief cells is induced 䡲 Argentaffin and argyrophilic cells, because they stain
by both neural and hormonal stimulation. Neural stim- with silver stains
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Figure 17–9 Electron micrograph

of a chief cell from the fundus of a
mouse stomach (×11,837). BM, base-
ment membrane; G, Golgi apparatus; L,
lumen; m, mitochondria; N, nucleus;
nu, nucleolus; rER, rough endoplasmic
reticulum; ZC, zymogenic (chief) cell;
zg, zymogen granules;. (From Karam
SF, Leblond CP: Identifying and count-
ing epithelial cell types in the “corpus”
of the mouse stomach. Anat Rec 232:
231-246, 1992.)
䡲 APUD cells, because some of them can take up the open type) and those that do not (the closed type).
precursors of amines and decarboxylate them The open type reach the lumen via long, thin apical
䡲 DNES cells, because they are members of the diffuse processes with microvilli, which may serve to monitor
neuroendocrine system of cells the contents of the gastric lumen. The cytoplasm of
䡲 Enteroendocrine cells because they secrete DNES cells has a well-developed RER and Golgi appa-
hormone-like substances and are located in the ratus and numerous mitochondria. Additionally, small
epithelium of the enteric (alimentary) canal. secretory granules are evident, disposed basally in most
cells (Fig. 17-10).
Some of these cells are individually designated
All DNES cells release the contents of their granules
according to the substance that they produce. Gener-
basally into the lamina propria. The substances that cells
ally, a single type of DNES cell secretes only one agent,
release either travel short distances in the interstitial
although occasional cell types may secrete two different
tissue to act on target cells in the immediate vicinity
agents. There are at least 13 different DNES cell types,
of the signaling cell (paracrine effect) or enter the
only some of which are located in the mucosa of the
circulation and travel a distance to reach their target
stomach (Table 17-2). Cells of the DNES have been
cell (endocrine effect). Furthermore, the substance
identified not only in the digestive tract but also in the
released may be identical to neurosecretions. Because
respiratory system and in the endocrine pancreas. Addi-
of these three possibilities, some researchers have used
tionally, some of the secretory products synthesized and
the terms endocrine, paracrine, and neurocrine to
released by these DNES cells are identical to neuro-
differentiate among the three variations of the secreted
secretions localized in the central nervous system. The
substances.
significance of their diverse location and the substances
they produce is only incompletely understood. Muscularis Mucosae of the Stomach
Electron micrographs of DNES cells reveal that
these small cells, which sit on the basal lamina, are of The smooth muscle cells that compose the muscu-
two types: those that reach the lumen of the gut (the laris mucosae are arranged in three layers. The inner
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TABLE 17–2 Diffuse Neuroendocrine System (DNES) Cells and Hormones of the
Gastrointestinal Tract
Hormone Granule
Cell* Location Produced Size (nm) Hormonal Action
A Stomach and Glucagon 250 Stimulates glycogenolysis by hepatocytes, thus

small intestine (enteroglucagon) elevating blood glucose levels
D Stomach, small Somatostatin 350 Inhibits release of hormones by DNES cells in its
and large vicinity
intestines
EC Stomach, small Serotonin 300 Increases peristaltic movement

and large Substance P
intestines
ECL Stomach Histamine 450 Stimulates HCl secretion
G Stomach and Gastrin 300 Stimulates HCl secretion, gastric motility (especially
small intestine contraction of the pyloric region and relaxation of
pyloric sphincter to regulate stomach emptying),
and proliferation of regenerative cells in the body
of the stomach
GL Stomach, small Glicentin 400 Stimulates hepatocyte glycogenolysis, thus elevating

and large blood glucose levels
intestines
I Small intestine Cholecystokinin 250 Stimulates the release of pancreatic enzymes and
contraction of the gallbladder
K Small intestine Gastric inhibitory 350 Inhibits HCl secretion

peptide
Mo Small intestine Motilin Increases intestinal peristalsis
N Small intestine Neurotensin 300 Increases blood flow to ileum and decreases
peristaltic action of small and large intestines
PP (F) Stomach and Pancreatic 180 Stimulates release of enzymes by chief cells;
large intestine polypeptide depresses release of HCl by parietal cells; inhibits
exocrine release of pancreas
S Small intestine Secretin 200 Stimulates release of bicarbonate-rich fluid from

pancreas
VIP Stomach, small Vasoactive Increases peristaltic action of small and large
and large intestinal intestines and stimulates elimination of water and
intestines peptide ions by GI tract
*This table lists most of the better-known DNES cells.

ECL, enterochromaffin-like cell; EC, enterochromaffin cell; G, gastrin-producing cell; GI, gastrointestinal; GL, glicentin-producing cell; HCl,
hydrochloric acid; MO, motilin-producing cell; N, neurotensin-producing cell; PP (F), pancreatic polypeptide–producing cell (F cell); VIP,
vasoactive intestinal peptide–producing cell.
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graph of a DNES cell from the body of
a mouse stomach. G, Golgi apparatus; g,
secretory granules; N, nucleus; nu,
nucleolus; m, mitochondria; rER, rough
endoplasmic reticulum; (From Karam
SF, Leblond CP: Identifying and count-
ing epithelial cell types in the “corpus”
of the mouse stomach. Anat Rec 232:
231-246, 1992)
circular and outer longitudinal layers are well defined;

however, an occasional third layer, whose fibers are dis-
posed circularly (outermost circular), is not always P
evident.
Differences in the Mucosa of the

Cardiac and Pyloric Regions
The mucosa of the cardiac region of the stomach
differs from that of the fundic region, in that the gastric
pits are shallower and the base of its glands is highly
coiled. The cell population of these cardiac glands is
composed mostly of surface-lining cells, some mucous
neck cells, a few DNES cells and parietal cells, and no
chief cells (Table 17-3).
The glands of the pyloric region contain the same
cell types as those in the cardiac region, but the pre-
dominant cell type in the pylorus is the mucous neck
cell. In addition to producing mucus, these cells secrete LP
lysozyme, a bactericidal enzyme. Pyloric glands are
MM
highly convoluted and tend to branch. Additionally, the
gastric pits of the pyloric region are deeper than in both
the cardiac and pyloric regions, extending approxi-
mately halfway down into the lamina propria (Fig. 17- Figure 17–11 Light micrograph of the pyloric stomach (×132).
The gastric pits are much deeper here than in the cardiac or fundic
11; also see Table 17-3). regions of the stomach. P, gastric pits; LP, lamina propria; MM, mus-
cularis mucosae.
Submucosa of the Stomach

Muscularis Externa
The dense, irregular collagenous connective tissue
of the gastric submucosa has a rich vascular and lym- The muscularis externa of the stomach is composed of
phatic network that supplies and drains the vessels of three layers of smooth muscle: the innermost oblique
the lamina propria. The cell population of the sub- layer, middle circular layer, and outer longitudinal layer.
mucosa resembles that of any connective tissue proper.
The submucosal plexus is in its accustomed location, The smooth muscle cells of the gastric muscularis
within the submucosa in the vicinity of the muscularis externa are arranged in three layers. The innermost
externa. oblique layer is not well defined except in the cardiac
TABLE 17–3 Histology of the Alimentary Canal
Cell Type of Lamina Cells of Muscularis Muscularis Serosa or

Organ Epithelium Epithelium Propria Glands Mucosae Submucosa Externa Adventitia
Esophagus Stratified Esophageal Mucus- Longitudinal Esophageal Inner circular Adventitia

squamous cardiac secreting layer only glands proper and outer (except serosa
nonkeratinized glands longitudinal in abdominal
cavity)
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Cardiac Simple Surface lining Cardiac Surface lining Inner circular, No glands Inner oblique, Serosa
stomach columnar cells (no glands; cells, mucous outer middle circular,
goblet cells) shallow neck cells, longitudinal outermost
gastric pits regenerative and, in places, longitudinal
cells, DNES outermost
cells, parietal circular
cells
Fundic Simple Surface lining Fundic Surface lining Inner circular, No glands Inner oblique, Serosa
stomach columnar cells (no glands cells, mucous outer middle circular,
goblet cells) neck cells, longitudinal outermost
parietal cells, and, in places, longitudinal
regenerative outermost
cells, chief cells circular

DNES cells
Pyloric Simple Surface lining Pyloric Mucous neck Inner circular, No glands Inner oblique, Serosa
stomach columnar cells (no glands; deep cells, surface outer middle circular
goblet cells) gastric pits lining cells, longitudinal (well developed
parietal cells, and, in places, to form pyloric
regenerative outermost sphincter),
cells, DNES circular outermost
cells longitudinal
Duodenum Simple Surface Crypts of Surface Inner circular, Brunner’s Inner circular, Serosa and
columnar absorptive Lieberkühn absorptive cells, outer glands outer adventitia
(goblet cells) cells, goblet goblet cells, longitudinal longitudinal
cells, DNES regenerative
cells cells, DNES
cells, Paneth
cells
Jejunum Simple Surface Crypts of Surface Inner circular, No glands Inner circular, Serosa
columnar absorptive Lieberkühn absorptive cells, outer outer
cells cells, DNES
cells, Paneth
cells
Ileum Simple Surface Crypts of Surface Inner circular, No glands Inner circular, Serosa
columnar absorptive Lieberkühn; absorptive cells, outer (Peyer’s outer
(goblet cells) cells, goblet Peyer’s goblet cells, longitudinal patches may longitudinal
cells, DNES patches regenerative extend into
cells cells, DNES this layer)
cells, Paneth
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cells
Colon* Simple Surface Crypts of Surface Inner circular, No glands Inner circular, Serosa and
columnar absorptive Lieberkühn absorptive cells, outer outer adventitia
cells, DNES regenerative modified to
cells cells, DNES form taeniae
cells coli
Rectum Simple Surface Shallow Surface Inner circular, No glands Inner circular, Adventitia
columnar absorptive crypts of absorptive cells, outer outer
(goblet cells) cells, goblet Lieberkühn goblet cells, longitudinal longitudinal
cells cells, DNES
cells, Paneth
cells
Anal canal Simple Rectal Inner circular, No glands; Inner circular Adventitia
cuboidal; columns; outer internal and (forms internal
stratified circumanal longitudinal external and sphincter),
squamous glands; at hemorrhoidal outer
nonkeratinized; anus: hair plexuses longitudinal
stratified follicles and (becomes
squamous sebaceous fibroelastic
keratinized glands sheet)
Appendix Simple Surface Shallow Surface Inner circular, No glands; Inner circular, Serosa
columnar absorptive crypts of absorptive cells, outer occasional outer
Chapter 17 䡲 Digestive System: Alimentary Canal
(goblet cells) cells, goblet Lieberkühn; goblet cells, longitudinal lymphoid longitudinal
cells, DNES lymphoid regenerative nodules;
■
cells nodules cells, DNES possible fatty

■
cells, Paneth infiltration

■
cells
395
*Includes cecum.
DNES, diffuse neuroendocrine system.
Ch017-X2945.qxd 12/8/06 3:39 PM Page 396
region. The middle circular layer is clearly evident is closed. Coordinated contraction of the muscularis
along the entire stomach and is especially pronounced externa and momentary relaxation of the pyloric sphinc-
in the pyloric region, where it forms the pyloric ter permit emptying of the stomach by intermittently
sphincter. The outer longitudinal muscle layer is delivering small aliquots of the chyme into the duode-
most evident in the cardiac region and the body of the num. The rate at which the stomach releases its chyme
stomach but is poorly developed in the pylorus. The into the duodenum is a function of the acidity, the
myenteric plexus is located between the middle circu- caloric and fat content, and the osmolality of the chyme.
lar and outer longitudinal layers of smooth muscle. The production of the peristaltic waves occurs in a
The entire stomach is invested by a serosa, com- rhythmic fashion and is generated by the gastric pace-
posed of a thin, loose, subserous connective tissue maker at a rate of about three per minute. Receptors in
covered by a smooth, wet, simple squamous epithelium. the duodenum, in response to the arrival of the chyme,
This external covering provides an almost friction-free cause a sudden closure of the pyloric sphincter and con-
environment during the churning movements of the traction of the muscularis externa of the pyloric antrum,
stomach. driving the chyme back into the body of the stomach for
a thorough mixing of the chyme with the digestive
Gastric Histophysiology enzymes.
The factors that facilitate emptying of the stomach
The lining and glands of the stomach produce and are the degree of its distention and the action of
release secretions into the lumen of the stomach. These gastrin, a hormone that stimulates contraction of the
secretions are composed of water, hydrochloric acid, muscularis externa of the pyloric region and relaxation
gastric intrinsic factor, pepsinogen, rennin, gastric lipase, of the pyloric sphincter. Factors that inhibit gastric
visible mucus, and soluble mucus. emptying include distention of the duodenum; over-
abundance of fat, proteins, or carbohydrates; and
The gastric glands of the stomach produce approxi- increased osmolarity and excessive acidity of the chyme
mately 2 to 3 L of gastric juices a day. These secretions in the duodenum. These factors activate a neural feed-
are composed of (1) water (derived from the extracel- back mechanism by stimulating release of cholecys-
lular fluid in the interstitial connective tissue and deliv- tokinin, which counteracts the action of gastrin, and
ered via parietal cells); (2) hydrochloric acid (HCl) stimulating the release of gastric inhibitory peptide,
and gastric intrinsic factor (manufactured by parietal which also inhibits gastric contractions.
cells); (3) the enzymes pepsinogen, rennin, and
gastric lipase (manufactured by chief cells); (4) a gly-
coprotein, visible mucus (manufactured by surface- Gastric Hydrochloric Acid
lining cells) which forms a coat of mucus that lines and (HCl) Production
protects the epithelium of the stomach and serves as a
favorable, mostly neutral pH, environment for the bac- The three phases in the production of hydrochloric acid
terium Helicobacter pylori; and (5) soluble mucus are cephalic, gastric, and intestinal.
that becomes part of the gastric content (produced by
mucous neck cells). Little absorption of food products Hydrochloric acid not only breaks down food material
but also activates the proenzyme pepsinogen to become
occurs in the stomach, although some substances, such
the active proteolytic enzyme pepsin. Because pepsin
as alcohol, can be absorbed by the gastric mucosa.
requires a low pH for its activity, the presence of HCl
The three muscle layers of the muscularis externa
also provides the necessary acidic conditions (pH 1 to
interact such that during the contraction, the contents
pH 2).
of the stomach are churned and the ingested food is liq-
HCl secretion occurs in three phases as a result of
uefied to form chyme, a viscous fluid with the consis-
different stimuli:
tency of split pea soup. Independent contraction of the
muscularis mucosae exposes the chyme to the entire 䡲 Cephalic: Secretion caused by psychological factors
surface area of the gastric mucosa. (e.g., the thought, smell, or sight of food; stress) is
elicited by parasympathetic impulses from the vagus
nerve, which cause the release of acetylcholine
Emptying of Gastric Contents 䡲 Gastric: Secretion resulting from the presence of
Interaction between neurons of the myenteric and sub- certain food substances in the stomach as well as from
mucosal plexuses, and mostly due to the effect of the the stretching of the stomach wall is elicited by the
hormone ghrelin, a constant intraluminal pressure is paracrine hormones gastrin and histamine and
maintained, irrespective of the degree of distention of by the neurocrine substance acetylcholine; gastrin
the stomach. In the empty stomach the pylorus is always and histamine are released by the DNES cells—G
open; however, during peristalsis the pyloric sphincter cells and enterochromaffin-like (ECL) cells—of the
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H2O
HCl
Tubulovesicles Canaliculus
ADP
+ Pi
H+
K+
Cl–
K+
ATP
KCl
A RESTING B STIMULATION C ACTIVE
Figure 17–12 Parietal cell. A, Well-developed tubulovesicular apparatus in the resting cell. B, Mechanism of hydrochloric acid release.
C, Numerous microvilli in the active cell.
stomach, respectively, and acetylcholine is released centration forces K+ to leave the cell via ion channels
by the vagus nerve located in the basal plasmalemma and in the plasma
䡲 Intestinal: Secretion due to the presence of food in membrane of the microvilli. Thus, K+ is constantly
the small intestine is elicited by the endocrine recirculated in and out of the parietal cell.
hormone gastrin, released by G cells of the small 5 Water, derived from the extracellular fluid, enters the
intestine parietal cell and then leaves the cytoplasm to enter
the intracellular canaliculus as a consequence of the
Mechanism of Gastric Hydrochloric osmotic forces generated by the movement of ions
Acid Production just described. Because the intracellular canaliculus
is an extension of the lumen of the stomach, HCl
HCl production is initiated when gastrin, histamine, and manufactured by the parietal cells enters the gastric
acetylcholine bind to their respective receptors in the lumen.
basal plasma membrane of parietal cells.
The lining of the stomach is protected from the high
Parietal cells have receptors for gastrin, histamine, and acidic content by the buffering activity of the HCO3−
acetylcholine on their basal plasmalemma. Binding of present in the layer of mucus manufactured by the
these signaling molecules to the appropriate receptors surface-lining cells and, to a certain limited extent, by
causes the cells to manufacture and release HCl into mucous neck cells. Additionally, the zonulae occlu-
the intracellular canaliculus. The process occurs as dentes of the epithelial cells prevent the influx of HCl
follows (Fig. 17-12): into the lamina propria, thus protecting the mucosa
from damage. Moreover, evidence suggests that
1 The enzyme carbonic anhydrase facilitates the prostaglandins not only protect the cells lining the
production of carbonic acid (H2CO3) (from water gastric lumen but also increase local circulation, espe-
[H2O] and carbon dioxide [CO2]), which then disso- cially when the integrity of the epithelial barrier is com-
ciates into hydrogen ions (H+) and bicarbonate promised. This increased blood flow removes the H+
(HCO3−) within the cytoplasm of the parietal cell. from the lamina propria.
2 An H+,K+-ATPase, using adenosine triphosphate (ATP)
as an energy source, pumps intracellular H+ out of Inhibition of Hydrochloric
the cell into the intracellular canaliculi and transfers
extracellular potassium ion (K+) into the cell.
Acid Release
3 Carrier proteins, utilizing ATP as an energy source, The hormones somatostatin, prostaglandin, and
pump K+ and chloride ion (Cl−) out of the cell and gastric inhibitory peptide (GIP) inhibit gastric HCl
into the intracellular canaliculus. Thus Cl-and H+ production. Somatostatin acts on G cells and ECL cells,
enter the lumen of the intracellular canaliculus sep- inhibiting their release of gastrin and histamine, respec-
arately to combine as HCl. tively. Prostaglandins and GIP act directly on parietal
4 K+ is actively transported into the cell at the basal cells and inhibit their ability to produce HCl.
plasmalemma as well as at the microvilli jutting into Additionally, urogastrone, produced by Brunner’s
the intracellular canaliculi, thus increasing the intra- glands of the duodenum, acts directly on parietal cells
cellular level of K+. The high intracellular K+ con- to inhibit HCl production.
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The luminal surface of the small intestine is modified to

CLINICAL CORRELATIONS increase its surface area. Three types of modifications
have been noted:
Possibly the most common cause of ulcers in the
䡲 Plicae circulares (valves of Kerckring) are trans-
United States is the prevalent use of the non-
verse folds of the submucosa and mucosa that form
steroidal anti-inflammatory drugs (NSAIDs) ibu-
semicircular to helical elevations, some as large as 8
profen and aspirin. Both of these drugs inhibit
mm tall and 5 cm long. Unlike rugae of the stomach,
the manufacture of prostaglandins, thus preclud-
these are permanent fixtures of the duodenum and
ing their protective effects on the stomach lining.
jejunum and end in the proximal half of the ileum.
The bacterium Helicobacter pylori, which is
They not only increase the surface area of the small
localized in the layer of mucus protecting the
intestine by a factor of 2 to 3 but also decrease the
gastric epithelium, has also been implicated as a
velocity of the movement of chyme along the ali-
possible factor in ulcer formation.
mentary canal.
Almost 12% of cancer-related fatalities are
䡲 Villi are epithelially covered, finger-like or oak
due to gastric carcinoma, one of the most
leaf–like protrusions of the lamina propria. The core
common gastrointestinal malignancies. Although
of each villus contains capillary loops, a blindly ending
the cancer may be localized to any region of the
lymphatic channel (lacteal), and a few smooth
stomach, the region of the lesser curvature and
muscle fibers, embedded in loose connective tissue
the pyloric antrum are the sites that are most
and rich in lymphoid cells. Villi are permanent struc-
generally involved.
tures ranging from 10 to 40 per mm2 (Figs. 17-13 to
17-15). Their numbers are greater in the duodenum
than in the jejunum or the ileum, and their height
decreases from 1.5 mm in the duodenum to about
SMALL INTESTINE 0.5 mm in the ileum. These delicate structures confer
a velvety appearance to the lining of the living organ.
The small intestine has three regions: duodenum, Villi increase the surface area of the small intestine
jejunum, and ileum. by a factor of 10.
䡲 Microvilli, modifications of the apical plasmalemma
Digestion begins in the oral cavity and continues in of the epithelial cells covering the intestinal villi,
the stomach and in the small intestine, which at 7 m is increase the surface area of the small intestine by a
the longest region of the alimentary tract. The small intes- factor of 20.
tine is divided into three regions: duodenum, jejunum,
and ileum. Although these regions are similar histologi- Thus, the three types of intestinal surface modifica-
cally, their minor differences permit their identification. tions increase the total surface area available for absorp-
The small intestine digests food material and absorbs tion of nutrients by a factor of 400 to 600.
end products of the digestive process. To perform its Invaginations of the epithelium into the lamina
digestive functions, the first region of the small intes- propria between the villi form intestinal glands, crypts
tine, the duodenum, receives enzymes and an alkaline of Lieberkühn, which also augment the surface area
buffer from the pancreas and bile from the liver. Addi- of the small intestine.
tionally, epithelial cells and glands of the mucosa con-
tribute buffers and enzymes to facilitate digestion. Intestinal Mucosa
The mucosa of the small intestine is composed of the
Common Histological Features usual three layers: a simple columnar epithelium, the
Because the three regions of the small intestine are lamina propria, and the muscularis mucosae.
similar histologically, their common features are
described first. Following this discussion, variations Epithelium
from this plan are described for each segment (see The simple columnar epithelium covering the villi and
Table 17-3), and then functional aspects are considered. the surface of the intervillar spaces is composed of
surface absorptive cells, goblet cells, and DNES cells.
Modifications of the
Luminal Surface SURFACE ABSORPTIVE CELLS
The surface area of the intestinal lumen is enlarged by Surface absorptive cells are tall columnar cells that
the formation of plicae circulares, villi, microvilli, and function in terminal digestion and absorption of water
crypts of Lieberkühn. and nutrients.
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Small intestine
Villus Villus
Villi
Surface absorptive cell
Goblet cell
Crypt of
Lieberkühn
Lacteal
Lamina propria
Lymphoid nodule Regenerative cell
Muscularis mucosae Crypt of Lieberkühn
Paneth cell
Figure 17–13 Mucosa, villi, crypts of Lieberkühn, and component cells of the small intestine. Note that the crypts of Lieberkühn open
into the intervillar spaces. There is a solitary lymphoid nodule in the lamina propria.
The most numerous cells of the epithelium are surface nents also function in terminal digestion of dipeptides
absorptive cells (Fig. 17-16; also see Figs. 17-13 and 17- and disaccharides into their monomers. The actin core
15). They are tall cells, about 25 µm in length, with of the microvilli is anchored into the actin and inter-
basally located oval nuclei. Their apical surface presents mediate filaments of the cell web. The cytoplasm of
a brush border, and in good tissue preparations, ter- surface absorptive cells is rich in organelles, especially
minal bars are also evident. The principal functions of endosomes, smooth endoplasmic reticulum (SER),
these cells are terminal digestion and absorption of RER, and Golgi apparatus.
water and nutrients. Additionally, these cells reesterify The lateral cell membranes of these cells form
fatty acids into triglycerides, form chylomicrons, and zonulae occludentes, zonulae adherentes, desmosomes,
transport the bulk of the absorbed nutrients into the and gap junctions with adjacent cells. The tight junc-
lamina propria for distribution to the rest of the body. tions prevent the passage of material via a paracellular
The process of absorption is discussed later in the route to or from the lumen of the gut.
chapter.
Electron micrographs of surface absorptive cells GOBLET CELLS
sport as many as 3000 microvilli, approximately 1 µm
long, whose tips are covered with a thick glycocalyx Goblet cells are unicellular glands (see Figs. 17-13 and
layer. The glycocalyx coat not only protects the 17-15; also see Chapter 5). The duodenum has the
microvilli from autodigestion, but its enzymatic compo- smallest number of goblet cells, and their number
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Figure 17–14 Scanning electron micrographs of villi from the mouse ileum. A, Observe the villi and the openings of the crypts of
Lieberkühn in the intervillar spaces (×160). B, Note that the villus is fractured, revealing its core of connective tissue and migrating cells (×500).
(From Magney JE, Erlandsen SL, Bjerknes ML, Cheng H: Scanning electron microscopy of isolated epithelium of the murine gastrointestinal
tract: Morphology of the basal surface and evidence for paracrine-like cells. Am J Anat 177:43-53, 1986.)
increases toward the ileum. These cells manufacture above the surface of the small intestine (Fig. 17-17;
mucinogen, whose hydrated form is mucin, a compo- also see Figs. 17-14 and 17-15). The remainder of the
nent of mucus, a protective layer lining the lumen. lamina propria, extending down to the muscularis
mucosae, is compressed into thin sheets of highly vas-
DNES CELLS cularized connective tissue by the numerous tubular
intestinal glands, the crypts of Lieberkühn. The lamina
The small intestine has various types of DNES cells that
propria also is rich in lymphoid cells and contains
produce paracrine and endocrine hormones (see the
occasional lymphoid nodules, which, as discussed later,
earlier section on the stomach and Table 17-2). Approx-
help protect the intestinal lining from invasion by
imately 1% of the cells covering the villi and intervillar
microorganisms.
surface of the small intestine are composed of DNES
cells.
CRYPTS OF LIEBERKÜHN
M CELLS (MICROFOLD CELLS) Crypts of Lieberkühn increase the surface area of the
intestinal lining. They are composed of DNES cells,
Microfold cells phagocytose and transport antigens from
surface absorptive cells, goblet cells, regenerative cells,
the lumen to the lamina propria.
and Paneth cells.
The simple columnar epithelial lining of the small intes-
Crypts of Lieberkühn are simple tubular (or branched
tine is replaced by squamous-like M cells in regions
tubular) glands (see Fig. 17-13) that open into the inter-
where lymphoid nodules abut the epithelium. These M
villar spaces as perforations of the epithelial lining.
cells, which are believed to belong to the mononuclear
Scanning electron micrographs indicate that the base of
phagocyte system of cells, sample, phagocytose, and
each villus is surrounded by the openings of several
transport antigens present in the intestinal lumen.
crypts (see Fig. 17-14). These tubular glands are com-
posed of surface absorptive cells, goblet cells, regener-
Lamina Propria
ative cells, DNES cells, and Paneth cells.
The loose connective tissue of the lamina propria forms Surface absorptive and goblet cells occupy the upper
the core of the villi, which like trees of a forest rise half of the gland. Goblet cells have a short life span; it
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Lu
Electron micrographs of these undifferentiated cells
LP
display few organelles but many free ribosomes. Their
E single, basally located, oval nuclei are electron-
lucent, indicating the presence of a large amount of
euchromatin.
Paneth cells are clearly distinguishable because of
the presence of large, eosinophilic, apical secretory
granules (Fig. 17-18; also see Fig. 17-13). These
pyramid-shaped cells occupy the bottom of the crypts
L of Lieberkühn and manufacture the antibacterial agent
lysozyme, defensive proteins (defensin), and tumor
necrosis factor-a. Unlike the other cells of the intes-
tinal epithelium, Paneth cells have a comparatively long
life span of 20 days and secrete lysozyme continuously.
CL Electron micrographs of these cells display a well-
developed Golgi apparatus, a large complement of
RER, numerous mitochondria, and large apical secre-
tory granules housing a homogeneous secretory
product.
Muscularis Mucosae
The muscularis mucosae of the small intestine is com-
posed of an inner circular layer and an outer longitudi-
nal layer of smooth muscle cells (see Fig. 17-17).
Muscle fibers from the inner circular layer enter the
villus and extend through its core to the tip of the
connective tissue, as far as the basement membrane.
During digestion, these muscle fibers rhythmically con-
tract, shortening the villus several times a minute.
Submucosa
Figure 17–15 Light micrograph of the duodenal mucosa, dis- The submucosa of the small intestine is composed of
playing the simple columnar epithelium (E), the cellular lamina dense, irregular fibroelastic connective tissue with a rich
propria (LP) with its lacteals of villi, and the muscularis mucosae
(×132). The submucosa houses Brunner’s glands, a clear indication
lymphatic and vascular supply. The intrinsic innervation
that this is a section of the duodenum. CL, crypts of Lieberkühn; Lu, of the submucosa is from the parasympathetic submu-
lumen. cosal (Meissner’s) plexus. The submucosa of the duo-
denum is unusual because it houses glands known as
Brunner’s glands (duodenal glands).
is believed that after they disgorge their mucinogen BRUNNER’S GLANDS
they die and are desquamated. The basal half of the
gland has no surface absorptive cells and only a few Brunner’s glands produce a mucous, bicarbonate-rich
goblet cells; instead, most of the cells are regenerative fluid as well as urogastrone (human epidermal growth
cells (and their progeny), DNES cells, and Paneth cells. factor).
Only regenerative cells and Paneth cells are described
here; the others have been discussed earlier. Brunner’s glands are branched, tubuloalveolar glands
Regenerative cells of the small intestine are stem whose secretory portions resemble mucous acini (see
cells that undergo extensive proliferation to repopulate Fig. 17-15). The ducts of these glands penetrate the
the epithelium of the crypts, mucosal surface, and villi. muscularis mucosae and usually pierce the base of the
These narrow cells appear to be wedged into limited crypts of Lieberkühn to deliver their secretory product
spaces among the newly formed cells (see Fig. 17-13). into the lumen of the duodenum. Occasionally, their
Their rate of cell division is high, with a relatively short ducts open into the intervillar spaces. Electron micro-
cell cycle of 24 hours. It has been suggested that 5 to 7 graphs of the acinar cells display a well-developed RER
days after the appearance of a new cell, the cell has pro- and Golgi apparatus, numerous mitochondria, and flat-
gressed to the tip of the villus and has been exfoliated. tened to round nuclei.
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Figure 17–16 Surface absorptive cells

from a villus of the mouse jejunum. A, Low-
A magnification electron micrograph displaying
two goblet cells (Gc) and numerous surface
absorptive cells (Su) (×1744). Note the stri-
ated border (Sb) facing the lumen (Lu).
Nuclei (Nu) and cell boundaries (Cb) are
clearly evident. Observe also that the epithe-
lium is separated from the lamina propria by
a well-defined basement membrane (Bm).
B, A higher-magnification electron micro-
graph of two adjoining surface absorptive cells
(×10,500). The striated border (Sb) is clearly
composed of numerous microvilli that project
into the lumen (Lu). The adjoining cell mem-
branes (Cm) are close to each other. Mi,
mitochondria; Ly, lysosomes; Re, rough endo-
plasmic reticulum; Ve, vesicles; asterisk
indicates membrane-bound lipid droplets.
C, Electron micrograph of the basal aspect of
the surface absorptive cells (×11,200). Bm,
basement membrane; Lp, lamina propria; Mi,
mitochondria; Ve, vesicles; asterisk indicates
chylomicrons. (From Rhodin JAG: An Atlas of
Ultrastructure. Philadelphia, WB Saunders,
B C 1963.)
Brunner’s glands secrete a mucous, alkaline fluid in intrinsic neural supply of the external muscle coat. The
response to parasympathetic stimulation. This fluid muscularis externa is responsible for the peristaltic
helps neutralize the acidic chyme that enters the duo- activity of the small intestine.
denum from the pyloric stomach. The glands also man- Except for the second and third parts of the duode-
ufacture the polypeptide hormone urogastrone (also num, which have adventitia, the entire small intestine
known as human epidermal growth factor), which is is invested by a serosa.
released into the duodenal lumen along with the alka-
line buffer. Urogastrone inhibits production of HCl (by
directly inhibiting parietal cells) and amplifies the rate Lymphatic and Vascular Supply of
of mitotic activity in epithelial cells. the Small Intestine
Muscularis Externa and Serosa Lymph drainage in the small intestine begins as blindly
ending lymphatic vessels known as lacteals.
The muscularis externa of the small intestine is com-
posed of an inner circular layer and an outer longitudi- The small intestine has a well-developed lymphatic and
nal smooth muscle layer. Auerbach’s myenteric vascular supply. Blindly ending lymph capillaries called
plexus, located between the two muscle layers, is the lacteals, which are located in the cores of villi, deliver
Ch017-X2945.qxd 12/8/06 3:40 PM Page 403
liver and digestive juices from the pancreas via the

common bile duct and pancreatic duct, respectively.
These ducts open into the lumen of the duodenum at
the duodenal papilla (of Vater). The duodenum
differs from the jejunum and ileum in that its villi are
broader, taller, and more numerous per unit area. It has
fewer goblet cells per unit area than the other segments,
and there are Brunner’s glands in its submucosa.
The villi of the jejunum are narrower, shorter, and
sparser than those of the duodenum. The number of
goblet cells per unit area is greater in the jejunum than
in the duodenum.
The villi of the ileum are the sparsest, shortest, and
narrowest of the three regions of the small intestine.
The lamina propria of the ileum houses permanent clus-
ters of lymphoid nodules, known as Peyer’s patches.
CL These structures are located in the wall of the ileum that
is opposite the attachment of the mesentery. In the
region of Peyer’s patches the villi are reduced in height
and may even be absent.
MM
S
Meckel’s diverticulum is a very common con-
Ic genital anomaly occurring in about 2% of the
Caucasian population. The diverticulum, a
remnant of the vitelline duct—an embryonic
Ol connection between the midgut and the yolk
sac—is a short, wide-mouthed extension of the
distal aspect of the ileum about 100 cm from the
cecum. Most Meckel’s diverticula are asympto-
matic, but some can cause bleeding and intes-
Figure 17–17 Light micrograph of the mucosa of a monkey tinal obstruction. The obstruction is usually due
jejunum (×132). Observe the well-developed villi, and note that there to intussusception—that is, the prolapse of the
are no Peyer’s patches in the lamina propria nor are there any ileum into the diverticulum.
Brunner’s glands in the submucosa; therefore, this must be a section
of the jejunum. CL, crypts of Lieberkühn; Ic, inner circular muscle
layer; MM, muscularis mucosae; Ol, outer longitudinal muscle layer;
S, submucosa.
Small Intestine Histophysiology
their contents into the submucosal lymphatic plexus. In addition to its roles in digestion and absorption, the
From here, lymph passes through a series of lymph small intestine exhibits immunological and secretory
nodes to be delivered to the thoracic duct, the largest activities. These activities are considered first, after
lymph vessel in the body. The thoracic duct empties its which the primary function of the small intestine is
contents into the circulatory system at the junction of described.
the left internal jugular and subclavian veins.
Capillary loops adjacent to the lacteals are drained Immunological Activity of the
by blood vessels that are tributaries of the submucosal Lamina Propria
vascular plexus. Blood from here is delivered to the
hepatic portal vein to enter the liver for processing. Immunoglobulin A produced by plasma cells in the
lamina propria is recirculated through the liver and
Regional Differences gallbladder.
The duodenum is the shortest segment of the small The lamina propria is rich in plasma cells, lymphocytes,
intestine, only 25 cm in length. It receives bile from the mast cells, extravasated leukocytes, and fibroblasts.
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Figure 17–18 Electron micrograph of a Paneth

cell from the rabbit ileum (×5900). Note the large,
round granules in the cytoplasm of the Paneth cell.
(From Satoh Y, Yamano M, Matsuda M, Ono K:
Ultrastructure of Paneth cell in the intestine of
various mammals. J Electron Microsc Tech 16:69-80,
1990.)
Additionally, solitary lymphoid nodules are frequently transported into the lumen, a process known as trans-
present in the lamina propria, adjacent to the epithelial cytosis, and bound to the glycocalyx to defend the body
lining of the mucosa. Moreover, as described previously, against antigenic onslaught.
the ileum has permanent clusters of lymphoid nodules Most of the IgA produced in the lamina propria
collectively known as Peyer’s patches. enters the circulatory system, is transported to the liver,
Where these lymphoid nodules come into contact where hepatocytes complex it with secretory compo-
with the epithelium, the columnar cells are replaced by nent, and is released as a complex into bile. Thus, much
M cells, which phagocytose luminal antigens (Figs. 17- of the luminal IgA enters the intestine through the
19 and 17-20). Endocytosed antigens enter the endoso- common bile duct, as a constituent of bile.
mal system of these cells; however, instead of being
processed, they are packaged in clathrin-coated vesi- Secretory Activity of the
cles, transferred to the basal aspect of the cell, and
released into the lamina propria. Antigen-presenting
Small Intestine
cells and dendritic cells of the lymphoid nodule endo- Glands of the small intestine secrete mucus and a
cytose the transferred antigens, process them, and watery fluid in response to neural and hormonal stimu-
present the epitopes to lymphocytes for the initiation of lation. Neural stimulation, originating in the submu-
an immune response. cosal plexus, is the principal trigger, but the hormones
Activated lymphocytes migrate to mesenteric lymph secretin and cholecystokinin also play a part in regulat-
nodes, where they form germinal centers, regions ing the secretory activities of Brunner’s glands in the
where B cells proliferate. The newly formed B cells duodenum and of the crypts of Lieberkühn, which col-
return to the lamina propria, where they differentiate lectively produce almost 2 L of slightly alkaline fluid per
into plasma cells that produce immunoglobulin A (IgA). day.
Some of the released antibodies bind to IgA recep- The DNES cells of the small intestine produce
tors of epithelial cells and are complexed to secretory numerous hormones that affect movement of the small
component (proteins manufactured by these cells) intestine and help regulate gastric HCl secretion and
within the epithelial cells. The IgA-protein complex is the release of pancreatic secretions (see Table 17-2).
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Bacteria Movement of the Small Intestine

M cells The small intestine participates in two types of
contraction: mixing and propulsive.
Lymphocytes
Movement of the small intestine may be subdivided into
two interrelated phases:
䡲 Mixing contractions are more localized and
Lymph node sequentially redistribute the chyme to expose it to the
digestive juices.
䡲 Propulsive contractions occur as peristaltic
Antigen B cell
presenting cell B cells waves that facilitate the movement of the chyme
along the small intestine. Because the chyme moves
Thoracic at an average of 1 to 2 cm/min, it spends several hours
duct in the small intestine. The rate of peristalsis is con-
B cells
trolled by neural impulses and hormonal factors. In
response to gastric distention, a gastroenteric reflex
mediated by the myenteric plexus provides the
neural impetus for peristalsis in the small intestine.
Liver The hormones cholecystokinin, gastrin, motilin, sub-
stance P, and serotonin increase intestinal motility,
IgA in bile output IgA whereas secretin and glucagon decrease it.
IgA
IgA CLINICAL CORRELATIONS

If the intestinal mucosa is exposed to profound
irritation by toxic substances, the muscularis
externa can undergo intense, swift contractions of
long duration known as peristaltic rush. These
B cells
strong contractions propel the chyme into the
IgA colon within minutes for elimination as diarrhea.
IgA
Plasma cells
Lamina propria Digestion
Figure 17–19 An M cell and its immunological relationship to the The chyme that enters the duodenum is in the process of
alimentary canal. Immunoglobulin A (IgA) is produced by plasma cells being digested by enzymes produced by glands of the oral
in the lamina propria. Some IgA then enters the lumen of the duodenum cavity and stomach. The process of digestion is intensified
directly via the surface absorptive cells. Most of the IgA enters the in the duodenum by enzymes derived from the exocrine
hepatic portal system and hepatocytes of the liver complex it with secre- pancreas. The final breakdown of proteins and carbohy-
tory protein and deliver it into the gallbladder, where it is stored with
bile. As bile is released into the duodenum, it will be rich in IgA. There- drates occurs at the microvilli, where dipeptidases and
fore, most of the IgA enters the lumen of the duodenum via the bile. disaccharidases, adherent to the glycocalyx, liberate
individual amino acids and monosaccharides. These
monomers are transported into the surface absorptive
cells by specific carrier proteins; however, dipeptides and
CLINICAL CORRELATIONS tripeptides are also endocytosed by the surface absorptive
The rate of fluid secretion into the small intes- cells. Lipids are emulsified by bile salts into small fat
tine is greatly increased in response to cholera globules that are split into monoglycerides and fatty acids.
toxin. The amount of fluid lost as diarrhea may Bile salts segregate monoglycerides and free fatty acids
amount to as much as 10 L/day and, if not into micelles, 2 nm in diameter, which diffuse into the
replaced, may lead to circulatory shock and death surface absorptive cells through their plasmalemma.
within a few hours. The fluid loss is accompanied
by electrolyte imbalance, a contributory factor in Absorption
the lethal effect of cholera. Approximately 6 to 7 L of fluid, 30 to 35 g of sodium,
0.5 kg of carbohydrates and proteins, and 1 kg of fat
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Figure 17–20 Electron micrograph of M cells

of the mouse colon (×6665). Observe the electron-
dense M cells surrounding the electron-lucent lym-
phocytes. (From Owen RL, Piazza AJ, Ermak TH:
Ultrastructural and cytoarchitectural features of lym-
phoreticular organs in the colon and rectum of adult
BALB/c mice. Am J Anat 190:10-18, 1991.)
are absorbed by the surface absorptive cells of the Short-chain fatty acids (<12 carbons in length) do not
small intestine each day. Water, amino acids, dipep- enter the SER for reesterification. These free fatty acids,
tides and tripeptides, ions, and monosaccharides which are short enough to be somewhat water-soluble,
enter the surface absorptive cells and are released progress to the basolateral membrane of the surface
into the intercellular space at the basolateral mem- absorptive cell, diffuse into the lamina propria, and enter
brane. These nutrients then enter the capillary the capillary loops to be delivered to the liver for processing.
bed of the villi and are transported to the liver for
processing.
Long-chain fatty acids and monoglycerides enter the CLINICAL CORRELATIONS
SER of the surface absorptive cell, where they are
reesterified to triglycerides (Fig. 17-21). The triglyc- Malabsorption in the small intestine may occur
erides are transferred to the Golgi apparatus, where even though the pancreas delivers its normal
they are combined with a β-lipoprotein coat, manufac- complement of enzymes. The various diseases
tured on the RER, to form chylomicrons. These large that result in malabsorption are called sprue. An
lipoprotein droplets, packaged by and released from the interesting form of sprue, gluten enteropathy
Golgi apparatus, are transported to the basolateral cell (nontropical sprue), is caused by gluten, a
membrane to be released into the lamina propria. The substance present in rye and wheat, that destroys
chylomicrons enter the lacteals, filling these blindly the microvilli and even the villi of susceptible
ending lymphatic vessels with a lipid-rich substance persons. These effects may result from an aller-
known as chyle. Rhythmic contractions of the smooth gic response to gluten. In people with this disor-
muscle cells located in the cores of the villi cause short- der, the surface area available for absorption of
ening of each villus, which acts as a syringe, injecting nutrients is reduced. Treatment involves elimi-
the chyle from the lacteal into the submucosal plexus of nation of gluten-containing grains from the diet.
lymph vessels.
Ch017-X2945.qxd 12/8/06 3:40 PM Page 407
Lipase
Bile
2 Monoglycerides and 1 Lipids

long-chain fatty acids
Glycerol, short-, medium-
chain fatty acids
Micelle 1 Lipids in the lumen of the small
intestine are broken down by
pancreatic lipase to fatty acids
and monoglycerides.
2 Monoglycerides and fatty acids

3 are emulsified by bile, forming
micelles that move into
Triglyceride
surface absorbing cells.
synthesis
RER Glycerol diffuses directly into
SER surface absorbing cells.
3 Monoglycerides and fatty
acids are esterified into
triglycerides within the
4 Protein smooth ER.
4 Triglycerides are complexed

with protein within the Golgi
Chylomicron Golgi apparatus, forming
chylomicrons that are released
Glycerol, short-, Lipoprotein and into the lacteals.
medium-chain glycoprotein 5 Glycerol and short- and
fatty acids synthesis
medium-chain fatty acids
are absorbed directly into
5 the blood.
Figure 17–21 Fat absorption, Blood capillary
fat processing, and chylomicron
release by surface absorptive cells.
SER, smooth endoplasmic reticulum; Lymphatic capillary
RER, rough endoplasmic reticulum. (lacteal)
cal sphincter that prevents reflux of the cecal contents

LARGE INTESTINE into the ileum.
The large intestine is subdivided into the cecum, colon,
rectum, and anus; the appendix is a small, blind Colon Histology
outpouching of the cecum. The colon has no villi but is richly endowed with crypts
of Lieberkühn that are similar in composition to those
The large intestine, composed of the cecum, colon
of the small intestine, except for the absence of Paneth
(ascending, transverse, descending, and sigmoid),
cells (Figs. 17-22 to 17-25). The number of goblet cells
rectum, and anus, is approximately 1.5 m long (see
increases from the cecum to the sigmoid colon, but,
Table 17-3). Its absorbs most of the water and ions from
throughout most of the colon, the surface absorptive
the chyme it receives from the small intestine and com-
cells are the most numerous cell type. DNES cells are
pacts the chyme into feces for elimination. The cecum
also present, although they are few in number. Rapid
and the colon are indistinguishable histologically and
mitotic activity of the regenerative cells replaces the
are discussed as a single entity called the colon. The
epithelial lining of the crypts and of the mucosal surface
appendix, a blind outpocketing of the cecum, is
every 6 to 7 days.
described separately.
The lamina propria, muscularis mucosae, and sub-
mucosa of the colon resemble those of the small
Colon
intestine. The muscularis externa is unusual in
The colon accounts for almost the entire length of the that the outer longitudinal layer is not of continuous
large intestine. It receives chyme from the ileum at the thickness along the surface; instead, most of it is gath-
ileocecal valve, an anatomical as well as a physiologi- ered into three narrow ribbons of muscle fascicles
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Large intestine
Absorptive cell
Goblet cell
Crypt of Regenerative cell

Lieberkühn
Lamina propria
Muscularis mucosae
Lymphoid (APUD cell)
Submucosa
nodule
Circular muscle
of muscularis externa
Figure 17–22 Colon, crypts of Lieberkühn, and associated cells.
Intense irritation of the colonic mucosa, as in to antibiotic therapy, Clostridium difficile plays a
enteritis, results in the secretion of large quantities major role in the genesis of this disease. Clinical
of mucus, water, and electrolytes. Voiding of copious manifestations include fluid accumulation in the
quantities of liquid stool, known as diarrhea, pro- small intestine as well as epithelial shedding and the
tects the body by diluting and eliminating the irri- formation of a thick, viscous membrane composed
tant. Long-term diarrhea and loss of a large amount of fibrin, mucus, neutrophils, and mononuclear
of fluid and electrolytes, without a regimen of cells. Symptoms include a low-grade fever (38°-
replacement therapy, may result in circulatory shock 40oC), copious watery diarrhea, severe abdominal
and even death. cramps and abdominal tenderness. Mortality is rel-
Pseudomembranous colitis, an inflammatory atively high (10%-15% of affected individuals) if the
disease of the bowel, may result from mercury poi- condition is not treated in a timely manner by fluid
soning, intestinal ischemia, and bronchopneumonia, replacement therapy (as much as 10-15 L per 24 to
but most frequently it is due to prolonged antibiotic 36 hours) to restore electrolyte balance and main-
therapy. Patients most at risk are those who are weak tain adequate fluid volume.
and/or elderly. As the intestinal flora is disrupted due
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L
O
G
LP
P
CL
MM
SM
Figure 17–24 Light micrograph of the crypts of Lieberkühn of

the monkey colon (×270). Observe that the base of the crypt displays
ME DNES cells whose granules are basally oriented. E, diffuse neuroen-
docrine system (DNES) cell; L, lumen of crypt; P, plasma cell.
pigment (1%). The odor of feces varies with the indi-

vidual and is a function of the diet and bacterial flora,
which produce varied amounts of indole, hydrogen
Figure 17–23 Light micrograph of the monkey colon (×132). It
appears as if most of the cells of the epithelial lining are goblet cells sulfide, and mercaptans. Bacterial by-products
(G), but in fact the surface absorptive cells constitute the largest pop- include riboflavin, thiamin, vitamin B12, and vitamin K.
ulation of this epithelium. CL, crypts of Lieberkühn; LP, lamina Bacterial action in the colon produces gases, released
propria; ME, muscularis externa; MM, muscularis mucosae; O, open as flatus, composed of CO2, methane, and H2, which
lumen of crypts of Lieberkühn; SM, submucosa.
then is mixed with nitrogen and oxygen from swallowed
air. The gas is combustible and, very infrequently, it may
explode when electrical cauterization is used during sig-
known as taeniae coli. The constant tonus main-
moidoscopy. The large intestine holds 7 to 10 L of gases
tained by the taeniae coli puckers the large intestine
each day, of which only 0.5 to 1 L is expelled as flatus;
into sacculations called haustra coli. The serosa dis-
the remainder is absorbed through the lining of the
plays numerous fat-filled pouches called appendices
colon.
epiploicae.
The colon also secretes mucus and HCO3−. Mucus
not only protects the mucosa of the colon but also facil-
Colon Histophysiology itates the compaction of feces, because it is the mucus
that permits adherence of the solid wastes into a
The colon functions in absorption of water, electrolytes, compact mass. HCO3− adheres to the mucus and acts
and gases as well as in the compaction and elimination as a buffer, protecting the mucosa from the acid by-
of feces. products of bacterial metabolism within the feces.
The colon absorbs water and electrolytes (~1400 mL/
Rectum and Anal Canal
day) and compacts and eliminates feces (~100 mL/day).
Feces are composed of water (75%), dead bacteria Histologically, the rectum resembles the colon, but
(7%), roughage (7%), fat (5%), inorganic substances the crypts of Lieberkühn are deeper and number fewer
(5%), and undigested protein, dead cells, and bile per unit area (see Table 17-3). The anal canal, the
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Anal Submucosa and

Muscularis Externa
The submucosa of the anal canal is composed of fibro-
elastic connective tissue. It houses two venous plexuses,
the internal hemorrhoidal plexus, situated above
the pectinate line, and the external hemorrhoidal
plexus, located at the junction of the anal canal with its
external orifice, the anus.
The muscularis externa consists of an inner circu-
lar and an outer longitudinal smooth muscle layer. The
inner circular layer becomes thickened as it encircles
the region of the pectinate line to form the internal
anal sphincter muscle. The smooth muscle cells of
the outer longitudinal layer continue as a fibroelastic
sheet surrounding the internal anal sphincter.
Skeletal muscles of the floor of the pelvis form an
external anal sphincter muscle that surrounds the
fibroelastic sheet and the internal anal sphincter. The
external sphincter is under voluntary control and
exhibits a constant tonus.
Figure 17–25 Scanning electron micrograph of a monkey colon
(×516). Observe the opening of the crypts. (From Specian RD, An increase in the size of the vessels of the sub-
Neutra MR: The surface topography of the colonic crypt in rabbit and mucosal venous plexuses of the anal canal results
monkey. Am J Anat 160:461-472, 1981.) in the formation of hemorrhoids, a condition
common in pregnancy and in persons older than
50 years of age. This condition may manifest as
painful defecation, the appearance of fresh blood
constricted continuation of the rectum, is about 3 to with defecation, and anal itching.
4 cm long. Its crypts of Lieberkühn are short and few As a rectal examination is performed by
and are no longer present in the distal half of the canal. insertion of the index finger through the external
The mucosa displays longitudinal folds, the anal col- anal orifice, the external anal sphincter tightens
umns (rectal columns of Morgagni). These meet one around the finger. Continued penetration results
another to form pouch-like outpocketings, the anal in activation of the internal anal sphincter, which
valves, with intervening anal sinuses. The anal valves also tightens around the finger. In males, struc-
assist the anus in supporting the column of feces. tures that may be palpated through the anal canal
include the bulb of the penis, the prostate,
Anal Mucosa enlarged seminal vesicles, the inferior aspect of
the distended bladder, and enlarged iliac lymph
The epithelium of the anal mucosa is simple cuboidal nodes; in females, palpable structures include
from the rectum to the pectinate line (at the level of the cervix of the uterus and, in pathological con-
the anal valves), stratified squamous nonkeratinized ditions, the ovaries and broad ligament.
from the pectinate line to the external anal orifice,
and stratified squamous keratinized (epidermis) at
the anus. The lamina propria, a fibroelastic con-
nective tissue, houses anal glands at the rectoanal
junction and circumanal glands at the distal end Appendix
of the anal canal. Additionally, hair follicles and seba-
The histological appearance of the appendix resembles
ceous glands are present at the anus. The muscularis
that of the colon, except that it is much smaller in
mucosae is composed of an inner circular layer and
diameter, has a richer supply of lymphoid elements and
an outer longitudinal layer of smooth muscle. These
contains many more DNES cells in its crypts of
muscular layers do not extend beyond the pectinate
Lieberkühn.
line.
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The vermiform appendix is a 5- to 6-cm-long diver-

ticulum of the cecum with a stellate lumen that usually CLINICAL CORRELATIONS
is occupied by debris. The mucosa of the appendix
is composed of a simple columnar epithelium, con- The incidence of inflammation of the appendix,
sisting of surface absorptive cells, goblet cells, and M appendicitis, is greater in teenagers and young
cells where lymphoid nodules adjoin the epithelium adults than in older people; it also occurs more
(see Table 17-3). The lamina propria is a loose con- frequently in men than in women. Appendicitis
nective tissue with numerous lymphoid nodules and usually is caused by obstruction of the lumen,
shallow crypts of Lieberkühn. The cells composing which results in inflammation accompanied by
these crypts are surface absorptive cells, goblet cells, swelling and an unremitting, severe pain in the
regenerative cells, numerous DNES cells, and infre- lower right quadrant of the abdomen. Additional
quent Paneth cells. The muscularis mucosae, submu- clinical signs are nausea and vomiting, fever
cosa, and muscularis externa do not deviate from the (usually below 102º F), tense abdomen, and ele-
general plan of the alimentary canal, although lym- vated leukocyte count. If the condition is not
phoid nodules and occasional fatty infiltration are treated within 1 to 2 days, the appendix may
present in the submucosa. The appendix is invested by rupture, leading to the onset of peritonitis, which
a serosa. may result in death if untreated.
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18 䡲䡲䡲
Digestive System: Glands
Extramural glands of the digestive system include the tubuloalveolar glands whose connective tissue
major salivary glands associated with the oral cavity capsule provides septa that subdivide the glands into
(parotid, submandibular, and sublingual glands), the lobes and lobules. Individual acini are also invested
pancreas, and the liver and gallbladder. Each of these by thin connective tissue elements. The vascular and
glands has numerous functions aiding the digestive neural components of the glands reach the secretory
process, and their secretory products are delivered to units via the connective tissue framework.
the lumen of the alimentary tract by a system of ducts.
Saliva produced by salivary glands facilitate the Anatomy of Salivary Glands
process of tasting food, initiate its digestion, and permit
Each of the major salivary glands has a secretory and a
its deglutition (swallowing). These glands also protect
duct portion (Fig. 18-1). Note that according to some
the body by secreting the antibacterial agents lysozyme
and lactoferrin as well as the secretory immunoglobulin authors, the acinus, intercalated duct, and striated duct
IgA. together constitute the salivon, the functional unit of a
The pancreas manufactures a bicarbonate-rich fluid salivary gland.
that buffers the acid chyme and produces enzymes nec-
essary for the digestion of fats, proteins, and carbohy- Secretory Portions
drates. The exocrine secretions of the pancreas are The secretory portions of salivary glands are composed
released into the lumen of the duodenum as necessary. of serous and/or mucous secretory cells arranged in acini
In addition, the pancreas synthesizes and releases (alveoli) or tubules that are couched by myoepithelial
endocrine hormones, including insulin, glucagon, cells.
somatostatin, gastrin, and pancreatic polypeptide.
Bile, the exocrine secretion of the liver, is required The secretory portions, arranged in tubules and acini,
for proper absorption of lipids, whereas many of the are composed of three types of cells:
liver’s endocrine functions are essential for life. These
䡲 Serous cells are seromucous cells because they
include metabolism of proteins, lipids, and carbohy-
drates; synthesis of blood proteins and coagulation secrete both proteins and a considerable amount of
factors; manufacture of vitamins; and detoxification of polysaccharides. These cells resemble truncated
blood-borne toxins. The gallbladder concentrates bile pyramids and have single, round, basally located
and stores it until its release into the lumen of the nuclei, a well-developed rough endoplasmic reticu-
duodenum. lum (RER) and Golgi complex, numerous basal mito-
chondria, and abundant apically situated secretory
granules rich in ptyalin (salivary amylase), which
MAJOR SALIVARY GLANDS they secrete along with kallikrein, lactoferrin, and
lysozyme. The basal aspects of the lateral cell mem-
There are three pairs of major salivary glands: parotid, branes form tight junctions with each other. Apical to
sublingual, and submandibular. the tight junctions, intercellular canaliculi communi-
cate with the lumen. The plasmalemma basal to the
The major salivary glands are the paired parotid, sub- tight junctions forms many processes that interdigi-
lingual, and submandibular glands. They are branched tate with those of neighboring cells.
413
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414 䡲䡲䡲 Chapter 18 䡲 Digestive System: Glands
Myoepithelial
S
cell
Intercalated
duct
Striated duct
M
Serous acinus
Mucous acinus
Serous
demilunes
Figure 18–2 Light micrograph of the monkey sublingual gland

displaying mucous acini (M) with serous demilunes (S). Note that
Serous Intercalated Mucous Striated duct serous demilunes may be fixation artifacts (×540).
cell cell cell cell
Figure 18–1 Salivary gland acini, ducts, and cell types.

on the acinus, facilitating release of the secretory
product into the duct of the gland.
䡲 Mucous cells are similar in shape to the serous cells. Duct Portions
Their nuclei are also basally located but are flattened
instead of being round (Fig. 18-2). The organelle The ducts of major salivary glands are highly branched
population of these cells differs from that of the and range from very small intercalated ducts to very
serous cells in that mucous secretory cells have fewer large principal (terminal) ducts.
mitochondria, a less extensive RER, and a consider-
ably greater Golgi apparatus, indicative of the greater The duct portions of the major salivary glands are highly
carbohydrate component of their secretory product branched structures. The smallest branches of the
(Fig. 18-3). The apical region of the cytoplasm is system of ducts are the intercalated ducts, to which
occupied by abundant secretory granules. The inter- the secretory acini (and tubules) are attached. These
cellular canaliculi and processes of the basal cell small ducts are composed of a single layer of small
membranes are much less extensive than those of cuboidal cells and possess some myoepithelial cells.
serous cells. Several intercalated ducts merge with each other to
䡲 Myoepithelial cells (basket cells) share the basal form striated ducts, composed of a single layer of
laminae of the acinar cells. They have a cell body that cuboidal to low columnar cells (see Fig. 18-1). The
houses the nucleus and several long processes that basolateral membranes of these cells are highly folded,
envelop the secretory acinus and intercalated ducts subdividing the cytoplasm into longitudinal compart-
(see Fig. 18-1). The cell body houses a small comments that are occupied by elongated mitochondria.
plement of organelles in addition to the nucleus The basolateral cell membranes of these cells have
and makes hemidesmosomal attachments with the sodium adenosine triphosphatase (Na+-ATPase) that
basal lamina. The cytoplasmic processes, which form pumps sodium out of the cell into the connective tissue,
desmosomal contacts with the acinar and duct cells, thus conserving these ions and reducing the tonicity of
are rich in actin and myosin; in electron micrographs saliva. Striated ducts join with each other, forming
these processes resemble smooth muscle cells. As the intralobular ducts of increasing caliber, which are sur-
processes of myoepithelial cells contract, they press rounded by more abundant connective tissue elements.
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Chapter 18 䡲 Digestive System: Glands ■ ■ ■ 415
Figure 18–3 Electron micrograph of the rat

sublingual gland displaying serous and mucous gran-
ules in the cytoplasm of the acinar cells (×5400). Note
that the nuclei of serous cells are round, whereas the
nuclei of mucous cells are flattened. Also observe that
the serous secretory products are present as round,
dense, dark structures. The mucous secretory prod-
ucts are mostly dissolved and appear light in color
and spongy. (From Redman RS, Ball WD: Cytodif-
ferentiation of secretory cells in the sublingual glands
of the prenatal rat: A histological, histochemical, and
ultrastructural study. Am J Anat 153:367-390, 1978.)
Ducts arising from lobules unite to form interlobular estimated that the basal rate of blood flow to salivary
ducts, which in turn form intralobar and interlobar glands is 20 times greater than the flow of blood to
ducts. The terminal (principal) duct of the gland skeletal muscle. During maximal secretion, the blood
delivers saliva into the oral cavity. flow is correspondingly increased.
Saliva has numerous functions: lubricating and
Histophysiology of the cleansing of the oral cavity, antibacterial activity, partic-
Salivary Glands ipating in the taste sensation by dissolving food mate-
rial, initial digestion via the action of ptyalin (salivary
Secretory cells of acini produce primary saliva that is amylase) and salivary lipase, aiding swallowing by mois-
modified by striated ducts to form secondary saliva. tening the food and permitting the formation of bolus,
and participating in the clotting process and wound
The major salivary glands produce approximately 700 to healing because of the clotting factors and epidermal
1100 mL of saliva per day. Minor salivary glands are growth factor present in saliva.
located in the mucosa and submucosa of the oral cavity, The saliva manufactured by the acinar cells, called
but they contribute only 5% of the total daily salivary primary saliva, is isotonic with plasma. The primary
output. To perform at this level, salivary glands have an saliva, is modified by the cells of the striated ducts
extraordinarily rich vascular supply. In fact, it has been by removing sodium and chloride ions from it and
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secreting potassium and bicarbonate ions into it. There- of saliva is also produced just before, during, and sub-
after, the altered secretion, called secondary saliva, is sequent to vomiting. Inhibitors of salivation include
hypotonic. fatigue, fear, and dehydration; moreover, salivary flow is
Acinar cells and duct cells also synthesize the secre- greatly reduced while we are asleep.
tory component required to transfer IgA from the con-
nective tissue into the lumen of the secretory acinus Properties of Individual
(or duct). Secretory IgA complexes with antigens in Salivary Glands
the saliva, mitigating their deleterious effects. Saliva
also contains lactoferrin, lysozyme, and thiocyanate Parotid Gland
ions. Lactoferrin binds iron, an element essential for
Although physically the largest of the salivary glands,
bacterial metabolism; lysozyme breaks down bacterial
the parotid gland produces only about 30% of the total
capsules, permitting the entry of thiocyanate ions, a
salivary output; the saliva it produces is serous.
bactericidal agent, into the bacteria.
Salivary glands also secrete the enzyme kallikrein The parotid gland, the largest salivary gland, weighs
into the connective tissue. Kallikrein enters the blood- about 20 to 30 g but produces only approximately 30%
stream, where it converts kininogens, a family of plasma of the total output of saliva. Although this gland is said
proteins, into bradykinin, a vasodilator that dilates to produce a purely serous secretion, the secretory
blood vessels and enhances blood flow to the region. product has a mucous component. Electron micro-
graphs of the apical regions of serous cells display
Role of Autonomic Nerve Supply in numerous secretory granules filled with an electron-
Salivary Secretion dense product that has an even more electron-dense
core of unknown composition.
The major salivary glands do not secrete continuously. The saliva produced by the parotid gland has high
Secretory activity is stimulated via parasympathetic and levels of the enzyme salivary amylase (ptyalin) and
sympathetic innervation. Innervation may be intraep- secretory IgA. Salivary amylase is responsible for diges-
ithelial (i.e., formation of a synaptic contact between the tion of most of the starch in food, and this digestion con-
end-foot and acinar cell) or subepithelial. In subepithe- tinues in the stomach until the acidic chyme inactivates
lial innervation, the end-feet of axons do not make the enzyme. Secretory IgA inactivates antigens located
synaptic contact with the acinar cells; instead, they in the oral cavity.
release their acetylcholine in the vicinity of the secre- The connective tissue capsule of the parotid gland is
tory cell, at a distance of approximately 100 to 200 nm well developed and forms numerous septa, which sub-
from its basal plasmalemma. The cell thus activated divide the gland into lobes and lobules. The duct system
stimulates neighboring cells via gap junctions to follows the distribution detailed earlier. By the 40th year
release their serous secretory product into the lumen of of age, the gland becomes invaded by adipose tissue,
the acinus. which spreads from the connective tissue into the glan-
Parasympathetic innervation is the major initia- dular parenchyma.
tor of salivation and is responsible for the formation of
a serous saliva. Acetylcholine, released by the postgan- Sublingual Gland
glionic parasympathetic nerve fibers, binds muscarinic
cholinergic receptors, with consequent release of ino- The sublingual gland is very small, is composed mostly of
sitol trisphosphate. This effects the liberation of calcium mucous acini with serous demilunes, and produces a
ions, a second messenger, into the cytosol, which facil- mixed saliva.
itates the secretion of serous saliva from the acinar cells.
Initially, sympathetic innervation reduces blood The sublingual gland, the smallest of the three major
flow to the salivons, but that reduction is reversed in salivary glands, is almond-shaped, weighs only 2 to 3 g,
short order. Norepinephrine, released by the postgan- and produces only about 5% of the total salivary output.
glionic sympathetic fibers, binds to β-adrenergic recep- The gland is composed of mucous tubular secretory
tors, resulting in the formation of cyclic adenosine units, many of which are capped by a small cluster of
monophosphate (cAMP). This secondary messenger serous cells, known as serous demilunes (see Fig. 18-2).
activates a cascade of kinases that result in the secretion Although routine light microscopy demonstrates the
of the mucous and enzymatic components of saliva by presence of serous demilunes, if the tissue is quick-
the acinar cells. The mucus is responsible for the adhe- frozen, these are absent, indicating that they may be
sion of food particles in the bolus as well as for the cre- fixation artifacts and are merely small clusters of
ation of a slippery surface, facilitating swallowing. serous cells that deliver their secretion into a lumen
Salivary output is enhanced by the taste and smell of in common with the mucous tubular secretory units.
food as well as by the process of chewing. A copious flow These serous cells have been shown to secrete
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lysozyme. The sublingual gland produces a mixed, but tological sections of this gland display many cross-
mostly mucous, saliva. The intercellular canaliculi are sectional profiles of these ducts, a characteristic feature
well developed between the mucous cells of the secre- of the submandibular gland.
tory units. Electron micrographs of the cells of the The connective tissue capsule of the submandibular
serous demilunes display apical accumulations of secre- gland is extensive and forms abundant septa, which sub-
tory vesicles; however, unlike the cells of the parotid and divide the gland into lobes and lobules. Fatty infiltra-
submandibular glands, these vesicles do not have an tion of the connective tissue elements into the
electron-dense core (see Fig. 18-3). parenchyma is evident by midlife.
The sublingual gland has a scant connective tissue
capsule, and its duct system does not form a terminal
duct. Instead, several ducts open into the floor of the
mouth and into the duct of the submandibular gland. CLINICAL CORRELATIONS
Because of the organization of the ducts, some authors Benign pleomorphic adenoma, a nonmalig-
consider the sublingual gland to be composed of several nant salivary gland tumor, usually affects the
smaller glandular subunits. parotid and the submandibular glands. Surgical
removal of the parotid gland must be performed
Submandibular Gland with care because of the presence of the facial
nerve plexus within the substance of the gland.
The submandibular gland produces 60% of the total The parotid gland (and occasionally other
salivary output; although it manufactures a mixed saliva, major salivary glands) is also affected by viral
the major portion is serous. infections, causing mumps, a painful disease
that usually occurs in children and that may
The submandibular gland (Fig. 18-4), although only 12
result in sterility when it affects adults.
to 15 g in weight, produces approximately 60% of the
total salivary output. About 90% of the acini produce
serous saliva, whereas the remainder of the acini man-
ufacture a mucous saliva. Electron micrographs of the
apical aspects of the serous cells of this gland display PANCREAS
electron-dense secretory products, with a denser core,
within membrane-bound secretory granules. The
The pancreas is both an exocrine gland that produces
number of serous demilunes is limited. The striated
digestive juices and an endocrine gland that
ducts of the submandibular gland are much longer than
manufactures hormones.
those of the parotid or sublingual glands; therefore, his-
SD
Se
M
Figure 18–4 In this light mi-
crograph, the submandibular gland
is characterized by the numerous
cross-sectional profiles of striated
ducts (×132). Note that the ducts
appear pale pink in color, and many SA
display a very small but clear lumen.
The mucous secretory product has a
frothy appearance. Se, septum; SA,
serous acinus; SD, serous demilune;
M, mucous cells of an acinus.
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The pancreas, situated on the posterior body wall, deep whose lumen is occupied by three or four centroaci-
to the peritoneum, has four regions: uncinate process, nar cells, the beginning of the duct system of the pan-
head, body, and tail. It is about 25 cm long, 5 cm wide, creas (Fig. 18-5). The presence of centroacinar cells in
and 1 to 2 cm thick, and it weighs approximately 150 g. the center of the acinus is a distinguishing characteris-
Its flimsy connective tissue capsule forms septa, which tic of this gland.
subdivide the gland into lobules. The vascular and nerve
supply of the pancreas, as well as its system of ducts, Secretory and Duct Portions
travels in these connective tissue compartments. The
pancreas produces exocrine and endocrine secretions. The acinar cells of the pancreas have receptors for
The endocrine components of the pancreas, islets of cholecystokinin and acetylcholine, whereas the
Langerhans, are scattered among the exocrine secre- centroacinar cells and intercalated ducts have receptors
tory acini. for secretin and perhaps for acetylcholine.
Each acinar cell is shaped like a truncated pyramid,

Exocrine Pancreas
with its base positioned on the basal lamina separating
The exocrine pancreas is a compound tubuloacinar the acinar cells from the connective tissue compart-
gland that produces daily about 1200 mL of a bicar- ment. The round nucleus of the cell is basally located
bonate-rich fluid containing digestive proenzymes. and is surrounded by basophilic cytoplasm (Fig. 18-6).
Forty to 50 acinar cells form a round to oval acinus The apex of the cell, facing the lumen of the acinus, is
Rough ER
Golgi
Main pancreatic duct Zymogen granules
Common bile duct

Capillary
Intralobular PANCREATIC ACINAR CELL

duct
Intercalated duct
Islet of Langerhans
Centroacinar
cell
Pancreatic
acinar cell
PANCREATIC ACINUS
CENTROACINAR CELL
Intercellular
canaliculi
Figure 18–5 The pancreas with secretory acini, their cell types, and the endocrine islets of Langerhans.
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The duct system of the pancreas begins within the

center of the acinus with the terminus of the interca-
lated ducts, composed of pale, low cuboidal cen-
troacinar cells (see Figs. 18-5 and 18-6). Centroacinar
CC Se cells and intercalated ducts both have receptors on their
basal plasmalemma for the hormone secretin and
possibly for acetylcholine, released by postganglionic
SA parasympathetic fibers. Intercalated ducts join each
other to form larger intralobular ducts, several of
which converge to form interlobular ducts. These
ducts are surrounded by a considerable amount of con-
nective tissue and deliver their contents into the main
pancreatic duct, which joins the common bile duct
before opening in the duodenum at the papilla of
Vater.
Histophysiology of the
Exocrine Pancreas
The acinar cells manufacture and release digestive
enzymes, whereas the centroacinar cells and intercalated
duct cells release a bicarbonate-rich buffer solution.
The acinar cells of the exocrine pancreas manufacture,

store, and release a large number of enzymes: pancre-
atic amylase, pancreatic lipase, ribonuclease, deoxyri-
bonuclease (DNase), and the proenzymes trypsinogen,
chymotrypsinogen, procarboxypeptidase, and elastase.
The cells also manufacture trypsin inhibitor, a protein
Figure 18–6 Light micrograph of the monkey exocrine pancreas that protects the cell from accidental intracellular acti-
(×540). Observe that the acini in section appear to be round struc-
tures and that much of the acinar cells have many secretory granules,
vation of trypsin.
known as zymogen granules. CC, centroacinar cells; Se, septum; SA, Release of the pancreatic enzymes is effected by the
serous acinus. hormone cholecystokinin (pancreozymin) manufac-
tured by DNES cells of the small intestine (especially
of the duodenum) as well as by acetylcholine released
by the postganglionic parasympathetic fibers.
filled with proenzyme-containing secretory granules The centroacinar cells and intercalated ducts manu-
(zymogen granules), whose number diminishes after facture a serous, bicarbonate-rich alkaline fluid, which
a meal. The Golgi region, located between the nucleus neutralizes and buffers the acid chyme that enters the
and the zymogen granules, varies in size in inverse rela- duodenum from the pyloric stomach. This fluid is
tion to the zymogen granule concentration. enzyme-poor, and its release is effected by the hormone
The basal cell membranes of acinar cells have recep- secretin, produced by enteroendocrine cells of the
tors for the hormone cholecystokinin and for the small intestine in conjunction with acetylcholine,
neurotransmitter acetylcholine, released by postgan- released by the postganglionic parasympathetic fibers.
glionic parasympathetic nerve fibers. Electron micro- Thus the enzyme-rich and enzyme-poor secretions are
graphs of acinar cells display an abundance of basally regulated separately, and the two secretions may be
located RER, a rich supply of polysomes, and numer- released at different times or concomitantly.
ous mitochondria exhibiting matrix granules. The Golgi The assumed mechanism of bicarbonate ion secre-
apparatus is well developed but fluctuates in size, being tion is facilitated by the enzyme carbonic anhydrase,
smaller when the zymogen granules are numerous and which catalyzes the formation of carbonic acid (H2CO3)
larger after the granules release their contents. from water (H2O) and carbon dioxide (CO2). In the
The zymogen granules may release their contents aquatic medium of the cytosol, H2CO3 dissociates to
individually, or several secretory vesicles may fuse with form H+ and HCO3−; the HCO3− is actively transported
each other, forming a channel to the lumen of the acinus into the lumen of the duct, whereas the hydrogen (H+)
from the apical cytoplasm. ion is transported into the connective tissue elements.
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Occasionally, the pancreatic digestive enzymes
become active within the cytoplasm of the acinar
cells, resulting in acute pancreatitis, which is
often fatal. The histological changes involve an
inflammatory reaction, necrosis of the blood
vessels, proteolysis of the pancreatic paren-
I Se
chyma, and enzymatic destruction of adipose
cells not only within the pancreas but also in the
SA
surrounding region of the abdominal cavity.
Pancreatic cancer is the fifth leading cause
of mortality from all cancers, killing about 25,000
people in the United States per year. Fewer than
50% of patients survive more than 1 year, and
fewer than 5% survive 5 years. Men are more
susceptible to this disease than are women. Cig-
arette smokers have a 70% greater risk for devel-
opment of pancreatic cancers than nonsmokers.
Endocrine Pancreas Figure 18–7 Light micrograph of the human pancreas display-
ing secretory acini and an islet of Langerhans (I) (×132). The histo-
The endocrine pancreas is composed of spherical logic difference between the exocrine and endocrine pancreas is very
aggregates of cells, known as islets of Langerhans, that evident in this photomicrograph because the islet is much larger than
are scattered among the acini. individual acini and is much lighter in color. Se, septum; SA, serous
acinus.
Each islet of Langerhans is a richly vascularized
spherical conglomeration of approximately 3000 cells.
The approximately 1 million islets distributed through-
out the human pancreas constitute the endocrine pan- Histophysiology of the
creas. A somewhat greater number of islets are present
in the tail than in the remaining regions. Each islet is
Endocrine Pancreas
surrounded by reticular fibers, which also enter the sub- The cells of the islets of Langerhans produce insulin,
stance of the islet to encircle the network of capillaries glucagon, somatostatin, gastrin, and pancreatic
that pervade it (Fig. 18-7; also see Fig. 18-5). polypeptide.
Cells Composing the Islets The two hormones produced in the greatest amounts by
the endocrine pancreas—insulin and glucagon—act to
of Langerhans decrease and increase blood glucose levels, respectively.
Five types of cells compose the parenchyma of each Insulin production begins with synthesis of a single
islet of Langerhans: beta (β) cells, alpha (α) cells, delta polypeptide chain, preproinsulin, on the RER of b
(δ) cells (D and D1 cells), PP (pancreatic polypep- cells. Within the RER cisternae, this initial product is
tide–producing) cells, and G (gastrin-producing) cells. converted to proinsulin by enzymatic cleavage of a
These cells cannot be differentiated from one another polypeptide fragment. Within the trans Golgi network,
by routine histological examination, but immunocyto- proinsulin is packaged into clathrin-coated vesicles,
chemical procedures allow them to be recognized. which lose their clathrin coat as they travel toward the
Electron micrographs also display the features that dis- plasmalemma. A segment of the proinsulin molecule
tinguish the various cells, especially the size and elec- near its center is removed by self-excision, thus forming
tron density of their granules (Fig. 18-8). Otherwise, the insulin, which is composed of two short polypeptide
cells do not exhibit any unusual morphological features chains linked by disulfide bonds. Insulin is released into
but resemble cells that specialize in protein synthesis. the intercellular space in response to increased blood
The characteristic features, locations, and hormones glucose levels, as occurs after consumption of a
synthesized by these cells are presented in Table 18-1. carbohydrate-rich meal.
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TABLE 18–1 Cells and Hormones of the Islets of Langerhans
Hormone and
% of Fine Structure Molecular
Cell Total Location of Granules Weight (Da) Function
β Cell 70% Scattered 300 nm in diameter; Insulin, 6000 Decreases blood glucose levels
throughout dense core granule
islet (but surrounded by wide
concentrated electron-lucent halo
in center)
α Cell 20% Islet periphery 250 nm in diameter; Glucagon, 3500 Increases blood glucose levels
dense core granule
with narrow
electron-lucent halo
δ Cell 5% Scattered 350 nm in diameter; D cell: Somatostatin, Paracrine: inhibits hormone

(D and throughout electron-lucent 1640 release from endocrine
D1) islet homogeneous pancreas and enzymes from
granule exocrine pancreas
Endocrine: reduces contractions
of alimentary tract and
gallbladder smooth muscles
D1 cell: Vasoactive Induces glycogenolysis;
intestinal peptide regulates smooth muscle
(VIP), 3800 tonus and motility of gut;
controls ion and water
secretion by intestinal
epithelial cells
G cell 1% Scattered 300 nm in diameter Gastrin, 2000 Stimulates production of

throughout hydrochloric acid by parietal
islet cells of stomach
PP cell 1% Scattered 180 nm in diameter Pancreatic Inhibits exocrine secretions of

(F cell) throughout polypeptide, 4200 pancreas
islet
The released insulin binds to cell-surface insulin glycogen down to glucose, which is released into the
receptors on many cells, especially skeletal muscle, bloodstream, increasing blood glucose levels. Glucagon
liver, and adipose cells. The plasma membranes of these also activates the hepatic enzymes responsible for glu-
cells also have glucose transport proteins, glucose per- coneogenesis (the synthesis of glucose from noncar-
mease (glucose transport units), which are activated bohydrate sources) if the intracellular glycogen depot of
to take up glucose, thus decreasing blood glucose levels. the hepatocytes is depleted.
It is interesting that subplasmalemmal vesicles, rich in Somatostatin, manufactured by one of the two
glucose permease, are added to the cell membrane types of d cells (D cells) has both paracrine and
during insulin stimulation and returned to their intra- endocrine effects. The hormone’s paracrine effects are
cellular position when insulin levels are reduced. inhibition of the release of endocrine hormones by
Glucagon, a peptide hormone produced by a cells, nearby α cells and β cells. Its endocrine effects are on
is released in response to low blood glucose levels as smooth muscle cells of the alimentary tract and gall-
well as by the consumption of a meal low in carbohy- bladder, reducing the motility of these organs. Somato-
drate and high in protein. As in insulin production, a statin is released in response to the increased levels
prohormone is produced first, and it undergoes prote- of blood glucose, amino acids, or chylomicrons that
olytic cleavage to yield the active hormone. Glucagon occur after a meal. Vasoactive intestinal peptide
acts mainly on hepatocytes, causing these cells to acti- (VIP) is produced by the second type of δ cells known
vate glycogenolytic enzymes. These enzymes break as D1 cells. This hormone induces glycogenolysis and
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graph of α cells (A) and β cells (B)
in the rabbit islet of Langerhans
(×5040). Note that the granules of
α cells are much more numerous,
more tightly packed, smaller, and
denser than those of β cells. (From
Jorns A, Grube D: The endocrine
pancreas of glucagon-immunized
and somatostatin-immunized rabbits.
Cell Tissue Res 265:261-273, 1991.)
hyperglycemia and also regulates intestinal motility and

the tone of smooth muscle cells of the wall of the gut. LIVER
Additionally, VIP controls the secretion of ions and The liver, weighing approximately 1500 g, is the largest
water by intestinal epithelial cells . gland in the body. It is located in the upper right-hand
Gastrin, released by G cells, stimulates gastric quadrant of the abdominal cavity, just inferior to the
release of HCl, gastric motility and emptying, and the diaphragm. The liver is subdivided into four lobes—
rate of cell division in gastric regenerative cells. right, left, quadrate, and caudate—the first two of which
Pancreatic polypeptide, a hormone produced by constitute its bulk (Fig. 18-9A).
PP cells, inhibits the exocrine secretions of the pan- Similar to the pancreas, the liver has both endocrine
creas and also stimulates the release of enzymes by the and exocrine functions; unlike the pancreas, however,
gastric chief cells while depressing the release of HCl the same cell (the hepatocyte) in the liver is responsi-
by the parietal cells of the stomach. ble for the formation of bile—the liver’s exocrine secre-
Diabetes mellitus is a hyperglycemic metabolic younger than 20 years of age. It is characterized by
disorder that results from (1) lack of insulin produc- the three cardinal signs of polydipsia (constant
tion by β cells of the islets of Langerhans or (2) defec- thirst), polyphagia (undiminished hunger), and
tive insulin receptors on the target cells. There are polyuria (excessive urination).
two major forms of diabetes mellitus, type 1 and type Type 2 diabetes (non–insulin-dependent dia-
2 (Table 18-2). The incidence of type 2 is about five betes) is the most common type and usually affects
to six times that of type 1. If uncontrolled, both types persons older than 40 years of age.
of diabetes may have debilitating sequelae, including Verner-Morrison syndrome (pancreatic
circulatory disorders, renal failure, blindness, gan- cholera) is characterized by explosive, watery diar-
grene, stroke, and myocardial infarcts. The most sig- rhea that results in hypokalemia and hypochlorhy-
nificant laboratory result indicative of diabetes is dria. It is caused by the excessive manufacture and
elevated blood glucose levels after an overnight fast. release of vasoactive intestinal peptide due to
Type 1 diabetes (insulin-dependent diabetes; adenoma of the D1 cells that produce this hormone.
juvenile-onset diabetes) usually affects persons Frequently, tumors of D1 cells are malignant.
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TABLE 18–2 Comparison of Type 1 and Type 2 Diabetes Mellitus
Common Clinical Patient Hereditary Islets of

Type Synonyms Characteristics Weight Component Langerhans
Type 1 Juvenile- Abrupt onset of Normal (or About 50% Decrease in the size
(insulin- onset symptoms; age younger weight loss concordance in and number of
dependent) diabetes; than 20 years; decreased in spite of identical twins; β cells; islets are
juvenile blood insulin level; increase in environmental atrophied and
diabetes; ketoacidosis is common; food factors fibrotic
idiopathic antibodies present intake) important in the
diabetes against β cells; possible development of
autoimmune disease; the disease
reacts to insulin;
polyphagia, polydipsia,
polyuria
Type 2 (non- Adult-onset Onset after 40 years of 80% of About 90%-100% Some decrease in
insulin- diabetes; age; mild decrease in affected concordance in number of β cells;
dependent) ketosis- blood insulin levels; individuals identical twins amylin present in
resistant ketoacidosis is rare; no are obese the tissue
diabetes antibodies against β surrounding
cells; impaired insulin β cells
release; insulin-resistant;
decrease in number of
insulin receptors;
impaired postreceptor
signaling
tion—and its numerous endocrine products. In addi- via the portal vein (75%). Both vessels enter the liver at
tion, hepatocytes convert noxious substances into non- the porta hepatis. Blood leaves the liver at the posterior
toxic materials that are excreted in bile. aspect of the organ through the hepatic veins, which
deliver their contents into the inferior vena cava. Bile
General Hepatic Structure and also leaves the liver at the porta hepatis, by way of the
Vascular Supply right and left hepatic ducts, to be delivered to the gall-
bladder for concentration and storage.
The inferior, concave aspect of the liver houses the porta Because the liver occupies a central position in
hepatis, through which the portal vein and hepatic metabolism, all nutrients (except for chylomicrons and
artery bring blood into the liver and through which the lipids less than 12 carbons in length) absorbed in the
bile ducts drain bile from the liver. alimentary canal are transported directly to the liver via
the portal vein. In addition, iron-rich blood from the
With the exception of the bare area, the liver is com- spleen is routed, by way of the portal vein, directly to
pletely enveloped by peritoneum, which forms a simple the liver for processing. Much of the nutritive material
squamous epithelium covering over the dense, irregu- delivered to the liver is converted by the hepatocytes
lar connective tissue capsule (Glisson’s capsule) of into storage products, such as glycogen, to be released
the gland. Glisson’s capsule is loosely attached over the as glucose when required by the body.
entire circumference of the liver except at the porta Hepatocytes are arranged in hexagon-shaped lobules
hepatis, where it enters the liver, forming a conduit for (classical lobules) about 2 mm in length and 700 µm in
the blood and lymph vessels and bile ducts. The liver is diameter. These lobules are clearly demarcated by slender
unusual in that its connective tissue elements are sparse; connective tissue elements (known as portal tracts) in
thus, the bulk of the liver is composed of uniform animals such as the pig and the camel. However, because
parenchymal cells, the hepatocytes. of the scarcity of connective tissue and the closely packed
The superior aspect of the liver is convex, whereas its arrangement of the lobules in humans, the boundaries of
inferior region presents a hilum-like indentation, the the classical lobules can only be approximated.
porta hepatis. The liver has a dual blood supply, receiv- Where three classical lobules are in contact with
ing oxygenated blood from the left hepatic artery and each other, the connective tissue elements are in-
the right hepatic artery (25%) and nutrient-rich blood creased, and these regions are known as portal areas
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Sublobular vein
Left lobe
Falciform ligament
Hepatic artery
Vena cava
Portal vein
Portal area
Hepatic lobule
Right lobe Central vein
A Hepatic artery
Portal triad Bile duct
Portal vein
B
Central vein
Liver plate
Sinusoids
Bile canaliculus
Bile duct
Portal vein Portal triad
Hepatic artery
Figure 18–9 Liver. A, Gross anatomy of the liver. B, Liver lobules displaying the portal areas and the central vein. C, Portion of the liver
lobule displaying the portal area, liver plates, sinusoids, and bile canaliculi.
(triads). In addition to lymph vessels, portal areas The portal areas are isolated from the liver
house the following three structures, each of which parenchyma by the limiting plate, a sleeve of modified
follows the longitudinal axis of each lobule (Fig. 18-9B): hepatocytes. A narrow space, the space of Möll, sepa-
rates the limiting plate from the connective tissue of the
䡲 Slender branches of the hepatic artery portal area.
䡲 Tributaries of the relatively large portal vein Although one would expect to find six portal areas
䡲 Interlobular bile ducts (recognized by their simple around each classical lobule, usually only three equally
cuboidal epithelium). distributed portal areas are present in a random section
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(see Fig. 18-9B). Along the length of each slender nates in the sublobular vein. Numerous central veins
branch of the hepatic artery within the portal area, fine deliver their blood into a single sublobular vein;
branches, known as distributing arterioles, arise; like sublobolar veins join each other to form collecting
outstretched arms, they reach toward their counterparts veins, which in turn form the right and left hepatic
in the neighboring portal areas. Smaller vessels, known veins.
as inlet arterioles, branch from the distributing arte-
rioles (or from the parent vessel). In addition, the inter- The Three Concepts of
lobular bile ducts are vascularized by a peribiliary Liver Lobules
capillary plexus. Venules are of two sizes: the larger
distributing veins and the smaller inlet venules. The three types of liver lobules are the classical lobules,
The longitudinal axis of each classical lobule is portal lobules, and the hepatic acinus (acinus of
occupied by the central vein, the initial branch of Rappaport).
the hepatic vein. Hepatocytes radiate, like spokes of a
wheel, from the central vein, forming anastomosing, There are three basic conceptualizations of the liver
fenestrated plates of liver cells, separated from each lobule (Fig. 18-11). The classical liver lobule was the
other by large vascular spaces known as hepatic sinu- first to be defined histologically because the connective
soids (Fig. 18-10; also see Fig. 18-9C). Inlet arteri- tissue arrangement in the pig liver afforded an obvious
oles, inlet venules, and branches from the peribiliary rationale. In this concept, blood flows from the
capillary plexus pierce the limiting plate (of modified periphery to the center of the lobule into the central
hepatocytes) to join the hepatic sinusoids (see Fig. 18- vein. Bile, manufactured by liver cells, enters into small
10). As blood enters the sinusoids, its flow slows intercellular spaces, bile canaliculi, located between
considerably and it slowly percolates into the central hepatocytes, and flows to the periphery of the lobule to
vein. the interlobular bile ducts of the portal areas.
Because there is only one central vein in each lobule, The concept of an exocrine secretion flowing to the
it receives blood from every sinusoid of that lobule and periphery of a lobule was not consistent with the situa-
its diameter increases as it progresses through the tion in the acini of most glands, where the secretion
lobule. As the central vein leaves the lobule, it termi- enters a central lumen of the acinus. Therefore, histol-
ogists suggested that all hepatocytes that deliver their
bile to a particular interlobular bile duct constitute a
lobule, called the portal lobule. In histological sec-
tions, the portal lobule is defined as the triangular
KC region whose center is the portal area and whose
periphery is bounded by imaginary straight lines
PA
Si Hepatic
Portal area (PA) acinus
CV
Hepatic artery
Bile duct PA
Portal vein
Classical
lobule
CV CV
Portal lobule
CV
Central
vein (CV)
PA PA PA
LP CV CV
Figure 18–10 Light micrograph of a dog liver displaying the Liver lobule
central vein (CV), liver plates (LP), and sinusoids (Si) (×270). This
animal was injected with India ink that was phagocytosed by Kupffer Figure 18–11 The three types of lobules in the liver: classical
cells (KC), which consequently appear as black spots. lobule, portal lobule, and hepatic acinus.
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connecting the three surrounding central veins that

form the three apices of the triangle.
A third conceptualization of hepatic lobules is based K
on blood flow from the distributing arteriole and, con-
sequently, on the order in which hepatocytes degener-
ate subsequent to toxic or hypoxic insults. This ovoid to
diamond-shaped lobule is known as the hepatic acinus N
(acinus of Rappaport). It is viewed as three poorly
defined, concentric regions of hepatic parenchyma sur-
rounding a distributing artery in the center. The outer- Si
most layer, zone 3, extends as far as the central vein and
is the most oxygen-poor of the three zones. The remain-
ing region is divided into two equal zones (1 and 2);
zone 1 is the richest in oxygen.
Hepatic Sinusoids and

Hepatocyte Plates
Plates of liver cells delineate vascular spaces between
them that are lined by sinusoidal lining cells. The
vascular spaces are known as hepatic sinusoids.
Anastomosing plates of hepatocytes, no more than

two cells thick prior to the age of 7 years and one cell Figure 18–12 Light micrograph of a canine liver demonstrating
thick after that age, radiate from the central vein toward plates of hepatocytes, sinusoids (Si), and India ink–containing Kupffer
the periphery of the classical lobule (see Fig. 18-9C). cells (K) (×540). N, nucleus.
The spaces between the plates of hepatocytes are occu-
pied by hepatic sinusoids, and the blood flowing in these
wide vessels is prevented from coming in contact with The sinusoidal lining cells are separated from the hepa-
the hepatocytes by the presence of an endothelial lining tocytes by a narrow space of Disse (perisinusoidal
composed of sinusoidal lining cells. Often, the cells space), and plasma escaping from the sinusoids has free
of this endothelial lining do not make contact with each access to this space (Fig. 18-14; also see Fig. 18-13).
other, leaving gaps of up to 0.5 µm between them. The Microvilli of the hepatocytes occupy much of the space
sinusoidal lining cells also have fenestrae that are of Disse; the extensive surface area of the microvilli
present in clusters, known as sieve plates. Thus, par- facilitates exchange of materials between the blood-
ticulate matter less than 0.5 µm in diameter may leave stream and the hepatocytes. Hepatocytes do not come
the lumen of the sinusoid with relative ease. into contact with the bloodstream; instead, the space of
Resident macrophages, known as Kupffer cells, are Disse acts as an intermediate compartment between
associated with the sinusoidal lining cells in the sinu- them.
soids (Figs. 18-12 and 18-13). Frequently, phagosomes Although the perisinusoidal space contains type III
of Kupffer cells contain endocytosed particulate matter collagen fibers (reticular fibers) that support the sinu-
and cellular debris, especially defunct erythrocytes that soids, as well as a limited amount of type I and type IV
are being destroyed by these cells. Electron micro- collagen fibers, a basal lamina is absent. Occasionally,
graphs of Kupffer cells display numerous filopodia-like nonmyelinated nerve fibers and stellate-shaped hepatic
projections, mitochondria, some RER, a small Golgi stellate cells (also known as Ito cells and fat storing
apparatus, and an abundance of lysosomes and late cells) have been noted in this space (see Fig. 18-13). It
endosomes. Because these cells do not make intercel- is believed that hepatic stellate cells store vitamin A,
lular junctions with the neighboring cells, it has been manufacture and release type III collagen into the
suggested that they may be migratory scavengers. space of Disse, secrete growth factors required by the
liver for generating new hepatocytes, and form fibrous
connective tissue to replace hepatocytes damaged by
Perisinusoidal Space of Disse toxins. In addition, pit cells, which display short
pseudopodia and cytoplasmic granules, have been
The narrow space between a plate of hepatocytes and
noted in the perisinusoidal space of mice and rats.
sinusoidal lining cells is known as the perisinusoidal
These cells, believed to be natural killer cells, are also
space of Disse.
assumed to be in the human liver.
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the shrew liver. A, Observe the sinusoid,
with its sinusoidal lining cell (E), Kupffer
cell (K), and a small region of a lipid droplet
(Li)–containing Ito cell (×8885). B, A higher
magnification of the hepatocyte displays its
numerous microvilli (arrowheads) protrud-
ing into the space of Disse and the process
of pinocytosis (arrow) (×29,670). (From
Matsumoto E, Hirosawa K: Some observa-
tions on the structure of Suncus liver with
special reference to the vitamin A–storing
cell. Am J Anat 167:193-204, 1983.)
Hepatic Ducts low cuboidal cells, but interspersed among them are
some ovoid cells that are capable of proliferation. The
The system of hepatic ducts is composed of cholangioles, progeny of these oval cells may give rise to cuboidal cells
canals of Hering, and bile ducts leading to larger and of the bile duct system as well as to hepatocytes.
larger bile ducts that finally culminate in the right and The cuboidal epithelial cells of the cholangioles,
left hepatic ducts. canals of Hering, and interlobular bile ducts secrete a
bicarbonate-rich fluid similar to that produced by the
Bile canuliculi anastomose with one another, forming duct system of the pancreas. The formation and release
labyrinthine tunnels among the hepatocytes. As these bile of this alkaline buffer are controlled by the hormone
canaliculi reach the periphery of the classic lobules, they secretin, produced by diffuse neuroendocrine system
merge with cholangioles, short tubules composed of a (DNES) cells of the duodenum. This fluid acts, with
combination of hepatocytes and low cuboidal cells, and fluid from the pancreas, to neutralize the acidic chyme
occasional oval cells. Bile from cholangioles enters the that enters the duodenum.
canals of Hering, slender branches of the interlobular
bile ducts, that radiate parallel to the inlet arterioles and Hepatocytes
inlet venules. Interlobular bile ducts merge to form
increasingly larger conduits, which eventually unite to Hepatocytes are 5- to 12-sided polygonal cells, approx-
form the right hepatic duct and the left hepatic duct. imately 20 to 30 µm in diameter, that are closely packed
The extrahepatic system of bile ducts is described later. together to form anastomosing plates of liver cells, one
Most of the cells of the canals of Hering are composed of cell in thickness. These cells exhibit variations in their
Ch018-X2945.qxd 12/8/06 3:41 PM Page 428
Sinusoidal
lining cell
Erythrocyte in
hepatic
Mitochondrion sinusoid
Smooth ER
Golgi complex
Rough ER
Space of Disse Bile canaliculus
Figure 18–14 A hepatocyte and

its sinusoidal and lateral domains. ER,
endoplasmic reticulum. (From Lentz
TL: Cell Fine Structure: An Atlas of
Drawings of Whole-Cell Structure.
structural, histochemical, and biochemical properties, through which bile can be secreted (see Fig. 18-14). The
depending on their location within liver lobules. actin cores of these microvilli mingle with the thickened
network of actin and intermediate filaments that rein-
Domains of Hepatocyte Plasmalemma force the region of the hepatocyte plasmalemma, which
participates in the formation of bile canaliculi.
The plasma membranes of hepatocytes are said to have The cell membranes that form the walls of bile
two domains: lateral and sinusoidal. canaliculi display high levels of Na+, K+-ATPase activ-
ity and the enzyme adenylate cyclase. The lateral
Hepatocytes are arranged in such a manner that each domains also have isolated gap junctions, whereby
cell not only comes in contact with other hepatocytes hepatocytes are able to communicate with each other.
but also borders a space of Disse. Thus, the plas-
malemma of hepatocytes is said to have lateral domains
and sinusoidal domains. SINUSOIDAL DOMAINS
LATERAL DOMAINS The sinusoidal domains form microvilli that protrude

into the perisinusoidal space of Disse.
The lateral domains are responsible for the formation of
bile canaliculi. The sinusoidal domains of hepatocyte plasma mem-
branes also have microvilli that project into the space of
The lateral domains of the hepatocyte cell membrane Disse (see Figs. 18-13 and 18-14). It has been calculated
form elaborate, labyrinthine intercellular spaces, 1 to that these microvilli increase the surface area of the sinu-
2 µm in diameter, known as bile canaliculi, channels that soidal domain by a factor of 6, facilitating the exchange of
conduct bile between hepatocytes to the periphery of the material between the hepatocyte and the plasma in the
classical lobules (see Fig. 18-9C). Leakage of bile from bile perisinusoidal space. This cell membrane is rich in
canaliculi is prevented by the formation of tight junctions mannose-6-phosphate receptors, Na+,K+-ATPase, and
(fasciae occludentes) between adjoining liver cells, isolat- adenylate cyclase because it is here that the endocrine
ing these conduits from the remaining extracellular space. secretions of the hepatocyte are released and enter the
Short, blunt microvilli project from the hepatocyte sinusoidal blood and that material carried by the blood-
into the bile canaliculi, thus increasing the surface areas stream is transported into the hepatocyte cytoplasm.
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Hepatocyte Organelles and Inclusions toxins in the blood induces an increase in the SER
content of liver cells because detoxification occurs
Hepatocytes are large, organelle-rich cells that within the cisternae of this organelle.
manufacture the exocrine secretion bile as well as a
large number of endocrine secretions; in addition, these
cells can perform a large array of metabolic functions.
Although hepatocytes constitute only 60% of the total
cell number, they compose about 75% of the weight of Persons who have consumed hepatotoxic sub-
the liver. These cells manufacture primary bile, which stances, such as alcohol, display an increased
is modified by the epithelial cells lining the bile ducts number of lipid deposits in their zone 3 hepato-
and gallbladder and becomes bile. Approximately 75% cytes. In addition, persons who are taking barbi-
of the hepatocytes have a single nucleus, and the turates display an increase in the SER content of
remainder have two nuclei. The nuclei vary in size, the zone 3 liver cells. Since this zone has the lowest
smallest ones (50% of the nuclei) being diploid and oxygen levels of the three zomes, this is the
the larger ones being polyploid, with the largest nuclei region of the liver acinus that is most susceptible
reaching 64 N. to necrosis in case of severe liver injury.
Hepatocytes actively synthesize proteins for their Alcoholics and people who suffer from
own use as well as for export. Thus, they have an abun- obstruction of the biliary tract or chronic poi-
dance of free ribosomes, RER, and Golgi apparatus soning are at risk for development of cirrhosis,
(Figs. 18-15 and 18-16). Each cell houses several sets of a disease characterized by fibrosis, degeneration
Golgi apparatuses, located preferentially in the vicinity of hepatocytes, and disintegration of the normal
of bile canaliculi. organization of the liver.
Because of the high energy requirements of hepato- Wilson’s disease is a hereditary condition in
cytes, each cell contains as many as 2000 mitochondria. which the liver does not eliminate copper by
Cells near the central vein (zone 3 of the liver acinus) transferring it into bile. Instead copper accumu-
have nearly twice as many, but considerably smaller, lates in the eyes, where it appears as green to gold
mitochondria as hepatocytes in the periportal area (zone rings in the cornea; in the brain, where it inter-
1 of the liver acinus). Liver cells also have a rich com- feres with normal brain function, causing tremors,
plement of endosomes, lysosomes, and peroxisomes. aphasia, and, occasionally, psychosis; and in the
The complement of smooth endoplasmic reticulum liver, where it causes cirrhosis. If left untreated
(SER) of hepatocytes varies not only by region but also the disease is fatal, but the use of a chelating
by function. Cells in zone 3 of the liver acinus have a agent, usually penicillamine, binds with copper
much richer endowment of SER than those in the peri- and facilitates its elimination from the body.
portal area. Moreover, the presence of certain drugs and
Pe
HC
HC
Figure 18–15 Low-magnifica-

tion electron micrograph of a mouse
liver (×2535). Most of the liver’s
surface is covered by peritoneum
(Pe), which overlies the collagenous
capsule (Co) of the liver. Observe
the sinusoids (Si), Kupffer cells
(Ku), and glycogen deposits (Gl) in
the hepatocyte (HC) cytoplasm. Bile
canaliculi are denoted by asterisks HC
(*). Mi, mitochondria; Pt, peritoneal
cavity. (From Rhodin JAG: An Atlas
of Ultrastructure. Philadelphia, WB
Saunders, 1963.)
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tecting the body from their deleterious effects) and

transfer secretory IgA from the space of Disse into bile.
In addition, Kupffer cells phagocytose blood-borne
foreign particulate matter and defunct erythrocytes.
Bile Manufacture
Bile, a fluid manufactured by the liver, is composed of
water, bile salts, phospholipids, cholesterol, bile
pigments, and IgA.
The liver produces approximately 600 to 1200 mL of

bile/day. This fluid, which is mostly water, contains bile
salts (bile acids), bilirubin glucuronide (bile pigment),
phospholipids, lecithin, cholesterol, plasma electrolytes
(especially sodium and bicarbonate), and IgA. It
absorbs fat, eliminates approximately 80% of the cho-
lesterol synthesized by the liver, and excretes blood-
borne waste products such as bilirubin.
Bile salts constitute almost half of the organic com-
Figure 18–16 Electron micrograph of a rat hepatocyte (×2500). ponents of bile. Most of the bile salts are resorbed from
(From Tandler B, Krahenbuhl S, Brass EP: Unusual mitochondria in the lumen of the small intestine, enter the liver via the
the hepatocytes of rats treated with a vitamin B12 analogue. Anat Rec portal vein, are endocytosed by hepatocytes, and are
231:1-6, 1991.)
transported into the bile canaliculi for subsequent re-
release back into the duodenum (enterohepatic recir-
culation of bile salts). The remaining 10% of bile salts
Hepatocytes contain varying amounts of inclusions in are manufactured de novo in the SER of hepatocytes
the form of lipid droplets and glycogen (Fig. 18-17). by the conjugation of cholic acid, a metabolic by-
The lipid droplets are mostly very-low-density- product of cholesterol, to either taurine (tauricholic
lipoproteins (VLDLs) and are especially prominent acid) or glycine (glycocholic acid).
after the consumption of a fatty meal.
Glycogen deposits are present as accumulations of
electron-dense granules 20 to 30 nm in size, known as
b particles, in the vicinity of the SER. The distribution CLINICAL CORRELATIONS
of glycogen varies with hepatocyte location. Liver cells Because bile salts are amphipathic molecules,
in the vicinity of the portal area (zone 1 of liver acinus) their hydrophilic regions are dissolved in aque-
display large clumps of β particles surrounded by SER, ous media and their hydrophobic (lipophilic)
whereas pericentral hepatocytes (zone 3 of liver acinus) regions surround lipid droplets. In the lumen of
exhibit diffuse glycogen deposits (see Fig. 18-17). The the duodenum, therefore, bile salts emulsify fats
number of these particles varies with the dietary state and facilitate their digestion. Absence of bile
of the individual. They are abundant subsequent to salts prevents fat digestion and absorption,
eating and fewer after fasting. resulting in fatty stool.
Histophysiology of the Liver

The liver has both exocrine and endocrine roles as well Bilirubin, a water-insoluble, yellowish green
as the protective function of detoxification of toxins and pigment, is the toxic degradation product of hemoglo-
elimination of defunct erythrocytes. bin. As defunct erythrocytes are destroyed by
macrophages in the spleen and by Kupffer cells in the
The liver may have as many as 100 different functions, liver, bilirubin is released into the bloodstream and is
most of which are performed by the hepatocytes. Each bound to plasma albumin. In this form, known as
of these liver cells produces not only the exocrine secre- free bilirubin, it is endocytosed by hepatocytes. The
tion bile but also various endocrine secretions. Hepato- enzyme glucuronyltransferase, located in the SER of
cytes metabolize the end products of absorption from the hepatocyte, catalyzes the conjugation of bilirubin
the alimentary canal, store them as inclusion products, with glucuronide to form the water-soluble bilirubin
and release them in response to hormonal and nervous glucuronide (conjugated bilirubin). Some of the
signals. Liver cells also detoxify drugs and toxins (pro- bilirubin glucuronide is released into the bloodstream,
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Figure 18–17 Electron micrograph of glycogen

and lipid deposits in the pericentral hepatocyte of a
rat. Bar = 1 µm. Inset: Glycogen particles at a higher
magnification. Bar = 1 µm. (From Cardell RR,
Cardell EL: Heterogeneity of glycogen distribution in
hepatocytes. J Electron Microsc Techn 14:126-139,
1987.)
but most of it is excreted into the bile canaliculi for compounds—acidoacetic acid, β-hydroxybutyric acid,
delivery into the alimentary canal for subsequent elim- and acetone—are known as ketone bodies. Phospho-
ination with the feces (Fig. 18-18). lipids, cholesterol, and ketone bodies are stored in
hepatocytes until their release into the space of Disse.
Lipid Metabolism In addition, the liver manufactures VLDLs, which are
also released into the space of Disse as droplets 30 to
Hepatocytes remove chylomicrons from the space of 100 nm in diameter.
Disse and degrade them into fatty acids and glycerol.
Chylomicrons released by surface-absorbing cells of the Carbohydrate and

small intestine enter the lymphatic system and reach the Protein Metabolism
liver through branches of the hepatic artery. Within
hepatocytes they are degraded into fatty acids and glyc- Additional responsibilities of the liver include the
erol. The fatty acids are subsequently desaturated and maintenance of normal blood glucose levels,
are used to synthesize phospholipids and cholesterol or deamination of amino acids, and the synthesis of many
are degraded into acetyl coenzyme A. Two molecules of blood proteins.
acetyl coenzyme A are combined to form acetoacetic
acid. Much of the acetoacetic acid is converted into β- The liver maintains normal levels of glucose in the
hydroxybutyric acid and some into acetone. These three blood by transporting glucose from the blood into the
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A—Protein synthesis and carbohydrate

storage in the liver
Endothelium
Sinusoid The yellowish discoloration of the skin that is the
Glucose hallmark of jaundice results from excessively
Glucose Amino high levels of free or conjugated bilirubin (which
acids is yellowish green) in the bloodstream. The two
primary types of jaundice have different causes.
Space
A decrease in bilirubin conjugation, because of
of Disse Synthesis
either hepatocyte malfunction (as in hepatitis)
Exocytosis
or, more commonly, obstruction of the bile
SER Golgi ducts, causes obstructive jaundice. Increased
Glycogenolysis secretory
vesicle hemolysis of erythrocytes, producing so much
free bilirubin that hepatocytes, even though
Glycogen unimpaired, cannot eliminate bilirubin rapidly
Protein enough, causes hemolytic jaundice.
synthesis Ketosis occurs when the concentration of
ketone bodies in the blood becomes too high (as
Golgi in persons suffering from diabetes or starvation).
It is recognizable by the typical acetone breath
RER of affected persons. If untreated, ketosis results
in decreased blood pH (acidosis), possibly
leading to death.
B—Secretion of bile acids and bilirubin
Excessive blood ammonia levels, indicative of
impaired liver function or drastic reduction in
Bilirubin from the break- blood flow to the liver, may lead to hepatic
Bile acids reabsorbed
down of hemoglobin coma, a condition that is incompatible with life.
enters the cell
in the intestines
Glucuronyltransferase from noncarbohydrate sources (such as amino acids), a

(conjugates water- process known as gluconeogenesis.
insoluble bilirubin
forming water-soluble
One of the most essential roles of the liver is the
bilirubin glucuronide) elimination of blood-borne ammonia by converting it
SER
into urea. There are two major sources of ammonia in
Cholic acid is
conjugated with taurine
the body, the deamination of amino acids by hepato-
and glycine in SER cytes and the synthesis of ammonia by bacterial action
Bile
canaliculus in the alimentary canal.
Approximately 90% of the blood proteins are manu-
Water-soluble
bilirubin factured by the liver (see Fig. 18-18). These proteins
glucuronide and related products include:
䡲 Factors necessary for coagulation (such as fibrinogen,
factor III, accelerator globulin, and prothrombin)
Figure 18–18 Hepatocyte function. SER, smooth endoplasmic 䡲 Proteins required for the complement reactions
epithelium. A, Protein synthesis and carbohydrate storage. B, Secre-
tion of bile acids and bilirubin. 䡲 Proteins that function in transport of metabolites
䡲 Albumins
䡲 All of the globulins except gamma (γ) globulins
䡲 All of the nonessential amino acids that the body
hepatocytes and storing it in the form of glycogen. If
requires
blood glucose levels drop below normal, hepatocytes
hydrolyze glycogen (glycogenolysis) into glucose and
transport it out of the cells into the space of Disse (see
Vitamin Storage
Fig. 18-18). Hepatocytes can also synthesize glucose Vitamin A is stored in the greatest amount in the liver,
from other sugars (such as fructose and galactose) or but vitamins D and B12 are also present in substantial
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quantities. The liver contains enough vitamin stores to the hepatic sinusoids and adhere to the luminal surface
prevent deficiency of vitamin A for about 10 months, of endothelial cells. Kupffer cells have Fc receptors as
vitamin D for about 4 months, and vitamin B12 for more well as receptors for complement and thus can phago-
than 12 months. cytose foreign particulate matter. The importance of
these cells is appreciable because blood from the portal
Degradation of Hormones and vein contains a considerable number of microorganisms
Detoxification of Drugs and Toxins that enter the bloodstream from the lumen of the ali-
mentary canal. These bacteria become opsonized in the
The liver endocytoses and degrades hormones of the lumen or mucosa of the gut or in the bloodstream.
endocrine glands. The endocytosed hormones are trans- Kupffer cells recognize and endocytose at least 99% of
ported into the bile canaliculi in their native form to be these microorganisms. Kupffer cells also remove cellu-
digested in the lumen of the alimentary canal or are lar debris and defunct erythrocytes from the blood.
delivered into late endosomes for degradation by lyso-
somal enzymes.
Drugs, such as barbiturates and antibiotics, and Liver Regeneration
toxins are inactivated by microsomal mixed-function
The liver has a great ability to regenerate after a
oxidases in hepatocytes. These drugs and toxins are
hepatotoxic insult or even after a portion of the liver is
usually inactivated in the cisterna of the SER by meth-
ylation, conjugation, or oxidation. Occasionally, detoxi- excised.
fication occurs in peroxisomes rather than in the SER.
Hepatocytes have a life span of approximately 150 days;
thus, mitotic figures are present only infrequently. If
hepatotoxic drugs are administered or a portion of the
CLINICAL CORRELATIONS liver is excised, however, hepatocytes proliferate, and
the liver regenerates its normal architecture and previ-
Continued long-term use of certain drugs, such ous size.
as barbiturates, decreases their effectiveness, The regenerative ability of the liver of rodents is so
requiring the prescription of increased doses. enormous that if 75% of the gland is excised, it regener-
This drug tolerance is due to hypertrophy of the ates to its normal size within 4 weeks. The human liver’s
SER complement of hepatocytes and a concomi- regenerative capacity is much less than that of mice and
tant increase in their mixed-function oxidases. rats. The mechanism of regeneration is controlled by
The increase in the organelle size and the enzyme transforming growth factor-α, transforming growth
concentration is induced by the barbiturate, factor-β, epidermal growth factor, interleukin-6, and
which is detoxified via oxidative demethylation. In hepatocyte growth factor. Many of these factors are
addition, these hepatocytes concurrently become released by the hepatic stellate cells (Ito cells) located in
more efficient in detoxifying other drugs and toxins. the space of Disse, although hepatocyte growth factor is
also present, bound to heparin, in the scant extracellular
matrix of the liver. In most cases, the regeneration is due
to the replicative capability of the remaining hepato-
Immune Function cytes; however, if the hepatotoxic insult is too great,
regeneration of the liver is due to the mitotic activity of
Hepatocytes complex IgA with secretory component and the oval cells of cholangioles and canals of Hering.
release the secretory IgA into the bile canaliculi.
Most of the IgA antibodies formed by plasma cells in GALLBLADDER

the mucosa of the alimentary canal enter the circulatory
system and are transported to the liver. Hepatocytes The gallbladder is a small, pear-shaped organ situated
complex the IgA with secretory component and release on the inferior aspect of the liver. It is about 10 cm in
the complex into bile, which then enters the lumen length and 4 cm in cross-section and can store about
of the duodenum. Thus, much of the luminal IgA enters 70 mL of bile. This organ resembles a sack with a single
the intestine through the common bile duct, accompa- opening. The bulk of the organ forms the body, and the
nying bile. The remainder of the luminal IgA is trans- opening, which is continuous with the cystic duct, is
ported from the intestinal mucosa into the lumen by called the neck. The neck has an outpocketing known
surface absorptive cells. as Hartmann’s pouch, a region where gallstones fre-
Kupffer cells, which are derived from monocyte quently lodge. The gallbladder stores and concentrates
precursors, are long-lived cells that are located within bile and releases it into the duodenum as required.
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Structure of the Gallbladder The lamina propria is composed of a vascularized

loose connective tissue that is well endowed with elastic
The wall of the gallbladder comprises four layers: and collagen fibers. In the neck of the gallbladder, the
epithelium, lamina propria, smooth muscle, and lamina propria houses simple tubuloalveolar glands,
serosa/adventitia. which produce a small amount of mucus to lubricate the
lumen of this constricted region. The thin, smooth
The mucosa of the empty gallbladder is highly folded muscle layer of the gallbladder is composed mostly of
into tall, parallel ridges (Fig. 18-19). As the gallbladder obliquely oriented fibers, whereas others are oriented
becomes distended with bile, the plication is reduced to longitudinally. Although the connective tissue adventi-
a few short folds, and the mucosa becomes relatively tia is attached to Glisson’s capsule of the liver, it may be
smooth. separated from it with relative ease. The nonattached
The lumen of the gallbladder is lined by a simple surface of the gallbladder is invested by peritoneum,
columnar epithelium, composed of two types of cells: providing it with a smooth, simple squamous epithelial
the more common clear cells and the infrequent serosa.
brush cells (Fig. 18-20). The oval nuclei of these cells
are basally positioned and the supranuclear cytoplasm Extrahepatic Ducts
displays occasional secretory granules containing
mucinogen. In electron micrographs, their luminal The right and left hepatic ducts unite to form the
surface displays short microvilli coated by a thin layer common hepatic duct, which is joined by the cystic
of glycocalyx. The basal region of the cytoplasm is par- duct, arising from the gallbladder. The merger of these
ticularly rich in mitochondria, providing abundant two ducts forms the common bile duct, 7 to 8 cm long,
energy for the Na+,K+-ATPase pump present in the which fuses with the pancreatic duct to form the
basolateral cell membrane. ampulla of Vater. The ampulla opens at the duodenal
papilla into the lumen of the duodenum.
The opening of the common bile duct and the
pancreatic duct is controlled by a complex of four
muscles—the sphincter choledochus, sphincter pancre-
aticus, sphincter ampullae, and fasciculus longitudi-
nalis—collectively called the sphincter of Oddi. The
locations and functions of these components are sum-
marized in Table 18-3.
TABLE 18–3 The Sphincter of Oddi and Its

Ep Component Parts
Component Location and Function
Sphincter Surrounds and controls terminal

choledochus region of common bile duct to
stop bile flow into duodenum
Sphincter Surrounds and controls terminal
pancreaticus portion of pancreatic duct to stop
pancreatic juices from entering
duodenum and prevents entry
of bile into pancreatic duct
Sphincter Surrounds and controls ampulla of
ampullae Vater and prevents entry of bile
and pancreatic juices into
duodenum
Fasciculus Located in triangular interval
longitudinalis delineated by ampulla of Vater,
Figure 18–19 Light micrograph of an empty gallbladder (×132). pancreatic duct, and common
Observe that the mucosa of the gallbladder is highly folded, indicat- bile duct; facilitates entry of bile
ing that it is empty. Note that the lumen of the gallbladder is lined by into lumen of duodenum
a simple columnar epithelium (Ep).
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the human gallbladder diverticulum dis-
playing brush cells (A) and clear cells (C)
of the epithelium. d, interdigitations;
g, granules; L, lumen; M, clear cells with
mucoid granules; V, erythrocytes. Arrows indi-
cate Golgi apparatus. Bar = 2 µm. Upper inset:
Clear cell microvilli. Bar = 0.5 µm. Lower
inset: Brush cell microvilli. Bar = 1.0 µm.
(From Gilloteaux J, Pomerants B, Kelly T:
Human gallbladder mucosa ultrastructure:
Evidence of intraepithelial nerve structures.
Am J Anat 184:321-333, 1989.)
Histophysiology of the Gallbladder Na+ is actively transported from the basolateral

region of the simple columnar epithelium of the gall-
The gallbladder stores, concentrates, and releases bile. bladder into the extracellular space and is passively
Bile release is triggered by cholecystokinin and vagal followed by chloride (Cl−) and water. To compensate
stimulation. for the loss of intracellular ions, apical ion channels
permit Na+ and Cl− to enter the simple columnar cells,
The primary functions of the gallbladder are to store, reducing the salt (NaCl) concentration of bile. The
concentrate, and release bile. Bile is constantly man- requirement for osmotic equilibrium drives water from
ufactured by the liver and must make its way to the gall- the bile into the simple columnar cell, thus concentrat-
bladder. This activity requires that choledochus, ing bile.
pancreaticus, and ampullae sphincter muscles be main- The signaling molecule cholecystokinin is released
tained in a closed position so that the bile backs up the by I cells (DNES cells) of the duodenum in response
common bile duct and the cystic duct to enter the to a fatty meal. This molecule comes in contact with
gallbladder. cholecystokinin receptors on the smooth muscle cells
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of the gallbladder and causes them to contract inter- der inject the bile into the lumen of the duodenum.
mittently. Concurrently, contact of cholecystokinin In addition, acetylcholine, released by the vagal
receptors with the smooth muscle cells of the sphincter parasympathetic fibers, stimulates contraction of the
of Oddi causes the sphincter muscles to relax. As a gallbladder.
result, the rhythmic contractile forces of the gallblad-
Gallstones (cholelithiasis) are more common in 80% of gallstones are composed of cholesterol (cho-
women than in men and occur most frequently in lesterol stones); most of the remainder are formed
the fourth decade in life. Approximately 20% of all from the calcium salt of bile, calcium bilirubinate
women and 8% of all men have gallstones. Usually, (pigment stones), or a combination of cholesterol
people are unaware of their presence because gall- and calcified bilirubinate. Cholesterol stones are
stones are either small enough to be eliminated with large (1 to 3 cm) and pale yellow, have numerous
normal bile flow or too large to leave the gallblad- facets, and are few in number. Pigment stones are
der. When they enter and become entrapped in the smaller (1 cm), black, and ovoid, and they occur in
cystic or common hepatic ducts, gallstones obstruct large numbers. Usually, both types of stones are
bile flow and cause excruciating pain. Approximately radiolucent.
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19 䡲䡲䡲
Urinary System
The urinary system removes toxic by-products of nous connective tissue with occasional elastic fibers and
metabolism from the bloodstream and removes urine smooth muscle cells.
from the body. These actions are performed by the two
kidneys, which not only remove the toxins from the Overview of Kidney Structure
bloodstream but also conserve salts, glucose, proteins,
and water as well as additional materials essential for The kidney is subdivided into an outer cortex and an
proper health. Because of these eliminating and con- inner medulla.
serving functions, the kidneys also help to regulate
blood pressure, hemodynamics, and the acid-base A hemisected view of the kidney shows that it is sepa-
balance of the body. Urine is delivered from the kidneys rated into a cortex and a medulla (Fig. 19-1). The cor-
into the two ureters, from which it passes to a storage tical region appears dark brown and granular, whereas
organ, the urinary bladder. During voiding, the the medulla contains 6 to 12 discrete, pyramid-shaped,
urinary bladder is emptied via the urethra, which deliv- pale striated regions, the renal pyramids. The base of
ers the urine to outside the body. In addition, the each pyramid is oriented toward the cortex, constitut-
kidneys have an endocrine function in that they pro- ing the corticomedullary border, whereas its apex,
duce renin, erythropoietin, and prostaglandins, among known as the renal papilla, points toward the hilum.
others; they also convert a circulating precursor of The apex is perforated by 20 or so openings of the
vitamin D to the active vitamin. ducts of Bellini; this sieve-like region is known as
the area cribrosa. The apex is surrounded by a
cup-like minor calyx, which, joining two or three
KIDNEY neighboring minor calyces, forms a major calyx. The
three or four major calyces are larger subdivisions that
The kidneys have a concave region, known as the hilum, empty into the renal pelvis, the expanded continua-
where the ureter, renal vein, renal artery, and lymph tion of the proximal portion of the ureter. Neighboring
vessels pierce the kidney. pyramids are separated from each other by material
resembling the cortex, the cortical columns (of
The kidneys are large, reddish, bean-shaped organs sit- Bertin).
uated retroperitoneally on the posterior abdominal wall. The portion of the cortex overlying the base of each
Because of the position of the liver, the right kidney is pyramid is known as a cortical arch. Macroscopically,
approximately 1 to 2 cm lower than the left. Each three types of substances may be observed in the cortex:
kidney is about 11 cm long, 4 to 5 cm wide, and 2 to (1) red, dot-like granules, the renal corpuscles; (2)
3 cm thick. The kidney, embedded in perirenal fat, lies convoluted tubules, the cortical labyrinth; and (3) lon-
with its convex border situated laterally and its concave gitudinal striations, medullary rays, which are cortical
hilum facing medially. Branches of the renal artery and continuations of material located in the renal pyramids.
vein, lymph vessels, and ureter pierce the kidney at its A renal pyramid, with its associated cortical arch and
hilum. The ureter is expanded at this region, forming cortical columns, represents a lobe of the kidney.
the renal pelvis. A fat-filled extension of the hilum Hence, the human kidney is a multilobar organ. Each
deeper into the kidney is called the renal sinus. medullary ray with part of the cortical labyrinth sur-
The kidney is invested by a thin, loosely adhering rounding it is considered a kidney lobule, which con-
capsule, consisting mainly of dense, irregular collage- tinues into the medulla as a cone-shaped structure.
437
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438 䡲䡲䡲 Chapter 19 䡲 Urinary System
Uriniferous Tubules
The uriniferous tubule, the functional unit of the kidney,
During fetal development, the lobes of the is composed of a nephron and a collecting tubule.
kidney are accentuated by deep clefts, but this
characteristic is normally obliterated in the adult. The functional unit of the kidney is the uriniferous
When the lobation is retained following infancy, tubule, a highly convoluted structure that modifies the
the condition is known as lobated kidney. fluid passing through it to form urine as its final output.
Another anomalous kidney development is This tubule consists of two parts, each with a different
known as polycystic kidney disease, which embryological origin, the nephron and the collecting
presents varied morphological features according tubule (see Fig. 19-1). There are approximately 1.3
to the severity of the affliction; it involves the million nephrons in each kidney. Several nephrons are
appearance of thin-walled cysts on and in the drained by a single collecting tubule, and multiple col-
kidneys. lecting tubules join in the deeper aspect of the medulla
to form larger and larger ducts. The largest of these
Capsule Interlobular
artery Cortex
Interlobar artery
Medulla
(renal pyramid)
Arcuate artery
Renal artery
Medullary Cortical
ray nephron
Medulla
Renal
Renal vein column
Renal pelvis Cortex
Fat in renal sinus Major calyx

Collecting Juxtamedullary
Ureter Minor calyx nephron
tubule
Figure 19–1 A, Hemisected kidney illustrating morphology and circulation. B, Arrangement of cortical and juxtamedullary nephrons.
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Chapter 19 䡲 Urinary System ■ ■ ■ 439
Cortex
Proximal
convoluted
tubule
Glomerulus
Bowman’s
capsule
Distal
convoluted
tubule
Arcuate vein
and artery outer
stripe
outer
zone
of
inner medulla
stripe
Medulla
Collecting
tubule
inner
zone
of
medulla
Henle’s loop
Figure 19–1, cont’d C, The uriniferous tubule and its vascular supply and drainage. The juxtamedullary nephron extends much deeper
into the medulla than does the cortical nephron.
ducts, the ducts of Bellini, perforate the renal papilla Nephrons

at the area cribrosa.
Uriniferous tubules are densely packed so that the There are two types of nephrons, depending on the
connective tissue stroma of the kidney is scant. The location of their renal corpuscles and the length of their
entire uriniferous tubule is epithelial in nature and is, Henle’s loop.
therefore, separated from the connective tissue stroma
by an intervening basal lamina. Much of the connec- Two types of nephrons are found in the human kidney:
tive tissue is occupied by the rich vascular supply of the shorter cortical nephrons, subdivided into two
kidney. The functional relationship between the vascu- groups, superficial and midcortical nephrons, neither
lar supply and the uriniferous tubules is discussed later of which extend deep into the medulla, and the longer
in this chapter. juxtamedullary nephrons, whose renal corpuscle is
Ch019-X2945.qxd 15/8/06 2:52 PM Page 440
located in the cortex and whose tubular parts extend

deep into the medulla (see Fig. 19-1). The specific
locations of the two types of nephrons, the cellular com-
position of their various regions, and the specific align-
ments of these regions in register with one another
permit the subdivision of the medulla into an outer M
zone and an inner zone. The outer zone of the
medulla is further subdivided into an outer stripe and
an inner stripe. Unless otherwise noted, all of the
descriptions in this textbook refer to juxtamedullary
R
nephrons, even though they constitute only 15% of all
nephrons.
Each juxtamedullary nephron is about 40 mm long. S
The constituent parts of the nephron are modified
to perform specific physiological functions. The renal P
corpuscle, with its attendant glomerulus, filters the
fluid expressed from the bloodstream. The subsequent
tubular portions of the nephron (i.e., the proximal
tubule, the thin limbs of Henle’s loop, and the distal
tubule) modify the filtrate to form urine.
Renal Corpuscle
The renal corpuscle is composed of a tuft of capillaries,
the glomerulus, surrounded by Bowman’s capsule.
Figure 19–2 Light micrograph of the kidney cortex in a monkey,
illustrating renal corpuscles (R), medullary ray (M), and cross-
sectional profiles of the uriniferous tubules (×132). A portion of the
The renal corpuscle, an oval to round structure about urinary space (S) is clearly evident at the periphery of the renal cor-
200 to 250 µm in diameter, is composed of a tuft of puscle and is bound by the simple squamous epithelium composing
capillaries, the glomerulus, which is invaginated into the parietal layer (P) of Bowman’s capsule.
Bowman’s capsule, the dilated, pouch-like, proximal
end of the nephron (Figs. 19-2 to 19-4; also see Fig.
19-1). During development, the capillaries become
invested by the blind end of the tubular nephron,
almost as if a hand were to push into the end of an
expanded balloon. Hence, the space inside Bowman’s
capsule, known as Bowman’s space (urinary space),
is decreased in volume. The glomerulus is in intimate P
contact with the visceral layer of Bowman’s capsule,
composed of modified epithelial cells called podocytes.
The outer wall surrounding Bowman’s space, composed
of simple squamous epithelial cells (sitting on a thin
basal lamina), is the parietal layer (see Fig. 19-4).
The region where the vessels supplying and draining
the glomerulus enter and exit Bowman’s capsule is
known as the vascular pole, whereas the region of con- S
tinuation between the renal corpuscle and the proximal
tubule, which drains Bowman’s space, is called the
urinary pole. The glomerulus is supplied by the short,
straight afferent glomerular arteriole and drained by
M
the efferent glomerular arteriole; thus the glomeru-
lus is a completely arterial capillary bed. Although the
outer diameter of the afferent arteriole is greater than
that of the efferent arteriole, their luminal diameters Figure 19–3 Light micrograph of the monkey renal corpuscle
surrounded by cross-sectional profiles of proximal and distal tubules
are approximately equal. (×270). The macula densa (M) and the parietal layer (P) of Bowman’s
The efferent glomerular arteriole presents greater capsule are clearly evident as it encloses the clear space, a part of the
resistance to blood flow, resulting in higher capillary urinary space (S).
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Visceral layer of
Parietal layer of Bowman’s capsule
Bowman’s capsule (podocytes)
Basal lamina
Bowman’s space
Efferent arteriole
Brush border
(microvilli) Vascular
pole
Basal lamina
Distal tubule
Proximal
convoluted
tubule
Urinary
pole
Macula densa
of distal tubule
Juxtaglomerular
Bowman’s cells
capsule Afferent arteriole
Figure 19–4 A renal corpuscle and its juxtaglomerular apparatus.
pressures in the glomerulus than in other capillary beds. Mesangial cells may also be contractile because they
Filtrate leaking out of the glomerulus enters Bowman’s have receptors for vasoconstrictors such as angiotensin
space through a complex filtration barrier composed II and thus reduce blood flow through the glomerulus.
of the endothelial wall of the capillary, the basal lamina, Moreover, they, along with podocytes and the glomeru-
and the visceral layer of Bowman’s capsule. lar basement membrane, provide physical support to
the capillaries of the glomerulus. The glomerulus is
GLOMERULUS composed of fenestrated capillaries (Fig. 19-7; also see
Figs. 19-5 and 19-6) whose endothelial cells are highly
The glomerulus is composed of tufts of fenestrated attenuated, except for the region containing the
capillaries supplied by the afferent glomerular arteriole nucleus; their fenestrae are usually not covered by a
and drained by the efferent glomerular arteriole. diaphragm. The pores are large, ranging between 70
and 90 nm in diameter; hence, these capillaries act as a
The glomerulus is formed as several tufts of anasto- barrier only to formed elements of the blood and to
mosing capillaries that arise from branches of the macromolecules whose effective diameter exceeds the
afferent glomerular arteriole. The connective tissue size of the fenestrae.
component of the afferent arteriole does not enter
Bowman’s capsule, and the normal connective tissue Basal Lamina
cells are replaced by a specialized cell type known as
mesangial cells. There are two groups of mesangial Investing the glomerulus is a glomerular basal lamina
cells: extraglomerular mesangial cells are located at (~300 nm thick), consisting of three layers (see Figs. 19-
the vascular pole, and pericyte-like intraglomerular 6 and 19-7). The middle dense layer, the lamina densa,
mesangial cells are situated within the renal corpus- is about 100 nm in thickness and consists of type IV
cle (Figs. 19-5 and 19-6). collagen, composed of α3, α4, and α5 chains (unlike the
Intraglomerular mesangial cells are probably phago- usual type, which is composed of α1 and α2 chains). Less
cytic and function in resorption of the basal lamina. electron-dense layers, the laminae rarae—which
Ch019-X2945.qxd 15/8/06 2:52 PM Page 442
VISCERAL LAYER OF
BOWMAN’S CAPSULE
The visceral layer of Bowman’s capsule is composed of

epithelial cells that become modified and are known as
podocytes.
The visceral layer of Bowman’s capsule is composed of

Pedicels epithelial cells that are highly modified to perform a
filtering function. These large cells, called podocytes,
Podocyte Cytoplasm of have numerous long, tentacle-like cytoplasmic exten-
endothelial cell sions, primary (major) processes, that follow but
Basal lamina usually do not come in close contact with the longitu-
dinal axes of the glomerular capillaries (see Fig. 19-7).
Capillary Intraglomerular Each primary process bears many secondary
mesangial cell
processes, known as pedicels, arranged in an orderly
Podocyte fashion. Pedicels completely envelop most of the
glomerular capillaries by interdigitating with pedicels
from neighboring major processes of different
podocytes (Figs. 19-8 and 19-9).
Capillary Pedicels have a well-developed glycocalyx composed
of the negatively charged sialoproteins podocalyxin
and podoendin. Pedicels rest on the lamina rara
externa of the basal lamina. Their cytoplasm is devoid
Capillary of organelles but does house microtubules and micro-
filaments. Interdigitation occurs in such a fashion that
narrow clefts, 20 to 40 nm in width, known as filtration
Podocyte slits, remain between adjacent pedicels. Filtration slits
are not completely open; instead, they are covered by a
Figure 19–5 Relationship between the intraglomerular mesan-
thin slit diaphragm that extends between neighboring
gial cell, podocytes, and glomerulus. pedicels and acts as a part of the filtration barrier (Fig.
19-10; also see Fig. 19-7). The slit diaphragm has a
central bar, on either side of which are rows of pores
14 nm2 in area. The cell body of the podocyte is not at
contain laminin, fibronectin, and the highly hydrated all unusual in organelle content. It houses the irregu-
polyanionic proteoglycans perlacan and agrin—both larly shaped nucleus as well as rough endoplasmic retic-
rich in heparan sulfate—are located on either side of ulum (RER), Golgi apparatus, and numerous free
the lamina densa. Some refer to a lamina rara interna, ribosomes.
between the endothelial cells of the capillary and the
lamina densa, and the lamina rara externa, between Filtration Process
the lamina densa and the visceral layer of Bowman’s Fluid leaving the glomerular capillaries through the
capsule. Fibronectin and laminin assist the pedicels and fenestrae is filtered by the basal lamina. The lamina
endothelial cells to maintain their attachment to the densa traps larger molecules (>69,000 Da), whereas the
basal lamina. polyanions of the laminae rarae impede the passage of
negatively charged molecules and molecules that are
incapable of deformation. The fluid, which contains
CLINICAL CORRELATIONS small molecules, ions, and macromolecules, penetrates
the lamina densa and must pass through the pores in
Mutations in the α3 and α4 chains of type IV col- the slit diaphragm of the filtration slits; if the macro-
lagen result in Alport’s syndrome, an autosomal molecules are uncharged and if they are 1.8 nm or less
recessive disorder that is distinguished by loss of in diameter, they can pass without any hindrance
hearing, vision problems, and nephritis accom- through the slit diaphragm. However, if the uncharged
panied by microscopic hematuria. Persons with macromolecules are greater than 4 nm in diameter
Alport’s syndrome frequently suffer from kidney they cannot pass through the slit diaphragm. The fluid
failure and may require a kidney transplant. entering Bowman’s space is called the glomerular
ultrafiltrate.
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Figure 19–6 Electron micrograph of a region of

the human kidney glomerulus containing red blood
cells (×4594). Note the association between the intra-
glomerular mesangial cell and the podocytes around
the glomerular capillaries. BS, Bowman’s space; CL,
capillary lumen; E, endothelial cell; M, mesangial
cells; V, podocyte. (From Brenner BM, Rector FC:
The Kidney, 4th ed. Vol 1. Philadelphia, WB
Saunders, 1991.)
Pedicel Filtration
slit diaphragm
Basal
lamina
Fenestrated
endothelium
Basal lamina
Podocyte
Filtration
slit
Podocyte
Fenestrated
cell body
endothelium
Secondary
Figure 19–7 The interrelation- process
ship of the glomerulus, podocytes, (pedicel) Primary
pedicels, and basal laminae. process
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micrograph of podocytes (P) and
their processes from the kidney of a
rat (×4700). (From Brenner BM,
Rector FC: The Kidney, 4th ed. Vol
1. Philadelphia, WB Saunders, 1991.)

the rat renal cortex displaying a renal corpuscle with
its glomerulus (g) (×543). The renal corpuscle below
it does not have its glomerulus, so the urinary pole
(arrow) is evident. c, capillaries; d, distal convoluted
tubule; p, proximal convoluted tubule; v, blood
vessels. (From Leeson TS, Leeson CR, Paparo AA:
Text/Atlas of Histology. Philadelphia, WB Saunders,
1988.)
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Figure 19–10 Electron micrograph of pedicels

(P) and diaphragms bridging the filtration slits of a
glomerulus in a rat (×86,700). BS, Bowman’s space;
CL, capillary lumen. Note the laminae rara externa
(short arrow) and the filtration slit diaphragm (long
arrow). (From Brenner BM, Rector FC: The Kidney,
4th ed, Vol 1. Philadelphia, WB Saunders, 1991.)
Because the basal lamina traps larger macromole- Proximal Tubule

cules, it would become clogged were it not continuously
phagocytosed by intraglomerular mesangial cells The proximal tubule has two regions: the proximal
and replenished by both the visceral layer of Bowman’s convoluted tubule and the pars recta of the proximal
capsule (podocytes) and glomerular endothelial cells. tubule.
Bowman’s space drains into the proximal tubule at the

urinary pole. In this junctional region, sometimes
CLINICAL CORRELATIONS called the neck of the proximal tubule (negligible in
humans), the simple squamous epithelium of the pari-
The presence of albumin in the urine (albu- etal layer of Bowman’s capsule joins the simple cuboidal
minuria) is the result of increased permeability epithelium of the proximal tubule (see Fig. 19-4). The
of the glomerular endothelium. Among the proximal tubule, constituting much of the renal cortex,
causes of this condition are vascular injury, is approximately 60 µm in diameter and about 14 mm
hypertension, mercury poisoning, and exposure long. The tubule consists of a highly tortuous region,
to bacterial toxins. the pars convoluta (proximal convoluted tubule),
The basal lamina may also become impaired located near renal corpuscles, and a straighter portion,
because of the deposition of antigen-antibody the pars recta (descending thick limb of Henle’s
complexes that are filtered from the glomeruli loop), which descends in medullary rays within the
or from the reaction of antibasement mem- cortex and then in the medulla to become continuous
brane antibody with the basal lamina itself. with the loop of Henle at the junction of the outer and
Both of these instances produce types of inner stripes.
glomerulonephritis. Viewed with the light microscope, the convoluted
In cases of lipoid nephrosis, the basal portion of the proximal tubule is composed of a simple
laminae are not congested with antibodies, but cuboidal type of epithelium with an eosinophilic, granu-
adjacent pedicels appear to fuse with one lar-appearing cytoplasm (Fig. 19-11; also see Fig. 19-3).
another. This disease is one of the most preva- The cells have an elaborate striated border and an intri-
lent kidney disorders in children. cate system of interlocking and interwoven lateral cell
processes. Thus, the lateral cell membranes are usually
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Cortical connecting tubule

Proximal convoluted tubule Collecting tubule
Distal convoluted tubule
Ascending thick segment of

loop of Henle
Ascending thin segment of

loop of Henle
Figure 19–11 A drawing of the
uriniferous tubule and its cross-sectional
morphology.
indistinguishable with the light microscope. The height fluted and ragged-appearing striated borders; few,
of the cells varies with their functional state—from a low basally placed nuclei per cross section of the tubule; and
cuboidal to an almost high cuboidal epithelium. a lack of distinct lateral cell membranes. The cuboidal
The method and rapidity of fixation modify the cells sit on a well-defined basement membrane, easily
microscopic morphology of the proximal convoluted demonstrated by the periodic acid–Schiff (PAS) reac-
tubule because its lumen is kept open by fluid pressure. tion. Each cross section is composed of approximately
Ideal fixation demonstrates wide-open, empty lumina 10 to 20 cells, but because these cells are large, usually
and no clumping of the striated border. However, paraf- only six to eight nuclei are included in the plane of
fin sections usually display mostly occluded lumina; section (see Fig. 19-3).
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On the basis of the ultrastructural features of its About 67% to perhaps as much as 80% of sodium,
component cells, the proximal tubule can be subdivided chloride (Cl−), and water is resorbed from the glomeru-
into three regions: lar ultrafiltrate and transported into the connective
tissue stroma by cells of the proximal tubule. Sodium is
䡲 The first two thirds of the pars convoluta, designated S1
actively pumped out of the cell at the basolateral cell
䡲 The remainder of the pars convoluta and much of the
membranes by a sodium pump associated with sodium-
pars recta, designated S2
potassium adenosine triphosphatase (Na+,K+-ATPase).
䡲 The remainder of the pars recta, designated S3
The sodium (Na+) is followed by chloride to maintain
Cells of the S1 region have long (1.3 to 1.6 µm), electrical neutrality and by water to maintain osmotic
closely packed microvilli and a system of intermicrovil- equilibrium. The water passes through aquaporin-1
lar caveolae, known as apical canaliculi, that extend channels located in the basolateral cell membrane. In
into the apical cytoplasm (Fig. 19-12). This system is addition, all of the glucose, amino acids, and protein in
more extensive during active diuresis, suggesting that the glomerular ultrafiltrate are resorbed by the vacuo-
it functions in resorption of proteins during tubular lar endocytic apparatus of the cells of the proximal
clearing of the glomerular ultrafiltrate. Mitochondria, tubule. Moreover, the proximal tubule also eliminates
Golgi apparatus, and other normal cellular components the organic solutes, drugs, and toxins that must be
are present in these cells. Elaborate lateral and basal rapidly excreted from the body.
processes may extend almost the entire height of the
cell. These processes are long and narrow and usually THIN LIMBS OF HENLE’S LOOP
accommodate elongated, tubular mitochondria.
Cells composing the S2 region are similar to those The thin limbs of the loop of Henle have three regions:
of the S1 region, but they have fewer mitochondria the descending thin limb, Henle’s loop, and the
and apical canaliculi, have less elaborate intercellular ascending thin limb.
processes, and are lower in height.
Cells of the S3 region are low cuboidal with few The pars recta of the proximal tubule continues as the
mitochondria. These cells have only infrequent inter- thin limb of Henle’s loop (see Fig. 19-11). This thin
cellular processes and no apical canaliculi. tubule, whose overall diameter is about 15 to 20 µm, is
Figure 19–12 Electron micrograph of the S1

segment of the rat proximal tubule (×7128). (From
Brenner BM, Rector FC: The Kidney, 4th ed. Vol 1.
Ch019-X2945.qxd 15/8/06 2:52 PM Page 448
composed of squamous epithelial cells with an average sodium, chloride, and other ions. The major difference
height of 1.5 to 2 µm. The length of the thin segments between the ascending and descending thin limbs is
varies with the location of the nephron (see Fig. 19-1). that the ascending thin limb is only moderately perme-
In cortical nephrons, the thin segment is only 1 to 2 mm able to water. The significance of this difference in
long or may be completely absent. Juxtamedullary water permeability is discussed later.
nephrons have much longer thin segments, 9 to 10 mm
in length, and they form a hairpin-like loop that extends Distal Tubule
deep into the medulla as far down as the renal papilla.
The region of the loop continuous with the pars recta The distal tubule has three regions: the pars recta (the
of the proximal tubule is called the descending thin ascending thick limb of Henle’s loop), the macula densa,
limb (of Henle’s loop), the hairpin-like bend is Henle’s and the pars convoluta (the distal convoluted tubule).
loop, and the region that connects Henle’s loop to the
pars recta of the distal tubule is known as the ascend- The distal tubule is subdivided into the pars recta,
ing thin limb of Henle’s loop. which, as the continuation of the ascending thin limb of
The nuclei of the cells composing the thin limbs Henle’s loop, is also known as the ascending thick limb
bulge into the lumen of the tubule; hence, in paraffin of Henle’s loop, and the pars convoluta (distal con-
section, these limbs resemble capillaries in cross section voluted tubule). Interposed between the ascending
(see Fig. 19-11). They may be distinguished from cap- thick limb and the distal convoluted tubule is a modified
illaries in that their epithelial lining cells are slightly region of the distal tubule called the macula densa.
thicker, their nuclei stain less densely, and their lumina The ascending thick limb of Henle’s loop is 9 to
contain no blood cells. 10 mm in length and 30 to 40 µm in diameter. It joins
The fine structure of the epithelial cells constituting the ascending thin limb of Henle’s loop at the junction
the thin segments is not unusual. They present a few of the inner stripe with the inner zone of the medulla
short, stubby microvilli on their luminal surfaces and a and ascends straight up through the medulla to reach
few mitochondria in the cytoplasm surrounding the the cortex. The low cuboidal epithelial cells composing
nucleus. Numerous processes project from the basal the ascending thick segment have centrally placed,
portion of the cell to interdigitate with those of neigh- round to slightly oval nuclei and a few club-shaped,
boring cells. short microvilli. Although the lateral aspects of these
It is possible to differentiate among four types of cells interdigitate with each other, the interrelationships
epithelial cells composing different regions of Henle’s between neighboring cells are not nearly as elaborate as
loop according to their fine structural features. The in the proximal convoluted tubules. Basal interdigita-
locations and fine structural features of the four cell tions are much more extensive, however, and the
types are listed in Table 19-1. number of mitochondria is greater in these cells than in
The descending thin limb is highly permeable to those of the proximal convoluted tubules. Moreover,
water due to the presence of numerous aquaporin-1 these cells form highly efficient zonulae occludentes
water channels; it is reasonably permeable to urea, with their neighboring cells.
TABLE 19–1 Cell Types Composing the Thin Limbs of Henle’s Loop
Cell Type Location Fine Structural Features
Type I Cortical nephrons Squamous cells with no lateral processes and no

interdigitations
Type II Juxtamedullary nephrons; descending thin Squamous cells with numerous long, radiating processes
limb of the outer zone of the medulla that interdigitate with those of neighboring cells; fascia
occludentes between cells; infoldings of the basal
plasmalemma
Type III Juxtamedullary nephrons; descending thin Squamous cells with fewer processes and interdigitations
limb of the inner zone of the medulla than those of type II
Type IV Juxtamedullary nephrons; ascending thin Squamous cells with numerous long, radiating processes
limb that interdigitate with those of neighboring cells as in
type II cells; no infoldings of the basal plasmalemma
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The thick ascending limb is not permeable to water convoluted tubules. Indeed, the ratio of cross sections
or urea. In addition, its cells have chloride (and perhaps of proximal to distal convoluted tubules surrounding
sodium) pumps that function in the active transport of any renal corpuscle is usually 7 : 1.
chloride (and sodium) from the lumen of the tubule. Distal convoluted tubules usually ascend slightly
Thus, as the filtrate reaches the cortex of the kidney above their own renal corpuscles and drain into the
within the lumen of the distal tubule, its salt concen- arched portion of the collecting tubules.
tration is low and its urea concentration remains high. Similar to the thick ascending limbs, the distal con-
These cells also manufacture Tamm-Horsfall protein, voluted tubule is impermeable to water and urea.
which they release into the lumen of the thick ascend- However, in the basolateral plasmalemma of its cells,
ing limb to impede the formation of kidney stones. high Na+,K+-ATPase activity powers sodium-potassium
As the ascending thick limb of the Henle loop passes exchange pumps. Thus, in response to the hormone
near its own renal corpuscle, it lies between the affer- aldosterone, these cells can actively resorb almost all
ent and efferent glomerular arterioles. This region of of the remaining sodium (and, passively, chloride) from
the distal tubule is called the macula densa. Because the lumen of the tubule into the renal interstitium. In
the cells of the macula densa are tall and narrow, the addition, potassium and hydrogen ions are actively
nuclei of these cells appear to be much closer together secreted into the lumen, thus controlling the body’s
than those of the remainder of the distal tubule. extracellular fluid potassium level and the acidity of
Distal convoluted tubules are short (4 to 5 mm) with urine, respectively.
an overall diameter of 25 to 45 µm. In paraffin sections,
the lumina of these tubules are wide-open, the granu- Juxtaglomerular Apparatus
lar cytoplasm of the low cuboidal lining epithelium is
paler than that of proximal convoluted tubules, and The juxtaglomerular apparatus has three components:
because the cells are narrower, more nuclei are appar- the macula densa of the distal tubule, juxtaglomerular
ent in tubular cross section. The ultrastructure of these cells of the afferent glomerular arteriole, and
cells demonstrates a clear, pale cytoplasm with a few, extraglomerular mesangial cells.
blunt apical microvilli (Fig. 19-13). Nuclei are more or
less round and apically located, having one or two dense The juxtaglomerular apparatus consists of the macula
nucleoli. Mitochondria are not as numerous, and the densa of the distal tubule, juxtaglomerular cells of the
basal interdigitations are not as extensive as those of the adjacent afferent (and, occasionally, efferent) glomeru-
ascending thick limb of Henle’s loop. lar arteriole, and the extraglomerular mesangial cells
Because distal convoluted tubules are much shorter (also known as polkissen, lacis cells, and polar cushion)
than proximal convoluted tubules, any section of the (Fig. 19-14).
kidney cortex presents many more cross sections of The cells of the macula densa are tall, narrow, pale
proximal convoluted tubules than cross sections of distal cells with centrally placed nuclei (Fig. 19-15; also see

graph of the distal convoluted tubule
(×8100). (From Brenner BM, Rector
FC: The Kidney, 4th ed. Vol 1.
Ch019-X2945.qxd 15/8/06 2:52 PM Page 450
Distal tubule Figs. 19-2 to 19-4 and Fig. 19-14). Because of the nar-
rowness of these cells, the densely staining nuclei are
Juxtaglomerular
cells near to each other; collectively, viewed with the light
microscope, they appear as a dense spot. With the elec-
Afferent Macula densa Efferent tron microscope, these cells demonstrate numerous
arteriole arteriole microvilli, small mitochondria, and an infranuclearly
located Golgi apparatus (see Fig. 19-15).
Juxtaglomerular cells, modified smooth muscle
cells located in the tunica media of afferent (and, occa-
sionally, efferent) glomerular arterioles, are richly
innervated by sympathetic nerve fibers. The nuclei
of these cells are round instead of elongated. Juxta-
Extraglomerular glomerular cells contain specific granules demonstrated
mesangial
cells to be the proteolytic enzyme renin (see Fig. 19-15).
Angiotensin-converting enzyme (ACE), angio-
tensin I, and angiotensin II are also present in these
cells (see later).
Juxtaglomerular cells and the cells of the macula
Podocyte densa have a special geographical relationship because
the basal lamina, normally present in epithelium and
other tissues, is absent at this point, permitting intimate
Bowman's contact between cells of the macula densa and the jux-
space
taglomerular cells.
Intraglomerular
The extraglomerular mesangial cells, the third
mesangial cells member of the juxtaglomerular apparatus, occupy the
Glomerular space bounded by the afferent arteriole, macula densa,
capillaries efferent arteriole, and vascular pole of the renal cor-
puscle. These cells may contain occasional granules and
Figure 19–14 The juxtaglomerular apparatus. are probably contiguous with the intraglomerular
JG
Figure 19–15 Electron micrograph of the jux-

taglomerular apparatus from the kidney of a rabbit
(×2552). The macula densa (MD), juxtaglomerular
cells (JG) (containing electron-dense granules), and
extraglomerular mesangial (EM) cells are displayed.
(From Brenner BM, Rector FC: The Kidney, 4th ed.
Vol 1. Philadelphia, WB Saunders, 1991.)
Ch019-X2945.qxd 15/8/06 2:52 PM Page 451
mesangial cells. The functional significance of the jux- The basal membranes of these cells display numerous
taglomerular apparatus is discussed later. infoldings. Because the lateral cell membranes are not
plicated, they are clearly evident with the light micro-
Collecting Tubules scope. These cells possess numerous aquaporin-2 chan-
nels that are very sensitive to antidiuretic hormone
Collecting tubules, composed of a simple cuboidal (ADH) and become completely permeable to water.
epithelium, convey and modify the ultrafiltrate from the Intercalated cells display numerous apical vesicles
nephron to the minor calyces of the kidney. 50 to 200 nm in diameter, microplicae on their apical
plasmalemma, and an abundance of mitochondria. The
Collecting tubules are not part of the nephron. They nuclei of these cells are round and centrally located.
have different embryological origins, and it is only later There are two types of intercalated cells: type A, whose
in development that they meet the nephron and join it luminal membrane possesses H+-ATPase that functions
to form a continuous structure. The distal convoluted in transporting H+ into the lumen of the tubule thus
tubules of several nephrons join to form a short con- acidifying urine; and type B, whose basolateral mem-
necting tubule that leads into the collecting tubule brane possesses H+-ATPase and functions in resorbing
(Fig. 19-16; also see Fig. 19-11). The glomerular ultra- H+ and secreting HCO3−.
filtrate that enters the collecting tubule is modified and Medullary collecting tubules are of larger caliber
delivered to the medullary papillae. Collecting tubules because they are formed by the union of several corti-
are about 20 mm long and have three recognized cal collecting tubules (see Fig. 19-11). Those in the
regions (see Fig. 19-1): outer zone of the medulla are similar to the cortical col-
lecting tubules in that they display both principal and
䡲 Cortical
intercalated cells, whereas tubules of the inner zone of
䡲 Medullary
the medulla have principal cells only (Fig. 19-17).
䡲 Papillary
Papillary collecting tubules (ducts of Bellini) are
Cortical collecting tubules are located in the each formed by the confluence of several medullary col-
medullary rays and are composed of two types of lecting tubules. These are large ducts, 200 to 300 µm in
cuboidal cells (see Figs. 19-2 and 19-11): diameter, and they open at the area cribrosa of the renal
papilla to deliver the urine that they convey into the
䡲 Principal cells
minor calyx of the kidney. These ducts are lined by tall
䡲 Intercalated cells
columnar principal cells only.
Principal cells have oval, centrally located nuclei, a Collecting tubules are impermeable to water.
few small mitochondria, and short, sparse microvilli. However, in the presence of ADH, they become
HL
CT
Figure 19–16 The medulla of
the kidney displays the simple
cuboidal epithelium of the collecting
tubules (CT) as well as the simple
squamous epithelium of the thin
limbs of Henle’s loop (HL) and the
endothelial cells (E) of the vasa
recta. Note that the connective
tissue components are sparse and
consist mostly of vascular elements
(×270).
Ch019-X2945.qxd 15/8/06 2:52 PM Page 452
Figure 19–17 Electron micrograph of a col-

lecting tubule from a rabbit kidney (×4790). (From
Brenner BM, Rector FC: The Kidney, 4th ed. Vol 1.
permeable to water (and, to a certain extent, urea). The cell population of this connective tissue consists of
Thus, in the absence of ADH, urine is copious and three cell types:
hypotonic, and in the presence of ADH the volume of 䡲 Fibroblasts
urine is low and concentrated. 䡲 Macrophages
䡲 Interstitial cells
Renal Interstitium
Interstitial cells appear to be situated like the rungs
The renal interstitium is a very flimsy, scant amount of of a ladder, one on top of the other, and are most
loose connective tissue housing three types of cells: numerous between straight collecting ducts and
fibroblasts, macrophages, and interstitial cells. between the ducts of Bellini. Interstitial cells have elon-
gated nuclei and numerous lipid droplets. It is believed
The kidney is invested by a dense, irregular collagenous that these cells synthesize medullipin I, a substance
type of connective tissue with some elastic fibers inter- that is converted in the liver to medullipin II, a potent
spersed among the bundles of collagen. This capsule is vasodilator that lowers blood pressure.
not attached firmly to the underlying cortex. As blood
vessels enter the hilum, they travel in a thin connective
tissue cover, some of which is derived from the capsule. Renal Circulation
The cortical region has only delicate connective tissue Arterial Supply
elements that constitute less than 7% of the cortical
volume and is associated mostly with the basement Each kidney receives 10% of the total blood volume per
membranes investing the uriniferous tubules and their minute via a large branch of the abdominal aorta
vascular supply. The two cellular components of the cor- known as the renal artery.
tical connective tissue are fibroblasts and cells that are
believed to be interstitial dendritic cells, members of The kidney receives an extremely extensive blood
the mononuclear phagocytic system. supply via the large renal artery, a direct branch of the
The medullary interstitial connective tissue compo- abdominal aorta (see Fig. 19-1). Before entering the
nent is more extensive than that found in the cortex, in hilum of the kidney, the renal artery bifurcates into an
fact it occupies nearly 30% of the volume of the inner anterior and a posterior division, which in turn subdi-
medulla. Embedded in this connective tissue are the vide to form a total of five segmental arteries. The
various components of the uriniferous tubules as well as branches of any one segmental artery do not form
the extensive vascular network located in the medulla. anastomoses with the branches of other segmental
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arteries. Hence, if blood flow through one of these

arteries is blocked, circulation to the region of the
kidney supplied by the affected vessel is interrupted.
Therefore, the kidney is said to be subdivided into vas-
cular segments, with each segment supplied by a spe-
cific artery.
The first subdivisions of the segmental arteries are
called lobar arteries, one for each lobe of the kidney.
These in turn branch to form two or three interlobar
arteries, which travel between the renal pyramids to
the corticomedullary junction. At the corticomedullary
junction, these arteries form a series of vessels (per-
pendicular to the parent vessel) that, to a large extent,
remain at that junction, occupying the same curved
plane. Because these arteries describe a slight arc over
the base of the renal pyramid, they are called arcuate
arteries.
Although arcuate arteries once were believed to
anastomose with each other, more recent studies
suggest that terminal branches of these arteries do not
join each other. Instead, terminal branches, as all other
branches of the arcuate arteries, ascend into the cortex,
forming interlobular arteries.
Interlobular arteries ascend within the cortical
labyrinth approximately halfway between neighboring
medullary rays. Hence, they travel in the interstices
between any two lobules. Many branches arise from
the interlobular arteries. These branches supply the Figure 19–18 Electron micrograph of the arteria recta of a rat
glomeruli of renal corpuscles and are known as affer- kidney. (From Takahashi-Iwanaga H: The three-dimensional cytoar-
chitecture of the interstitial tissue in the rat kidney. Cell Tissue Res
ent glomerular arterioles. Some of the interlobular 264:269-281, 1991.)
arteries ascend through the cortex to perforate the
kidney capsule. Here they contribute to the formation
of the capsular plexus. Most of the interlobular arteries, frequently, the arteriolae rectae and venae rectae
however, terminate as afferent glomerular arterioles. together are referred to as the vasa recta—the term
Each glomerulus is drained by another arteriole, we shall use in this textbook. The hairpin-like shape of
the efferent glomerular arteriole. There are two the vasa recta, which closely follows and wraps around
types of efferent glomerular arterioles, those draining the two limbs of Henle’s loop and the collecting tubule,
glomeruli of cortical nephrons and those draining is essential in the physiology of urine concentration (see
glomeruli of juxtamedullary nephrons. later.)
Efferent glomerular arterioles from cortical
nephrons are short and branch to form a system of cap- Venous Drainage
illaries, the peritubular capillary network. This cap-
illary bed supplies the entire cortical labyrinth, with the The arcuate veins receive blood from the cortex via
obvious exception of the glomeruli. It is thought that the the stellate veins and interlobular veins and from the
endothelial cells of the peritubular capillary network medulla via the venae rectae; arcuate veins are drained
(and perhaps connective tissue cells of the cortex and by the interlobar veins that deliver their blood into the
outer medulla) manufacture and release the hormone renal vein.
erythropoietin.
The efferent glomerular arterioles, derived from Venae rectae deliver their blood to arcuate veins,
glomeruli of juxtamedullary nephrons as well as from vessels that follow the paths of the same-named arter-
glomeruli located in the lower quadrant of the cortex, ies. Blood is thus drained from the medulla. Cortical
each give rise to 10 to 25 long, hairpin-like capillaries blood is collected into a star-shaped system of subcap-
that dip deep into the medulla (Figs. 19-18 and 19-19). sular veins called stellate veins, which are tributaries
Their descending limbs have a narrow bore and are of the interlobular veins. Stellate veins also receive
called arteriolae rectae; their ascending limbs are blood from the terminal portions of the efferent glom-
much greater in diameter and are called venae rectae; erular arterioles. The interlobular veins, paralleling the
Ch019-X2945.qxd 15/8/06 2:52 PM Page 454

of injected kidney displaying the rich
vascular supply of the kidney cortex
(×132). The glomeruli (G) are clearly
evident.
same-named arteries, deliver their blood to the arcuate traveling along the renal artery. The cell bodies of
veins. Hence, arcuate veins drain both the medulla and these fibers are probably located in the aortic and
the cortex. Arcuate veins are tributaries of interlobar celiac plexuses. Sympathetic fibers are distributed by
veins that unite, near the hilum, to form the renal branches of the renal arterial tree, and these vessels are
vein. This large vein delivers the blood to the inferior modulated by some of these fibers. Additional sympa-
vena cava. Note the absence of lobar and segmental thetic fibers reach the epithelium of the renal tubules,
veins in contrast to the presence of such named arter- the juxtaglomerular and interstitial cells, and the
ies in the arterial system of the kidney. capsule of the kidney. Sensory fibers and parasympa-
thetic fibers (probably from the vagus nerve) have also
Lymphatic Supply of the Kidney been described in the kidney.
Lymph vessels of the kidney probably follow the larger General Functions of the Kidney
arteries.
The kidneys play a role in excretion as well as in regu-
The lymphatic supply of the kidney is not completely lation of body fluid composition and volume. Specifi-
understood. It is believed that most lymphatic vessels cally, they regulate solute components (e.g., sodium,
follow the larger arteries. According to most investiga- potassium, chloride, glucose, amino acids) and acid-
tors, the lymphatic supply of the kidney may be subdi- base balance. Thus, during the summer, when a great
vided into superficial and deep aspects located in the deal of fluid is lost through perspiration, the urinary
subcapsular region and in the medulla, respectively. output is reduced in volume and increased in osmolar-
The two systems may or may not join each other near ity. During the winter months, when fluid loss through
the hilum, where they form several large lymphatic perspiration is minimal, the urinary output is increased
trunks. Lymph nodes in the vicinity of the vena cava and in volume and the urine is dilute.
the abdominal aorta receive lymph from the kidneys. In addition, the kidneys excrete detoxified end prod-
There are lymph vessels in the cortex that do not follow ucts, regulate the osmolality of urine, and secrete sub-
the larger arteries, but they do drain their lymph into a stances such as erythropoietin, medullipin I, renin, and
plexus of lymph vessels at the hilum. prostaglandins.
Finally, the kidneys regulate blood pressure and,
Renal Innervation in the presence of parathyroid hormone, aid in the
conversion of a less active form of vitamin D to 1,25-
Most nerve fibers that reach the kidney are unmyeli- dihydroxycholecalciferol, its most active form, which is
nated, sympathetic fibers that form the renal plexus, responsible for the increased absorption of calcium and
Ch019-X2945.qxd 15/8/06 2:52 PM Page 455
phosphate ions by the digestive system and their trans- Resorption in the Proximal Tubule
port into the extracellular fluid compartment of the
body. Although all of these functions are important The proximal tubule is the site of mass movement,
aspects of kidney histophysiology, only the mechanism where a tremendous amount of electrolytes, glucose,
of urine formation is discussed in this chapter. amino acids, protein, and water is conserved.
The ultrafiltrate leaves Bowman’s space via the urinary

Mechanism of Urine Formation pole to enter the proximal convoluted tubule, where
modification of this fluid begins. Materials resorbed
The two kidneys receive about one fifth of the total
from the lumen of the proximal tubule enter the tubular
blood volume (1220 mL) per minute, and they
epithelial cells, from which they are exocytosed into the
manufacture about 1 to 2 mL of urine per minute.
interstitial connective tissue. Here, the resorbed sub-
The two kidneys receive a large volume of circulating stances gain entrance to the rich peritubular capillary
blood because the renal arteries are large and they are network and thus are returned to the body via the
direct branches of the abdominal aorta. Inulin, a fruc- bloodstream.
tose polymer, can be used to measure the glomerular Most resorption of materials from the ultrafiltrate
filtration rate (GFR). Such studies have shown that occurs in the proximal tubule. Normally, the following
the entire blood supply circulates through the two amounts are absorbed in the proximal tubule: 100% of
kidneys every 5 minutes. Thus, approximately 1220 mL proteins, glucose, amino acids, and creatine; almost
of blood enters the two kidneys each minute, from 100% of bicarbonate ions; 67% to 80% of sodium and
which 125 mL/min of glomerular filtrate is formed in chloride ions; and 67% to 80% of the water.
the average male. Thus, 180 L of glomerular filtrate is The Na+,K+-ATPase-powered sodium pumps in
formed each day, of which only 1.5 to 2.0 L is excreted the basolateral plasma membrane of the proximal
as urine. Therefore, every day at least 178 L is resorbed tubule cell pump sodium into the renal interstitium.
by the kidneys, and only about 1% of the total glomeru- This movement of sodium ions out of the cell at the
lar filtrate is excreted. basolateral membrane causes sodium in the lumen of
the tubule to leave the ultrafiltrate and enter the cell
through its apical cell membrane. In this fashion, the
Filtration in the Renal Corpuscle net sodium movement is from the ultrafiltrate into the
renal connective tissue. To maintain electrical neutral-
Fluid component from the blood passes through the
ity, chloride ions passively follow sodium. Further, to
filtration barrier to become the ultrafiltrate.
maintain osmotic equilibrium, water passively follows
As blood passes from the afferent glomerular arteriole sodium (by osmosis).
into the glomerulus, it encounters a region of differen- Additional energy-requiring pumps, located in the
tial pressure, where the intracapillary blood pressure is apical plasmalemma of proximal tubule cells, cotrans-
greater than the opposing fluid pressure in Bowman’s port amino acids and glucose with sodium into the cell
space, forcing fluid from the capillary into that space. to be released into the renal interstitium. Proteins,
An additional factor, colloid osmotic pressure of the brought into the cell by pinocytotic vesicles, are
blood proteins, opposes the entry of fluid into the degraded by hydrolytic enzymes within late endosomes.
Bowman space, but the net effect, the filtration force, Each day, as much as 140 g of glucose, 430 g of
is high (25 mm Hg). The fluid entering Bowman’s space sodium, 500 g of chloride, 300 g of bicarbonate, 18 g of
is called the (glomerular) ultrafiltrate. potassium ions, 54 g of protein, and approximately
Because of the tripartite filtration barrier 142 L of water are conserved by the proximal tubules
(endothelial cell, basal lamina, filtration slit or of the kidney.
diaphragm), cellular material and large macromolecules The proximal tubule also releases certain substances
cannot leave the glomerulus; thus, the ultrafiltrate into the tubular lumen. These include hydrogen (H+),
is similar to plasma (without its constituent macro- ammonia, phenol red, hippuric acid, uric acid, organic
molecules). Molecules greater than 69,000 Da (e.g., bases, and ethylenediaminetetraacetate as well as
albumin) are trapped by the basal lamina. In addition certain drugs, such as penicillin.
to molecular weight, the molecular shape and charge of
a molecule and the functional state of the filtration Henle’s Loop and the Countercurrent
barrier all influence the ability of a molecule to traverse Multiplier System
the filtration barrier. Because the filtration barrier has
The long Henle loop of the juxtamedullary nephron is
negatively charged components, macromolecules that
responsible for the establishment of the countercurrent
are negatively charged are less able to cross it compared
multiplier system.
with positively charged or neutral macromolecules.
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The osmolarity of the glomerular ultrafiltrate is the osmotic forces in its microenvironment. The thin
same as that of circulating blood. This osmolarity is not ascending limb is relatively impermeable to water, but
altered by the proximal tubule because water has left its salts can enter or leave the tubule, depending on con-
lumen in response to the movement of ions. However, ditions in the interstitium. It is important to understand,
the osmotic pressure of formed urine is different from at this point (to be explained later), that urea enters the
that of blood. The osmotic pressure differential is estab- lumina of the thin limbs of Henle’s loop.
lished by the remaining regions of the uriniferous The thick ascending limb of Henle’s loop is com-
tubule. Interestingly, the osmolarity and volume of pletely impermeable to water; however, a chloride
urine vary, indicating that the kidneys can modulate pump actively removes chloride ions from the lumen
these factors. of the tubules and these ions enter the renal intersti-
A gradient of osmolarity, increasing from the corti- tium. Sodium ions follow passively (although some
comedullary junction to deep into the medulla, is main- suggest the presence of a sodium pump also) to pre-
tained in the renal medullary interstitium. The long serve electrical neutrality. As the filtrate ascends, it
loops of Henle of juxtamedullary nephrons aid not contains fewer and fewer ions; hence, the amount of
only in the creation but also in the maintenance of this salts that may be transferred out into the interstitium
osmotic gradient via a countercurrent multiplier decreases. Thus, a gradient of salt concentration is
system (Fig. 19-20). The cells of the thin descending established in which the highest interstitial osmolarity
limb of Henle’s loop are freely permeable to water and is deep in the medulla, and the osmolarity of the inter-
salts. Therefore, the movement of water reacts to the stitium decreases toward the cortex.
DIURESIS ANTIDIURESIS
H2O
Cl– H2O
Cl–
Na+ Na+
Cl– Cl–
Na+ Na+
300 300
50 300
75
Arcuate
vein
Cortex Cortex
300 300
Outer 100
Outer 100
medulla medulla
Na+ Na+
50 300
Cl– Cl–
H2O
200
400 500 400
200 600
400 600
Inner Inner
medulla medulla
H2O Na+ H2O
Na+
H2O Cl– 600 Cl–
Urea
Urea Urea
H2O
Urea
50
Urea 1200
Urea 1200
700
A B
Figure 19–20 Histophysiology of the uriniferous tubule. A, Diuresis (in the absence of antidiuretic hormone [ADH]). B, Antidiuresis (in
the presence of ADH). Numbers indicate milliosmoles per liter. Areas outlined by a thick line indicate that the tubule is impermeable to water.
In the presence of ADH, the collecting tubule changes so that it becomes permeable to water and the concentration in the interstitium of the
inner medulla increases. The vasa recta is simplified in this drawing because it encompasses the entire uriniferous tubule (see Fig. 19-1).
Ch019-X2945.qxd 15/8/06 2:52 PM Page 457
Because the medulla is tightly packed with thick and

thin (ascending and descending) limbs of Henle’s loop TABLE 19–2 Effects of Angiotensin II
and collecting tubules, the gradient of osmolarity that is
established is pervasive and affects all the tubules Function Result
equally (see Fig. 19-20).
Therefore, keeping the foregoing in mind, we can Acts as a potent Increased blood pressure
recap the movement of ions and water, once again start- vasoconstrictor
ing as the ultrafiltrate, which, as the student should Facilitates synthesis Resorption of sodium and
recall, is isotonic with blood as it leaves the pars recta and release of chloride from lumen of
of the proximal tubule. As the ultrafiltrate descends in aldosterone distal convoluted tubule
the thin descending limb of Henle’s loop, it loses water
(reducing volume and increasing osmolarity), reacting Facilitates release Resorption of water from
to the osmotic gradient of the interstitium, so that the of ADH lumen of collecting tubule
intraluminal filtrate more or less becomes equilibrated Increases thirst Increased tissue fluid volume
with that of the surrounding connective tissue. This
fluid of high osmolarity now ascends in the thin ascend- Inhibits renin release Feedback inhibition
ing limb of Henle’s loop, which is mostly impermeable
Facilitates release of Vasodilation of afferent
to water but not to salts. Thus, the volume of the ultra-
prostaglandins glomerular arteriole, thus
filtrate does not change (i.e., the volume is the same maintaining glomerular
when the ultrafiltrate leaves the ascending thin limb as filtration rate
when it entered it), but the osmolarity of the ultrafil-
trate inside the tubule adjusts to the osmolarity of the ADH, antidiuretic hormone.
interstitium.
The fluid entering the ascending thick limb of
Henle’s loop passes a region that is impermeable to
water but has a chloride pump, which removes chloride of the lungs, and also to a lesser extent in those of the
ions from the lumen, followed passively (or perhaps also kidneys and other organs of the body, angiotensin-
actively) by sodium ions. Because water cannot leave converting enzyme (ACE) converts angiotensin I to
the lumen, the ultrafiltrate becomes hypotonic but its angiotensin II, an octapeptide hormone with numer-
volume remains constant as it ascends to the cortex in ous biological effects (Table 19-2). As a potent vaso-
the ascending thick limb. The chloride and sodium that constrictor, angiotensin II reduces the luminal diameter
were transferred from the lumen of the ascending thick of blood vessels, thus constricting the efferent glomeru-
limb into the connective tissue are responsible for the lar arterioles, further increasing pressure within the
establishment of a concentration gradient in the renal glomerulus. The increased intraglomerular pressure
interstitium of the outer medulla. along with the increased volume of blood flow results
in the increased glomerular filtration rate of a larger
volume of blood. Angiotensin II also influences the
Monitoring the Filtrate in the adrenal cortex to release aldosterone, a hormone
Juxtaglomerular Apparatus that acts primarily on cells of the distal convoluted
tubules, increasing their resorption of sodium and
When cells of the macula densa detect a low
chloride ions.
sodium concentration in the ultrafiltrate, they cause
juxtaglomerular cells to release the enzyme renin, which
converts angiotensinogen to angiotensin I.
The cells of the macula densa probably monitor the fil-
trate volume and sodium concentration. If sodium con- One of the causes contributing to chronic
centration is below a specific threshold, macula densa essential hypertension is the presence of ele-
cells do two things: vated levels of angiotensin II. Elevated blood
levels of angiotensin II were once believed to be
䡲 They cause dilation of the afferent glomerular arteri- due to the excessive release of renin from the jux-
oles, thus increasing blood flow into the glomerulus. taglomerular cells of the juxtaglomerular appara-
䡲 They instruct juxtaglomerular cells to release the tus. It is now realized that the increased activity
enzyme renin into circulation. of angiotensin-converting enzyme, rather than
The enzyme renin converts angiotensinogen, nor- the renal release of renin, is directly responsible
mally present in the bloodstream, into the decapeptide for elevating the concentration of angiotensin II.
angiotensin I, a mild vasoconstrictor. In the capillaries
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Loss of Water and Urea from Filtrate

in Collecting Tubules CLINICAL CORRELATIONS
Antidiuretic hormone (vasopressin) causes the Congenital nephrogenic diabetes insipidus
conservation of water and the excretion of a is an X-linked disorder evidenced clinically only
concentrated urine. in male infants, although it may also have a
certain degree of clinical penetrance in female
The filtrate that leaves the distal convoluted tubule to infants. This condition, in affected males, mani-
enter the collecting tubule is hypotonic. As the collect- fests itself in the formation of copious quantities
ing tubule passes through the medulla to reach the area of dilute urine due to the malformation of the V2
cribrosa, it is also subject to the same osmotic gradients receptor. Additional symptoms include fever,
as the ascending and descending limbs of Henle’s loop. vomiting, hypernatremia, and extreme dehydra-
In the absence of antidiuretic hormone (ADH), the tion. The blood level of ADH is normal or some-
cells of the collecting tubule and, to a lesser extent, of what elevated, however, the aberrant ADH
the distal convoluted tubule are completely imperme- receptor cannot activate Gs proteins, and conse-
able to water (see Fig. 19-20). Therefore, the filtrate, or quently aquaporins are not inserted into the
urine, is not modified in the collecting tubule and the luminal plasma membranes of collecting ducts,
urine remains dilute (hypotonic). resulting in the inability to concentrate urine.
Under the influence of ADH, however, the cells of
the collecting tubule (and, in animals other than
humans and monkeys, the distal convoluted tubules)
become freely permeable to water and urea. As the fil- Vasa Recta and Countercurrent
trate descends through the renal medulla in the col- Exchange System
lecting tubule, it is subject to the osmotic pressure
gradients established by the hairpin-like loops of Henle The lumen of the arterial limb of the vasa recta has a
and the vasa recta, and water leaves the lumina of the smaller diameter than that of the venous limb; both
collecting tubules to enter the interstitium. Hence, the limbs are freely permeable to electrolytes and water.
urine, in the presence of ADH, becomes concentrated
and hypertonic. The vasa recta helps maintain the osmotic gradient in
In addition, the concentration of urea becomes the medulla because both arterial and venous limbs are
extremely high in the lumen of the collecting tubule, freely permeable to water and salts (Fig. 19-21). More-
and in the presence of ADH it passively enters the inter- over, as indicated previously, the luminal diameter of
stitium of the inner medulla. Thus, much of the con- the arterial limb is smaller than that of the venous limb.
centration gradient of the renal interstitium in the inner Therefore, as the blood courses down the arterial limb,
medulla is due to the presence of urea rather than it loses water and gains salts, and as it returns via the
sodium and chloride. venous limb, it loses salts and gains water, thus acting
The action of ADH is believed to be dependent on as a countercurrent exchange system.
V2 receptors located in the basolateral plasma mem- This mechanism ensures that the system of osmotic
branes of principal cells of the collecting ducts. Once gradients remains undisturbed, because the osmolarity
ADH binds to a V2 receptor, the following occurs: of the blood in the vessels is more or less equilibrated
with that of the interstitium. However, the volume of
䡲 Gs proteins are activated.
salts and fluid being brought in by the arterial limb is
䡲 Adenylate cyclase generates cyclic adenosine
less than that being taken away by the venous limb. This
monophosphate (cAMP).
exchange system causes salt and water to be resorbed
䡲 Aquaporin-2 (AQP2) channels are inserted into the
(returned back to the body) because of the concentra-
luminal plasma membrane (Table 19-3)
tion gradient in the renal medulla.
䡲 Water, from the lumen of the collecting duct, enters
The structure and function of the various regions of
the cell.
the uriniferous tubule are presented in Table 19-4.
䡲 Water leaves the cell via aquaporin 3 (AQP 3) and
aquaporin 4 (AQP 4) channels (that are always
present in the basolateral cell membranes) to enter EXCRETORY PASSAGES
the renal interstitium.
The excretory passages of the urinary system consist
of the minor and major calyces, the pelvis of the kidney,
the ureter, the single urinary bladder, and the single
urethra.
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TABLE 19–3 Structure and Function of the Uriniferous Tubule
Structure Major Functions Comments
Renal corpuscle: Simple Filtration Filtration barrier: endothelial cell, fused basal
squamous epithelium, laminae, filtration slits
fused basal laminae,
podocytes
Proximal tubule: Simple Resorption of 67%–80% of water, Sodium pump in basolateral membrane;
cuboidal epithelium sodium, and chloride (reducing ultrafiltrate is isotonic with blood
volume of ultrafiltrate); resorption
of 100% of protein, amino acids,
glucose, and bicarbonate
Descending thin limb of Completely permeable to water and Ultrafiltrate is hypertonic with respect to
Henle’s loop: Simple salts (reducing volume of blood; urea enters lumen of tubule
squamous epithelium ultrafiltrate)
Ascending thin limb of Impermeable to water, permeable to Ultrafiltrate is hypertonic with respect to blood;
Henle’s loop: Simple salts; sodium and chloride leave urea leaves renal interstitium and enters the
squamous epithelium tubule to enter renal interstitium lumen of tubule
Ascending thick limb of Impermeable to water; chloride and Ultrafiltrate becomes hypotonic with respect to
Henle’s loop: Simple sodium leave tubule to enter renal blood; chloride pump in basolateral cell
cuboidal epithelium interstitium membrane is responsible for establishment
of osmotic gradient in interstitium of outer
medulla
Macula densa: Simple Monitors sodium level and volume of Contacts and communicates with
columnar cells ultrafiltrate in lumen of distal tubule juxtaglomerular cells
Juxtaglomerular cells: Synthesize and release renin into Renin initiates the reaction for the eventual
Modified smooth bloodstream formation of angiotensin II (see Table 19-2)
muscle cells
Distal convoluted tubule: Responds to aldosterone by resorbing Ultrafiltrate becomes more hypotonic (in the
Simple cuboidal sodium and chloride from lumen presence of aldosterone); sodium pump in
epithelium basolateral membrane; potassium is secreted
into the lumen
Collecting tubule: Simple In the presence of ADH, water and Urine becomes hypertonic in the presence of
cuboidal epithelium urea leave the lumen to enter the ADH; urea in interstitium is responsible for
urea interstitium gradient of concentration in interstitium of
the inner medulla
ADH, antidiuretic hormone.
Calyces projects into the minor calyx is covered by transitional

epithelium, which acts as a barrier, separating the
Each minor calyx accepts urine from the renal papilla of urine from the underlying interstitial connective tissue.
a renal pyramid; as many as four minor calyces may Deep to the lamina propria is a thin muscular coat com-
deliver their urine to a major calyx. posed entirely of smooth muscle. This muscular layer
propels the urine into a major calyx, one of three or
The renal papilla of each renal pyramid fits into a minor four larger, funnel-shaped chambers, each of which col-
calyx, a funnel-shaped chamber that accepts urine lects urine from two to four minor calyces. The major
leaving the ducts of Bellini at the area cribrosa (see Fig. calyces are similar in structure to the minor calyces as
19-1). The portion of the apex of the pyramid that well as to the expanded proximal region of the ureters,
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TABLE 19–4 Types of Aquaporins and Their Locations In The Uriniferous Tubule
Aquaporin Location Function
Aquaporin-1 (AQP 1) Proximal tubule and thin descending These segments are always permeable to water
limb of Henle’s loop
Aquaporin-2 (AQP 2) In the presence of ADH, is present In the presence of ADH, AQP-2 channels are
in the luminal surface of principal inserted into the luminal membranes of
cells of the collecting ducts principal cells and water can traverse the cell
In the absence of ADH, is stored in to enter the renal interstitium
apically located vesicles of principal
cells of collecting ducts
Aquaporin-3 and Always present in the basolateral cell The basolateral cell membranes of principal cells
aquaporin-4 (AQP 3 membranes of principal cells of of collecting ducts are always permeable to
and AQP 4) collecting ducts water
Each ureter is about 3 to 4 mm in diameter, is approx-

300 imately 25 to 30 cm long, and pierces the base of the
300 350 urinary bladder. The ureters are hollow tubes consist-
Cortex ing of:
Medulla 350 Cl– 䡲 A mucosa, which lines the lumen
Cl– 450 䡲 A muscular coat (muscularis)
Na+
䡲 A fibrous connective tissue covering
Na+ 400
400 H2O
The mucosa of the ureter presents several folds,
H2O
which project into the lumen when the ureter is empty
but are absent when the ureter is distended. The tran-
Arteriola Venula sitional epithelial lining, three to five cell layers in
recta recta thickness, overlies a layer of dense, irregular fibroelas-
tic connective tissue, which constitutes the lamina
700
propria. As always, the epithelium is separated from
900
Cl– the underlying lamina propria by a basal lamina.
Cl–
The muscularis of the ureter is composed of two
Na+ Na+ predominantly inseparable layers of smooth muscle
800 800 cells. The arrangement of the layers is opposite that
H2O H2O
found in the digestive tract, because the outer layer is
arranged circularly and the inner layer is longitudinally
1200 1200 disposed. This arrangement is true for the proximal two
thirds of the ureter, but in the lower third, near the
1200
urinary bladder, a third muscle layer, whose fibers are
oriented longitudinally, is added onto the existing
surface of the existing muscle coat. Hence, the muscu-
Figure 19–21 Histophysiology of the vasa recta. Numbers rep- lar fiber orientation in the lower one third of the ureter
resent milliosmoles per liter. The arteriola recta is smaller in diame- is outer longitudinal, middle circular, and inner
ter than the venula recta. longitudinal. However, it should be noted that, just as
in the digestive tract, these muscle layers are arranged
the renal pelvis. The walls of the excretory passages in a helical configuration, in which the pitch of the
thicken from the minor calyces to the urinary bladder. helices varies from short to long, thus giving the appear-
ance of circular or longitudinal orientations.
Ureter The fibrous outer coat of the ureter is unremark-
able. At its proximal and distal terminals, it blends with
The ureters deliver urine from the kidneys to the urinary
the capsule of the kidney and the connective tissue of
bladder.
the bladder wall, respectively. Contrary to expectation,
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urine does not pass down the ureter because of gravi- Plaques appear to be impermeable to water and salts;
tational forces; instead, muscular contraction of the thus these cells act as osmotic barriers between the
ureteric wall establishes peristalsis-like waves that urine and the underlying lamina propria. The superfi-
convey urine to the urinary bladder. As the ureters cial cells of the transitional epithelium are held together
pierce the posterior aspect of the base of the bladder, a by desmosomes and, possibly, by tight junctions, which
valve-like flap of mucosa hangs over each ureteric also aid in the establishment of the osmotic barrier by
orifice, preventing regurgitation of urine from the preventing the passage of fluid between the cells.
bladder back into the ureters. The triangular region of the bladder, whose apices
are the orifices of the two ureters and the urethra, is
Urinary Bladder known as the trigone. The mucosa of the trigone is
always smooth and is never thrown into folds. The
The urinary bladder stores urine until it is ready to be embryonic origin of the trigone differs from that of the
voided. remainder of the bladder.
The lamina propria of the bladder may be subdivided
The urinary bladder is essentially an organ for storing into two layers: a more superficial, dense, irregular col-
urine until the pressure becomes sufficient to induce lagenous connective tissue and a deeper, looser layer of
the urge for micturition, or voiding. Its mucosa also connective tissue composed of a mixture of collagen and
acts as an osmotic barrier between the urine and the elastic fibers. The lamina propria contains no glands
lamina propria (Figs. 19-22 and 19-23). The mucosa of except at the region surrounding the urethral orifice,
the bladder is arranged in numerous folds, which disap- where mucous glands may be found. Usually, these
pear when the bladder becomes distended with urine. glands extend only into the superficial layer of the
During distention, the large, round, dome-shaped lamina propria. They secrete a clear viscous fluid that
cells of the transitional epithelium become stretched apparently lubricates the urethral orifice.
and change their morphology to become flattened.
The accommodation of cell shape is performed by a
unique feature of the transitional epithelial cell plas-
malemma, which is composed of a mosaic of special-
ized, rigid, thickened regions, plaques, interspersed by
normal cell membrane, interplaque regions. When
the bladder is empty, the plaque regions are folded into
irregular, angular contours, which disappear when the
cell becomes stretched. These rigid plaque regions,
anchored to intracytoplasmic filaments, resemble gap
junctions, but this similarity is only superficial.
CT
E LP
Figure 19–22 Low-power light micrograph of the monkey Figure 19–23 Light micrograph of transitional epithelium from
urinary bladder (×58). Observe the epithelium (E), the subepithelial the bladder of a monkey (×540). Observe the very large, dome-shaped
connective tissue (CT), and the muscular coat (M) of the bladder. cells abutting the lumen. LP, lamina propria.
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The muscular coat of the urinary bladder is com- along the remainder of its length. Interspersed in the
posed of three interlaced layers of smooth muscle, epithelium are patches of pseudostratified columnar
which can be separated only in the region of the neck epithelium. The mucosa is arranged in elongated folds
of the bladder. Here, they are arranged as a thin inner because of the organization of the fibroelastic lamina
longitudinal layer, a thick middle circular layer, and a propria. Along the entire length of the urethra are
thin outer longitudinal layer. The middle circular layer numerous clear, mucus-secreting glands of Littre.
forms the internal sphincter muscle around the A thin, vascular, erectile coat surrounds the mucosa,
internal orifice of the urethra. resembling the corpus spongiosum of the male. The
The adventitia of the bladder is composed of a dense, muscular layer of the urethra is continuous with that of
irregular collagenous type of connective tissue contain- the bladder but is composed of two layers only, an inner
ing a generous amount of elastic fibers. Certain regions longitudinal and an outer circular smooth muscle layer.
of the adventitia are covered by a serosa, a peritoneal As the urethra pierces the perineum (urogenital
reflection onto the wall of the bladder, whereas other diaphragm), a sphincter of skeletal muscle surrounds it
regions may be surrounded by fat. and permits voluntary control of micturition.
Urethra Male Urethra

The urethra conveys urine from the urinary bladder to The male urethra is 15 to 20 cm long, and its three
outside the body. regions are named according to the structures through
which it passes:
The urinary bladder is drained by a single tubular struc- 䡲 The prostatic urethra, 3 to 4 cm long, lies entirely
ture, the urethra, which communicates with the outside, in the prostate gland. It is lined by a transitional
permitting elimination of urine from the body. As the epithelium and receives the openings of many tiny
urethra pierces the perineum, skeletal muscle fibers ducts of the prostate, the prostatic utricle (a rudi-
form the external sphincter muscle surrounding the mentary homologue of the uterus), and the paired
urethra. This muscle permits voluntary control of mic- ejaculatory ducts.
turition. The urethra of the male is longer than that of 䡲 The membranous urethra is only 1 to 2 cm long.
the female and has a dual function, acting as a route for This segment is so-named because it passes through
semen as well as for urine. the perineal membrane (urogenital diaphragm). It
is lined by stratified columnar epithelium inter-
spersed with patches of pseudostratified columnar
CLINICAL CORRELATIONS epithelium.
䡲 The spongy urethra (penile urethra), the longest
Loss of voluntary control over the external portion of the urethra (15 cm long), passes through
sphincter muscle of the urethra causes urinary the length of the penis, terminating at the tip of the
incontinence, a condition affecting primarily glans penis as the external urethral orifice. This
older women. segment is so-named because it is located in the
corpus spongiosum. It is lined by stratified columnar
epithelium interspersed with patches of pseudostrati-
fied columnar and stratified squamous nonkeratinized
Female Urethra epithelia. The enlarged terminal portion of the ure-
thra in the glans penis (the navicular fossa) is lined
The female urethra is about 4 to 5 cm in length and by stratified squamous nonkeratinized epithelium.
5 to 6 mm in diameter. It extends from the urinary
bladder to the external urethral orifice just above and The lamina propria of all three regions is composed
anterior to the opening of the vagina. Normally, the of a loose fibroelastic connective tissue with a rich vas-
lumen is collapsed except during micturition. It is lined cular supply. It houses numerous glands of Littre,
by a transitional epithelium near the bladder and by whose mucous secretion lubricates the epithelial lining
a stratified squamous nonkeratinized epithelium of the urethra.
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20 䡲䡲䡲
Female
Reproductive System
The female reproductive system consists of the internal The paired ovaries, located within the pelvis, are
reproductive organs (the paired ovaries and oviducts, almond-shaped bodies 3 cm long, 1.5 to 2 cm wide, and
the uterus, and the vagina; Fig. 20-1), and the the exter- 1 cm thick, each weighing approximately 14 g. The
nal genitalia (the clitoris, the labia majora, and the labia ovaries are suspended in the broad ligament of the
minora). Although the mammary glands are not con- uterus by an attachment called the mesovarium,
sidered part of the female reproductive system, their a special fold of the peritoneum that conveys blood
physiology and function are so closely associated with vessels to the ovaries (see Fig. 20-1).
the reproductive system that they are discussed in this The surface epithelium covering the ovaries, called
chapter. the germinal epithelium, is a modified peritoneum.
The reproductive organs are incompletely developed This low cuboidal epithelium, derived from the
and remain in a state of rest until gonadotropic hor- mesothelial epithelium covering the developing
mones secreted by the pituitary gland signal the initia- ovaries, was originally believed to give rise to the germ
tion of puberty. Thereafter, many changes take place in cells; although this is now known to be untrue, the name
the entire reproductive system, including further dif- persists. Directly beneath this epithelium is the tunica
ferentiation of the reproductive organs, culminating in albuginea, a poorly vascularized, dense, irregular
menarche, the first menstrual flow, occurring from collagenous connective tissue capsule whose collagen
about 9 to 15 years of age, with the average age 12.7 fibers are oriented more or less parallel to the ovary
years. After the first menstrual flow, the menstrual surface. Each ovary is subdivided into the highly cellu-
cycle, which involves many hormonal, histological, and lar cortex and a medulla, which consists mostly of a
psychological changes, is repeated approximately each richly vascularized loose connective tissue. The blood
month (28 days) throughout the entire reproductive vessels of the medulla are derived from the ovarian
years, unless it is interrupted by pregnancy. As a woman arteries. Histologically, however, the division between
nears the end of her reproductive years, her menstrual the cortex and the medulla is indistinct.
cycles become less regular as hormonal and neurologi-
cal signals begin to change, initiating menopause. Ovarian Cortex
Eventually, menstrual cycles cease; after menopause,
limited involution of the reproductive organs occurs. The ovarian cortex is composed of the connective tissue
Thus, the female reproductive system is controlled by stroma that houses ovarian follicles in various stages of
complex orchestrations of hormonal, neurological, and development.
psychological factors.
The ovarian cortex is composed of a connective tissue
framework, the stroma (also known as the interstitial
OVARIES compartment), housing fibroblast-like stromal cells
(also known as interstitial cells) as well as ovarian fol-
licles in various stages of development (Fig. 20-2A).
The ovaries, covered by the germinal epithelium, are
Primordial germ cells, called oogonia, develop in
indistinctly divided into a cortex and a medulla.
the yolk sac endoderm shortly after the first month of
463
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464 䡲䡲䡲 Chapter 20 䡲 Female Reproductive System
Uterine tube Isthmus of uterine tube
Ovary Intramural portion

of uterine tube
Endometrium
Myometrium
Adventitia
Round
ligament
Broad
ligament
Infundibulum
Fimbria
Ovary
Mesovarium
Ovarian ligament
Uterus
Bladder
Cervix
Vagina
Figure 20–1 Female reproductive tract. The ovary is sectioned to show the developing follicles. The uterus and fallopian tube are both
open to display their respective lumina.
gestation. They undergo several mitotic divisions and, follicles. Generally, ovulation will occur every 28 days
during the 6th week after fertilization, migrate to the for the next 30 to 40 years, with one oocyte released
germinal ridges to populate the cortex of the develop- each month, for a total of about 450 oocytes released
ing ovaries. Here they continue to undergo mitotic over the reproductive period. The remaining follicles
divisions until near the end of the 5th fetal month. At degenerate and die over the same period of time.
this time, each ovary contains about 5 million to 7
million oogonia. About 1 million of the oogonia become Phenotypic Sexual Development
surrounded by follicular cells and survive to the time of during Embryogenesis
birth. The remaining oogonia do not become incorpo-
rated into follicles. Instead, they undergo atresia; that The default phenotypic development is female.
is, they degenerate and die.
The oogonia that survive enter the prophase stage During early embryogenesis, in the absence of both
of meiosis I and are known as primary oocytes (Fig. testosterone and antimüllerian hormone, the default
20-3). Meiosis is then arrested in the diplotene stage phenotypic development is that of a female. The lack of
by paracrine factors such as meiosis-preventing testosterone does not permit the development of the
substance, produced by the follicular cells. Primary wolffian ducts, the precursor of the male genital tract,
oocytes remain in that phase until just before ovulation, and the lack of antimüllerian hormone permits the
when they are triggered, in response to the surge of development of the müllerian ducts, the precursor of
luteinizing hormone (LH), and by meiosis-inducing the female genital tract.
substance to complete their first meiotic division,
forming the secondary oocyte and the first polar body.
The Ovarian Cortex at Onset
Of the 1 million oogonia that survive to become in- of Puberty
corporated into the primordial follicles, 600,000 become
The pulsatile release of gonadotropin-releasing hormone
atretic over the next decade or so of life, and at menar-
has the major responsibility for the initiation of puberty.
che a young woman has only about 300,000 to 400,000
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Chapter 20 䡲 Female Reproductive System ■ ■ ■ 465
Primordial follicle
Primordial Follicular cell
Primary follicle follicle Oocyte
Multilaminar Primary Basal lamina

primary follicle
follicle Follicular cells
Corpus
albicans Multilaminar
Secondary follicle primary Theca folliculi
follicle Zona pellucida
Follicular cells
Corpus
luteum:
Theca folliculi
Theca
Granulosa cells
lutein
Secondary Zona pellucida
Granulosa
follicle Basement membrane
lutein
Theca externa
Graafian Theca interna
follicle Membrana
granulosa
Corona radiata
Graafian
follicle Antrum
Oocyte in the
cumulus
oophorus
Zona
pellucida
Discharged
oocyte
Corona radiata
A B
Figure 20–2 Ovarian structure (A) and follicular development (B). Note the corpus luteum and corpus albicans. All the stages of follicu-
lar development, from the primordial follicle stage to the graafian follicle stage, are presented.
Before the onset of puberty, all of the follicles of the The pulsatile release of LHRH results in a similar,
ovarian cortex are in the primordial follicle stage. pulsatile, release of gonadotropins (follicle-stimulating
The decapeptide luteinizing hormone-releasing hormone [FSH], and LH) from the basophils of
hormone (LHRH), also known as gonadotropin- the anterior pituitary that culminates in the com-
releasing hormone (GnRH), produced by the neu- mencement of follicular development and the onset of
rosecretory neurons of the arcuate nucleus and preoptic the ovulatory cycle. The ovulatory cycle, follicular
area of the hypothalamus, plays a major role in initiat- development, and the hormonal interrelationships are
ing puberty. It is interesting that release of LHRH is described next.
pulsatile, occurring approximately every 90 minutes,
and that its half-life in the bloodstream is only about 2
to 4 minutes. The pulsatility of LHRH release is a pre- Ovarian Follicles
requisite not only for the onset of menarche but also for
Ovarian follicles evolve through four developmental
the maintenance of the normal ovulatory and menstrual
stages: primordial, primary, secondary, and graafian.
cycles throughout the reproductive life of the female.
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development usually culminates in the release of a

single oocyte (ovulation).
P
Primordial Follicles
Primordial follicles, composed of a single layer of
flattened follicular cells that surround the primary
oocyte, are separated from the ovarian stroma by a
St basement membrane.
Primordial follicles, the most primitive follicles, are

abundant before birth, after which they become fewer
GE in number. The primordial follicle is composed of a
P primary oocyte surrounded by a single layer of flat-
tened follicular cells (Fig. 20-4; also see Fig. 20-3).
The primary oocyte (arrested in the prophase
stage of meiosis I) is a spherical cell about 25 µm in
diameter. It has a large, acentric nucleus containing a
single nucleolus. The nucleoplasm appears vesicular
because of the uncoiled chromosomes. The organelles
include numerous mitochondria, abundant Golgi com-
plexes, rough endoplasmic reticulum (RER) displaying
only a few ribosomes, and occasional annulate lamellae.
The squamous follicular cells completely surround
Figure 20–3 Light micrograph of the ovarian cortex demon- the primary oocyte and are attached to each other by
strating mostly primordial follicles (P), which are primary oocytes sur- desmosomes. They are separated from the connective
rounded by follicular cells (×270). The germinal epithelium (GE) tissue stroma by a basal lamina.
and the ovarian stroma (St) of the cortex also are evident in this
micrograph.
Primary Follicles
There are two types of primary follicles, unilaminar and
Ovarian follicles are surrounded by stromal tissue and multilaminar, depending on the number of layers of
consist of a primary oocyte and its associated follicu- follicular cells that surround the primary oocyte.
lar cells (granulosa cells) arranged in a single spher-
ical layer or several concentric layers around the Primordial follicles develop into primary follicles (see
primary oocyte. Follicular cells, similar to the germinal Fig. 20-3) distinguished as a result of changes in the
epithelium, are derived from the mesothelial epithe- primary oocyte, the follicular cells, and the surrounding
lium and possibly also from a second source, the prim- stromal tissue.
itive sex cords of the mesonephros, a precursor of The primary oocyte grows to about 100 to 150 µm
the metanephros, the structure that develops into the in diameter with an enlarged nucleus (sometimes called
definitive kidney. the germinal vesicle). Several Golgi complexes are
There are two stages of follicular development based scattered throughout the cell, the RER becomes rich
on the growth of the follicle; the stages also are catego- with ribosomes, free ribosomes are abundant, and mito-
rized by the development of the oocyte and of the fol- chondria are numerous and dispersed throughout the
licular cells (Table 20-1; also see Fig. 20-2B): cell.
Follicular cells become cuboidal in shape. As long
䡲 Nongrowing, or primordial, follicles
as only a single layer of follicular cells encircles the
䡲 Growing follicles
oocyte, the follicle is called a unilaminar primary fol-
䡲 Unilaminar and multilaminar primary follicles
licle. When the follicular cells proliferate and stratify,
䡲 Secondary (antral) follicles
forming several layers of cells around the primary
䡲 Graafian (mature) follicles
oocyte, the follicle is called a multilaminar primary
The development of the primary follicles is inde- follicle, and the follicular cells are more commonly
pendent of FSH; instead, the differentiation and prolif- referred to as granulosa cells. The proliferative activ-
eration of the follicular cells are triggered by as yet ity of the granulosa cells is due to the signaling mole-
uncharacterized local factors secreted probably by the cule activin produced by the primary oocyte.
follicular cells of the ovary. Secondary and later follicles, During this stage, an amorphous substance (the
however, are under the influence of FSH. Follicular zona pellucida) appears, separating the oocyte from
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TABLE 20–1 Stages of Ovarian Follicular Development
Follicular
FSH- Zona Cells or Liquor Theca Theca
Stage Dependent Oocyte Pellucida Granulosa Folliculi Interna Externa
Primordial No Primary None Single layer None None None

follicle of flat cells
Unilaminar No Primary Present Single layer None None None

primary of cuboidal
follicle cells
Multilaminar No Primary Present; Several layers None Present Present

primary plasmalemma of follicular
follicle of primary cells (now
oocyte forms called
gap junctions granulosa
with filopodia cells)
of corona
radiata cells
Secondary Yes Primary Present with Spaces Accumulates Present Present

follicle gap junctions develop in spaces
between between
granulosa granulosa
cells cells
Graafian Yes, until it Primary, Present with Forms Fills the Present Present
follicle becomes surrounded gap junctions membrana antrum
the by corona granulosa
dominant radiata in and
follicle cumulus cumulus
oophorus oophorus
FSH, follicle-stimulating hormone.

graph of a primordial ovarian follicle
of a rat ovary (×6200). Observe the
oocyte surrounded by follicular cells.
(From Leardkamolkarn V, Abraham-
son DR: Immunoelectron micro-
scopic localization of laminin in rat
ovarian follicles. Anat Rec 233:4152,
1992.)
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the surrounding follicular cells. The zonula pellucida is

composed of three different glycoproteins, ZP1, ZP2,
and ZP3, secreted by the oocyte. Filopodia of the fol-
licular cells invade the zonula pellucida, come in contact
with the oocyte plasmalemma and form gap junctions T
through which they communicate with the oocyte
throughout follicular development. The presence of gap
junctions is necessary for the oocyte to be able to G
progress through meiosis.
Stromal cells begin to be organized around the LF
multilaminar primary follicle, forming an inner theca
interna, composed mostly of a richly vascularized cel-
lular layer, and an outer theca externa, composed
mostly of fibrous connective tissue. The cells compos-
ing the theca interna possess LH receptors on their
plasmalemma, and these cells assume the ultrastruc-
tural characteristics of steroid-producing cells. Their
cytoplasm accumulates numerous lipid droplets and
has abundant smooth endoplasmic reticulum (SER),
and the cristae of their mitochondria are tubular.
These theca interna cells produce the male sex hor-
mone androstenedione, which enters the granulosa
cells where it is converted by the enzyme aromatase
into the estrogen estradiol. The granulosa cells are sep-
arated from the theca interna by a thickened basal Figure 20–5 Light micrograph of a secondary follicle (×132).
lamina. Observe the primary oocyte and the follicular fluid surrounded by
membrana granulosa. Note also the presence of the basement mem-
brane between the granulosa cells (G) and the theca interna (T). LF,
Secondary (Antral) Follicles liquor folliculi.
Secondary follicles are similar to primary follicles except

for the presence of accumulations of liquor folliculi
among the granulosa cells. the granulosa cells to manufacture receptors for LH,
which become incorporated into their plasmalemma.
The multilaminar primary follicle continues to develop As more fluid is produced, individual droplets of
and increase in size, reaching up to 200 µm in diame- liquor folliculi coalesce to form a single, fluid-filled
ter. A large spherical follicle is formed with numerous chamber, the antrum. The granulosa cells become
layers of granulosa cells around the primary oocyte rearranged so that the primary oocyte is now sur-
(whose size from this point on remains constant). rounded by a small group of granulosa cells that project
Several intercellular spaces develop within the mass out from the wall into the fluid-filled antrum. This struc-
of granulosa cells and become filled with a fluid known ture is called the cumulus oophorus. The loosely
as liquor folliculi. Once the multilaminar primary arranged low cuboidal granulosa cells immediately
follicle displays the presence of liquor folliculi, it is adjacent to the zona pellucida move slightly away from
known as a secondary follicle (Fig. 20-5; also see the oocyte, but their filopodia remain within the zona
Fig. 20-2B). pellucida, maintaining contact with the primary oocyte.
Continued proliferation of the granulosa cells of This single layer of granulosa cells that immediately sur-
the secondary follicle depends on FSH released by rounds the primary oocyte is called the corona radiata.
basophil cells of the anterior pituitary. Under the influ- At this time two different types of granulosa cells may
ence of FSH, the number of layers of the granulosa be distinguished: membrana granulosa and cumulus
cells increases, as does the number of liquor folliculi– granulosa cells (Table 20-2).
containing intercellular spaces. This fluid, an exudate of Toward the end of this stage, stromal cells become
plasma, contains glycosaminoglycans, proteoglycans, enlarged and the theca interna is invaded by capillaries
and steroid-binding proteins produced by the granulosa that nourish them as well as the avascular granulosa
cells. Moreover, it contains the hormones proges- cells. Most of the follicles that reach this stage of devel-
terone, estradiol, inhibin, folliostatin (folliculo- opment undergo atresia, but some of the granulosa cells
statin), and activin, which regulate the release of LH associated with the atretic follicles do not degenerate;
and FSH. In addition, FSH (along with estrogen) induces instead, they form interstitial glands, which secrete
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ated follicular cells to become detached from its base to

TABLE 20–2 Types of Granulosa Cells float freely within the liquor folliculi (see Fig. 20-2B).
Cell Type Characteristics Ovulation

Membrana granulosa The process of releasing the secondary oocyte from the
graafian follicle is known as ovulation.
Granulosa mural Abut the basement membrane
cells Have LH and FSH receptors By the 14th day of the menstrual cycle, estrogen pro-
Function in steroidogenesis duced mostly by the developing graafian follicle, but also
due to the presence of the
by secondary follicles, causes elevation of blood estrogen
enzyme aromatase (estradiol,
progesterone) to levels high enough to have the following effects:
Produce the regulatory 䡲 Negative feedback inhibition shuts off FSH release
hormones activin, inhibin, by the anterior pituitary.
folliculostatin, and insulin- 䡲 A sudden surge of LH is released by basophils of the
like growth factor type I
anterior pituitary.
Form the bulk of the corpus
luteum The surge in LH levels results in increased blood
flow to the ovaries, and capillaries within the theca
Antral granulosa Line the antrum
cells Are not active in externa begin leaking plasma, resulting in edema.
steroidogenesis Concomitant with edema formation, histamine, prosta-
glandins, and collagenase are released in the vicinity of
Cumulus oophorus Surround the oocyte the graafian follicle. Additionally, plasminogen activator
granulosa cells Contact the oocyte level, the enzyme that catalyzes the conversion of plas-
plasmalemma by their minogen to plasmin, increases in the follicle, and the
filopodia newly formed plasmin facilitates the proteolysis of the
Do not possess many LH
membrana granulosa, permitting ovulation to occur.
receptors
Divide to form cells of the In addition, the LH surge is responsible for the fol-
membrana granulosa lowing events:
Are ovulated along with the 1 A local factor, meiosis-inducing substance, is
oocyte released.
2 Under the influence of meiosis-inducing substance,
FSH, follicle-stimulating hormone; LH, luteinizing hormone.
the primary oocyte of the graafian follicle resumes
and completes its first meiotic division, resulting in
the formation of two daughter cells, the secondary
small amounts of androgens until menopause is con- oocyte and the first polar body. Because of the
cluded. A few secondary follicles continue to develop uneven distribution of the cytoplasm, the first polar
into mature follicles. body is composed of a nucleus surrounded by only a
narrow rim of cytoplasm.
Graafian (Mature) Follicles 3 The newly formed secondary oocyte enters the
second meiotic division and is arrested in
Graafian follicles, also known as mature follicles, may be metaphase.
as large as the entire ovary; it is these follicles that 4 The presence and continued formation of proteogly-
undergo ovulation. cans and hyaluronic acid by the granulosa cells attract
water, thus causing an even greater increase not only
Continued proliferation of the granulosa cells and con- in the size of the graafian follicle but also in the loos-
tinued formation of liquor folliculi result in the forma- ening of the membrana granulosa.
tion of a graafian (mature) follicle whose diameter may 5 Just before ovulation, the surface of the ovary, where
reach as much as 2.5 cm by the time of ovulation. The the graafian follicle is pressing against the tunica
graafian follicle may be observed as a transparent bulge albuginea, loses its blood supply.
on the surface of the ovary, nearly as large as the ovary 6 This thinned, avascular region becomes blanched and
itself. is known as the stigma. The connective tissue at the
The follicular cells of the wall of the follicle compose stigma degenerates, as does the wall of the graafian
the membrana granulosa. Continued formation of follicle in contact with the stigma, forming an
liquor folliculi causes the cumulus oophorus composed opening between the peritoneal cavity and the
of the primary oocyte, the corona radiata, and associ- antrum of the graafian follicle.
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7 Through this opening, the secondary oocyte and its

attendant follicular cells and some of the liquor folli-
culi are gently released from the ovary, resulting in
ovulation. Although the average menstrual cycle is
28 days long, some cycles are longer and others are
shorter; however, ovulation is always on the 14th day
before the beginning of menstruation. T
8 The remnants of the graafian follicle are converted
into the corpus hemorrhagicum and then into the
corpus luteum.
The distal, fimbriated end of the oviduct, which
presses against the ovary, whisks the secondary oocyte
and follicular cells into the infundibulum of the
oviduct to begin the journey into the ampulla, where
the oocyte may be fertilized (see Fig. 20-1). If it is not G
fertilized within approximately 24 hours, the secondary
oocyte degenerates and is phagocytosed. The process of
fertilization is discussed later in the chapter.
Corpus Luteum
The corpus luteum, formed from the remnants of the
graafian follicle, is a temporary endocrine gland that
manufactures and releases hormones that support the Figure 20–6 Light micrograph of the corpus luteum (×132).
uterine endometrium. Note the difference between the large granulosa-lutein (G) and small
theca-lutein (T) cells.
After the secondary oocyte and its associated cells are
ovulated, the remainder of the graafian follicle collapses
and becomes folded; some of the ruptured blood vessels Theca-Lutein Cells
leak blood into the follicular cavity, forming a central
clot. The resulting structure is known as the corpus Theca-lutein cells, derived from the cells of the theca
hemorrhagicum. As the clot is removed by phagocytes, interna, secrete progesterone, androgens, and estrogens.
continued high levels of LH convert the corpus hemor-
rhagicum into a temporary structure known as the The theca interna cells at the periphery of the corpus
corpus luteum, which functions as an endocrine gland luteum account for about 20% of the luteal cell popu-
(Fig. 20-6). This highly vascularized structure is com- lation. These dark-staining cells remain small (15 µm in
posed of granulosa-lutein cells (modified granulosa cells) diameter) but become modified into hormone-secreting
and theca-lutein cells (modified theca interna cells). cells known as theca-lutein cells. They specialize in
the production of progesterone, some estrogens, and
Granulosa-Lutein Cells androgens.
Granulosa cells of the graafian follicle differentiate into Degeneration of Corpus Luteum
hormone-producing granulosa-lutein cells.
The absence of LH leads to the degeneration of the
The granulosa cells remaining in the central region of corpus luteum.
the follicle account for about 80% of the cell population
of the corpus luteum. They become modified into large, Progesterone and estrogens secreted by granulosa-
pale-staining cells (30 to 50 µm in diameter) called lutein and theca-lutein cells inhibit the secretion of LH
granulosa-lutein cells. These cells have many long and FSH, respectively. The absence of FSH prevents
microvilli and develop all of the organelles necessary for the development of new follicles, thus preventing a
steroid production, including abundant SER and RER, second ovulation. If pregnancy does not occur, the
abundant mitochondria, several well-developed Golgi absence of LH leads to degeneration of the corpus
complexes, and some lipid droplets scattered through- luteum, forming the corpus luteum of menstruation.
out the cytoplasm (Fig. 20-7). The granulosa-lutein cells If pregnancy occurs, human chorionic gonadotropin
produce progesterone and convert androgens pro- (hCG), secreted by the placenta, maintains the corpus
duced by the theca-lutein cells into estrogens. luteum for 3 months. Now called the corpus luteum
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process known as luteolysis, and are phagocytosed by

macrophages. The fibrous connective tissue that forms in
its place is known as the corpus albicans and persists for
some time before being resorbed. The remnants of the
corpus albicans persist as a scar on the surface of the ovary.
Atretic Follicles
N
Follicles that undergo degeneration are known as atretic
follicles.
The ovaries contain many follicles in various stages of

development. Most follicles degenerate before reaching
the mature stage, but multiple graafian follicles develop
RER during each menstrual cycle. Nevertheless, once a single
mature follicle ruptures and releases its secondary
G
M oocyte and associated cells, the remaining maturing
follicles undergo atresia; the resulting atretic follicles
are eventually phagocytosed by macrophages. Thus,
normally, only a single follicle ovulates during each men-
strual cycle. Occasionally, two separate follicles develop
SER to maturity and ovulate, leading to fraternal twins if
L
both oocytes are fertilized. Although about 2% of all fol-
licles reach the mature stage and are primed to undergo
ovulation, only 5% to 6% of these actually do. Of all the
follicles present in the ovaries at menarche, just 0.1%
to 0.2% develop to maturity and undergo ovulation.
Ovarian Medulla
Figure 20–7 Electron micrograph of a rhesus monkey granu- The ovarian medulla is a richly vascularized fibroelastic
losa-lutein cell with its large acentric nucleus and numerous organelles connective tissue housing connective tissue cells,
(×6800). G, Golgi apparatus; L, lipid droplet; M, mitochondria (dis- interstitial cells, and hilar cells.
played at a higher magnification in inset, lower left); N, nucleus; RER,
rough endoplasmic reticulum; SER, smooth endoplasmic reticulum. The central region of the ovary, the medulla, is com-
(From Booher C, Enders AC, Hendrick X, Hess DL: Structural char-
acteristics of the corpus luteum during implantation in the rhesus
posed of fibroblasts loosely embedded in a collagen-
monkey (Macaca mulatta). Am J Anat 160:1736, 1981.) rich meshwork containing elastic fibers (see Fig. 20-2A).
The medulla also contains large blood vessels, lymph
vessels, and nerve fibers. The medulla of the premen-
of pregnancy, it grows to a diameter of 5 cm and con- strual human ovary has a few clusters of epithelioid
tinues to secrete hormones necessary for the mainte- interstitial cells that secrete estrogens. In mammals
nance of pregnancy. Although the placenta becomes having large litters, the ovaries contain many clusters of
the main site of production of the various hormones these interstitial cells, which collectively are called the
involved in maintaining pregnancy 2 to 3 months after interstitial gland. In humans, most of these intersti-
its formation, the corpus luteum continues to form tial cells involute during the first menstrual cycle and
these hormones for several months (see later). have little, if any, function.
Hilus cells constitute another group of epithelioid
Corpus Albicans cells in the ovarian medulla. These cells have a similar
configuration of organelles and contain the same sub-
As the corpus luteum degenerates and is being stances in their cytoplasm as Leydig cells of the testes.
phagocytosed by macrophages, fibroblasts enter, These cells secrete androgens.
manufacture type I collagen, and form a fibrous
structure known as the corpus albicans. Summary of Hormonal Regulation
of Ovarian Function
The corpus luteum of menstruation (and also of preg-
nancy) is invaded by fibroblasts, becomes fibrotic, and As mentioned previously, FSH and LH regulate matu-
ceases to function. Its remnants undergo autolysis, a ration of ovarian follicles and ovulation. The pulsatile
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Hypothalamus
LHRH
Estradiol
Progesterone
Anterior
pituitary
Estradiol
Progesterone
Estradiol
FSH Progesterone
LH
Ovulation Corpus luteum
Folliostatin
Inhibin
Activin
Figure 20–8 Hormonal interactions
between the hypothalamo-pituitary axis
and the female reproductive system.
FSH, follicle-stimulating hormone; LH,
Follicular development Estradiol luteinizing hormone; LHRH, luteiniz-
Progesterone ing hormone–releasing hormone. Note
Relaxin that folliostatin and inhibin both sup-
press FSH release, whereas activin
Female tissue facilitates its release.
secretion of these gonadotropic hormones, which are the granulosa cells of secondary follicles stimulates
produced in the pars distalis of the anterior pituitary, is their development into graafian follicles. FSH also
in turn controlled by LHRH released in a pulsatile induces the theca interna cells of developing follicles to
manner, every 90 minutes or so, by neurosecretory express LH receptors. LH binds to these receptors, thus
neurons located in the arcuate nucleus of the hypothal- inducing the theca interna cells to produce androgens
amus (Fig. 20-8 and Table 20-3). The pulsatility of from cholesterol. Androgens, released from the theca
LHRH release is essential for the normal functioning of interna cells, cross the basement membrane and enter
the female ovulatory cycle because the up-regulation the granulosa cells. The enzyme aromatase of the
of LHRH receptors on basophils of the pars anterior of granulosa cells converts androgens into estrogens. The
the pituitary gland can occur only if the pulsatility is granulosa cells of secondary follicles also produce
maintained between 60 and 90 minutes (Table 20-4). several other hormones, (e.g., inhibin, folliostatin,
Although it is unclear what signal stimulates primor- activin) that help to regulate release of FSH (see
dial and early (unilaminar) primary follicles to develop, Fig. 20-8).
it is known that the signaling molecule activin, pro- As the blood levels of estrogen and other hormones
duced by granulosa cells, stimulates release of FSH produced by the granulosa cells rise, they continue to
from the pituitary which, in turn, results not only in the stimulate production of LH by the basophils of the ante-
proliferation of the granulosa cells of secondary and rior pituitary. When the blood concentration of estro-
more developed follicles but also in enhancing the gen reaches a threshold level, it restricts secretion of
actions of FSH in those follicles. The development of FSH in two ways: indirectly, by suppressing LHRH
the early follicles appears to be independent of FSH, release from the hypothalamus, and directly, by inhibit-
whereas continued development of secondary follicles ing FSH release from the anterior pituitary.
into graafian follicles depends on FSH. Just before the midpoint of the menstrual cycle (the
Binding of LHRH to receptors on the basophils of 14th day before onset of menstruation), the high estro-
the pars distalis induces the release of stored FSH and gen level in the blood causes a surge of LH by
LH and stimulates continued FSH and LH synthesis. gonadotrophs of the pituitary gland. The sudden high
Subsequent binding of FSH to specific receptors on blood LH level stimulates the primary oocyte (by acti-
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TABLE 20–3 Major Hormones Involved in the Female Reproductive System
Hormone Source Function
Luteinizing Hypothalamus Stimulates release of FSH and LH from anterior pituitary

hormone–releasing gland
hormone (LHRH)
Prolactin-inhibiting Hypothalamus Inhibits release of prolactin by acidophils of anterior

factor pituitary gland
Follicle-stimulating Basophils of anterior pituitary Stimulates secretion of estrogen and development of

hormone (FSH) gland ovarian follicles (from secondary follicle onward)
Luteinizing Basophils of anterior pituitary Stimulates formation of estrogen and progesterone;

hormone (LH) gland promotes ovulation and formation of corpus luteum
Estrogens Granulosa cells of ovary; Inhibits release of FSH and LHRH; triggers surge of LH;
granulosa-lutein cells of causes proliferation and hypertrophy of myometrium of
corpus luteum; and the uterus; causes development of female sexual
placenta characteristics, including breasts and body fat
Progesterone Granulosa cells of ovary; Inhibits release of LHRH from hypothalamus and of LH
theca-lutein and granulosa- from basophils of the anterior pituitary; causes
lutein cells of corpus development of uterine endometrium and regulates
luteum; placenta viscosity of mucus produced by glands of uterine cervix;
causes development of female sexual characteristics
including breasts
Inhibin Granulosa cells of ovary; Inhibits FSH secretion by basophils of the anterior
granulosa-lutein cells of pituitary
corpus luteum
Activin Oocyte Promotes granulosa cell proliferation
Human chorionic Placenta Assists in maintenance of corpus luteum; promotes release

gonadotropin of progesterone
(hCG)
Human placental Placenta Promotes mammary gland development during pregnancy;

lactogen promotes lactogenesis
Relaxin Placenta Facilitates parturition by softening the fibrocartilage of
pubic symphysis; softens the cervix and facilitates its
dilation in preparation for parturition
Oxytocin Hypothalamus via the Stimulates smooth muscle contraction of uterus during
posterior pituitary orgasm and during parturition; stimulates contraction of
myoepithelial cells of mammary gland, assisting in milk
ejection
vating meiosis-inducing substance) to complete meiosis interna cells of the remaining ovulated follicle, both of
I, forming a secondary oocyte and the first polar body. which have LH receptors, are activated by LH to form
The secondary oocyte then enters meiosis II and pro- the corpus luteum. The granulosa cells and the theca
ceeds to metaphase. Meiosis II is interrupted in interna cells are converted into granulosa-lutein cells
metaphase until fertilization triggers its completion. and theca-lutein cells, respectively. Both of these luteal
This surge of LH also launches the process of ovu- cell types now actively produce progesterone,
lation, whereby the secondary oocyte is expelled from although most of it is produced by the granulosa-lutein
the mature follicle. The granulosa cells and theca cell. In addition, inhibin, folliostatin, and activin-
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TABLE 20–4 Pulsatility Rate of LHRH Release
Rate of Release Direct Results Effects of Direct Results
Less than 60 minutes Down-regulates LHRH receptor formation Anovulation due to lack of gonadotropin
responsivity
Greater than 90 minutes Inadequate stimulation of basophils Anovulation and amenorrhea
Between 60 and 90 Adequate number of LHRH receptors on Normal ovulatory cycle

minutes basophils
LHRH, luteinizing hormone–releasing hormone.
feedback regulators of FSH release continue to be pro- nant follicle stage, it has to pass through three ovulatory
duced by the corpus luteum. cycles; once the follicle becomes dominant, it still has
If fertilization and implantation do not occur, the to wait for about 15 days before it can become ovulated.
secretory activity of the corpus luteum continues for Thus the period of time that has to pass between the
about 14 days and the organ is called the corpus multilaminar primary follicle stage and ovulation is
luteum of menstruation. When fertilization and approximately 100 days.
implantation occur, the corpus luteum increases in size
and the organ is known as the corpus luteum of preg- Oviducts (Fallopian Tubes)
nancy. This organ continues its secretory function even
though the placenta assumes the primary responsibility The oviducts act as a conduit for spermatozoa to reach
for hormonal regulation (see Fig. 20-8). the primary oocyte and to convey the fertilized egg to
Progesterone stimulates development of the uterine the uterus.
endometrium during each menstrual cycle and inhibits
the production of LH directly and indirectly (acting on The oviducts, or fallopian tubes, are paired, muscular-
both the hypothalamus and the pituitary gonadotrophs). walled tubular structures approximately 12 cm long,
In the absence of pregnancy, LH level soon falls below each with an open end and an attached end (see Fig.
that required to maintain the corpus luteum, and the 20-1). The oviducts become continuous with the wall of
process of corpus luteum degeneration begins. If preg- the uterus at their attached ends, where they traverse
nancy occurs, hCG produced by the placenta provides the uterine wall to open into its lumen. The free ends
positive feedback to the corpus luteum of pregnancy, open into the peritoneal cavity close to the ovaries.
thereby maintaining the production of progesterone The oviducts are divided into four anatomical
early in pregnancy. By the 4th month of pregnancy, regions:
much of the hormonal control is assumed by the pla-
䡲 Beginning at the open end is the infundibulum,
centa. Another hormone, relaxin, produced by the
whose open end is fringed with projections called
placenta, facilitates parturition by softening of the fibro-
fimbriae. These fimbriae help to capture the sec-
cartilage of the pubic symphysis to ease the widening of
ondary oocyte.
the pelvic outlet.
䡲 The expanded ampulla is where fertilization usually
Although as many as 50 follicles begin to mature in
takes place.
each menstrual cycle and as many as five may reach the 䡲 The isthmus is the narrowed portion between the
graafian follicle stage, usually only one of these follicles ampulla and the uterus.
ovulates. The precise reason is not known; however,
䡲 The intramural region passes through the uterine
when a graafian follicle reaches a particular stage of wall to open into the lumen of the uterus.
development, when it is known as the dominant folli-
cle, it is no longer FSH-dependent. The dominant fol- The oviducts are covered by visceral peritoneum.
licle begins to produce large quantities of inhibin, the Their walls are composed of three layers (Fig. 20-9):
hormone that suppresses FSH release by the anterior 䡲 Mucosa
pituitary. The lack of FSH, in turn, causes the remain- 䡲 Muscularis
ing graafian follicles that are still FSH-dependent to 䡲 Serosa
atrophy, leaving only the dominant graafian follicle in
the position of becoming ready for ovulation. In order The mucosa is characterized by many longitudinal
for a multilaminar primary follicle to reach the domi- folds. These folds are present in all four regions of the
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ovum is fertilized, the same secretions provide nutrients

to the embryo during the initial phases of its develop-
ment. The secretions of peg cells coupled with the
movement of the fluid toward the uterus inhibit
microorganisms in the uterus from moving to the
oviduct and into the peritoneal cavity.
The cilia of the columnar ciliated cells beat in
M unison toward the uterus. As a result, the fertilized
ovum, spermatozoa, and the viscous liquid produced
by the peg cells are all propelled toward the uterus
(Fig. 20-10).
The lamina propria of the oviduct mucosa is unre-
markable; it is composed of loose connective tissue con-
taining fibroblasts, mast cells, lymphoid cells, collagen,
and reticular fibers. The muscularis consists of poorly
defined inner circular and outer longitudinal layers of
smooth muscle. Loose connective tissue also fills spaces
I between the bundles of muscle. A simple squamous
epithelium provides the serosal covering of the
oviduct. The loose connective tissue between the serosa
and the muscularis contains many blood vessels and
autonomic nerve fibers.
Because the oviducts are so richly vascularized with
mostly large veins, contractions of the muscularis during
O ovulation constrict the engorged veins. This constriction
causes distention of the entire oviduct and brings the
fimbriae into contact with the ovary, thereby aiding the
capture of the released secondary oocyte. Continued
Figure 20–9 Light micrograph of the oviduct in cross section
(×132). Observe the outer longitudinal (O) and inner circular (I) rhythmic contractions of the layers of the muscularis,
muscle layers and the mucosa (M). The mucosa is thrown into folds coupled with the beating of the cilia within, help to
that reduce the size of the lumen. propel the captured oocyte to the uterus.
Uterus
oviduct but are most pronounced in the ampulla, where
they branch; in the other regions, the mucosal folds
The uterus is a muscular organ consisting of a fundus,
are reduced to low elevations. The simple columnar
body, and cervix.
epithelium that lines the lumen is tallest in the infun-
dibulum and shortens as the oviduct approaches the The uterus, a single, thick, pear-shaped structure
uterus. Two different cell types constitute this epithelium: located in the midline of the pelvis, receives at its broad,
䡲 Nonciliated peg cells closed end the terminals of the paired oviducts. The
䡲 Ciliated cells uterus is a robust muscular organ about 7 cm long, 4 cm
wide, and 2.5 cm thick. It is divided into three regions
Peg cells have no cilia. They have a secretory func- (see Fig. 20-1):
tion, providing a nutritive and protective environment
for maintaining spermatozoa on their migration route to 䡲 The body, the broad portion into which the oviducts
reach the secondary oocyte. Products within the secre- open
tions of the peg cells facilitate capacitation of sperma- 䡲 The fundus, the rounded base located superior to
tozoa, a process whereby spermatozoa become fully the exit ports of the oviducts in the body
mature and capable of fertilizing the ovum. It is not 䡲 The cervix, the narrow circular portion that pro-
known whether human spermatozoa require capacita- trudes and opens into the vagina
tion, because they are capable of in vitro fertilization of
the ovum without being exposed to the female repro- Body and Fundus
ductive tract. If there is such a requirement, the sojourn
The uterine wall of the body and the fundus is
in the female reproductive tract necessitates only a
composed of an endometrium, myometrium, and either
minimal amount of time. Secretory products also
an adventitia or a serosa.
provide nutrition and protection to the ovum; if the
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oviduct epithelium (×40,000). Note the bulbous
apices of the peg cells as well as the cilia of the
ciliated cells. (From Hollis DE, Frith PA,
Vaughan JD, et al: Ultrastructural changes in the
oviductal epithelium of merino ewes during the
estrous cycle. Am J Anat 171:441-456, 1984.)
Endometrium of the menstrual cycle are controlled by various hor-

mones (see later).
The endometrium is the mucosal lining of the uterus, The endometrium consists of two layers (see
consisting of two layers, the superficial functionalis and Fig. 20-11):
the deeper located basalis. 䡲 The functionalis, a thick, superficial layer that is
sloughed at menstruation
The endometrium, or mucosal lining of the uterus, is
䡲 The basalis, a deep, narrow layer whose glands and
composed of a simple columnar epithelium and a
connective tissue elements proliferate and thereby
lamina propria. The epithelium is composed of non-
regenerate the functionalis during each menstrual
ciliated secretory columnar cells and ciliated
cycle
cells, whereas the lamina propria houses simple
branched tubular glands that extend as far as the The functionalis is vascularized by numerous coiled
myometrium (Fig. 20-11). Although the glandular cells helical arteries, which originate from the arcuate
resemble those of the surface epithelium, there are arteries of the stratum vasculare, located in the middle
no ciliated cells in the glands. The dense, irregular layer of the myometrium. The coiled arteries give rise
collagenous connective tissue of the lamina propria to a rich capillary network that supplies the glands and
is highly cellular and contains star-shaped cells, connective tissue of the functionalis. Another set of
macrophages, leukocytes, and an abundance of reticu- arteries, the straight arteries, also originate from the
lar fibers. The morphological and physiological alter- arcuate arteries but are much shorter and supply only
ations that occur in the endometrium during the phases the basalis.
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Epithelium Uterine gland Secretion Vein
Functional
layer
Endometrium
Basal
layer
Figure 20–11 The uterine endo-

metrium, showing the basal and func- Myometrium
tional layers. The basal layer is supplied
by the straight arteries, whereas the
functional layer is served by the coiled Straight artery Helical artery Arcuate artery
vessels known as helical arteries. and vein
Myometrium of smooth muscle cells or also from differentiation

of undifferentiated cells into smooth muscle
The myometrium is composed of inner longitudinal, fibers.
middle circular, and outer longitudinal layers of smooth Sexual stimulation causes moderate uterine con-
muscle. tractions. During menstruation, the contractions may
be painful in some women. Powerful, rhythmic
The thick muscular wall of the uterus, the myometrium, contractions of the pregnant uterus during delivery
is composed of three layers of smooth muscle. Longi- expel the fetus and later the placenta from the uterus.
tudinal muscle makes up the inner and outer layers, The process of uterine contractions during parturition
whereas the richly vascularized middle layer contains is due to hormonal actions:
mostly circularly arranged smooth muscle bundles.
This richly vascularized region houses the arcuate 䡲 Under the influence of corticotropic hormone, the
arteries and is called the stratum vasculare. As the myometrium and the fetal membranes produce
uterus narrows toward the cervix, the amount of muscle prostaglandins.
tissue diminishes and is replaced by fibrous connective 䡲 The posterior pituitary gland releases the hormone
tissue. At the cervix, the myometrium is composed of oxytocin.
dense, irregular connective tissue containing elastic 䡲 Prostaglandins and oxytocin stimulate uterine
fibers and only a small number of scattered smooth contractions.
muscle cells. 䡲 After delivery, oxytocin continues to stimulate uterine
The size and number of the myometrial muscle contractions, which inhibit excessive blood loss from
cells are related to estrogen levels. The muscle cells the detachment site of the placenta.
are largest and most numerous during pregnancy,
when estrogen levels are the highest; they are smallest
after the conclusion of menstruation, when estrogen
Uterine Serosa and Adventitia
levels are low. When estrogen is absent, the myome- Because the uterus is tipped anteriorly and lies against
trial muscle atrophies, with some cells succumbing the bladder, much of its anterior portion is covered by
to apoptosis. Although most of the increase in uterine adventitia (connective tissue without an epithelial cov-
size during pregnancy is related to hypertrophy of ering); thus, this area is retroperitoneal. The fundus
the smooth muscle cells, the smooth muscle cell and posterior portion of the body are covered by a
population also increases, suggesting that hyper- serosa, composed of a layer of squamous mesothelial
plasia also occurs. However, it is unclear whether cells resting on areolar connective tissue; therefore this
the increase in cell number results only from division area is intraperitoneal.
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At the time of parturition, another luteal hormone,

CLINICAL CORRELATIONS relaxin, induces lysis of collagen in the cervical walls.
This results in a softening of the cervix, thus facilitating
The presence of endometrial tissue in the pelvis cervical dilation.
or in the peritoneal cavity is known as
endometriosis. This often painful condition
may cause dysmenorrhea and even infertility.
The origin of endometrial tissue outside the CLINICAL CORRELATIONS
uterus is not known, but three theories have
The Papanicolaou (“Pap smear”) technique
been proposed.
is a diagnostic tool for detecting cervical cancer.
The regurgitation theory proposes that
It is performed by aspirating cervicular fluid
menstrual flow escapes from the uterus via the
from the vagina or taking scrapings directly from
fallopian tubes to enter the peritoneal cavity. The
the cervix. The tissue or fluid is prepared and
metaplastic theory suggests that the epithelial
stained on a microscope slide and then examined
cells of the peritoneum differentiate into
for variations in the cell populations to detect
endometrial cells. The vascular (lymphatic)
anaplasia, dysplasia, and carcinoma.
dissemination theory proposes that endome-
Cervical carcinoma is one of the most
trial cells enter vascular (or lymphatic) channels
common cancers in women, although it is rare in
during menstruation and are distributed by the
virgins and in nulliparous women (women who
blood (or lymph) vascular system.
have not given birth). The incidence increases in
These extrauterine endometrial tissues also
women with multiple sex partners and herpes
undergo cyclic changes. Hemorrhaging of this
infections. It develops from the stratified squa-
tissue may cause adhesions and extreme pain. If
mous nonkeratinized epithelium of the cervix,
endometriosis is not corrected, the pelvic viscera
where it is called carcinoma in situ. If detected
may be embroiled in a fibrotic mass, possibly
by Pap smear in this stage, it can usually be suc-
resulting in sterility.
cessfully treated with surgery. If not detected
early, however, it may invade other areas and
metastasize, thus changing to invasive carci-
Cervix noma, which carries a poor prognosis.
The cervix—the terminal end of the uterus—extends

into the vagina.
The cervix is the terminal end of the uterus that pro- Menstrual Cycle
trudes into the vagina (see Fig. 20-1). The lumen of the
The menstrual cycle is divided into the menstrual,
cervix is lined by a mucus-secreting simple colum-
proliferative (follicular), and secretory (luteal) phases.
nar epithelium; however, its external surface, where
the cervix protrudes into the vagina, is covered by a Normally, the average menstrual cycle is a 28-day cycle.
stratified squamous nonkeratinized epithelium Although the successive events constituting the cycle
similar to that of the vagina. The wall of the cervix con- occur continuously, they can be described in three
sists mostly of dense, collagenous connective tissue phases: menstrual phase, proliferative (follicular)
containing many elastic fibers and only a few smooth phase, and secretory (luteal) phase (Fig. 20-12).
muscle fibers. Cervical mucosa contains branched cer-
vical glands. Although the cervical mucosa changes Menstrual Phase (Days 1 to 4)
during the menstrual cycle, it does not slough during
menstruation. The menstrual phase of the menstrual cycle is
At the midpoint in the menstrual cycle, around the characterized by the desquamation of the functionalis
time of ovulation, the cervical glands secrete a serous layer of the endometrium.
fluid that facilitates entry of the spermatozoa into the
uterus. At other times, including during pregnancy, the Menstruation, which begins on the day that bleeding
secretions of the cervical glands become more viscous, from the uterus starts, occurs when fertilization does
forming a plug of thickened mucus in the orifice of the not take place. In this case, the corpus luteum becomes
cervix, thus preventing the entry of sperm and microor- nonfunctional about 14 days after ovulation, thus reduc-
ganisms into the uterus. The hormone progesterone ing the levels of progesterone and estrogen.
regulates the changes in the viscosity of the cervical A couple of days before bleeding begins, the functio-
gland secretions. nalis layer of the endometrium becomes deprived of
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Events in ovary
Follicle Corpus luteum
Endometrial changes Ovulation
Menses Preovulatory Postovulatory
0 5 10 15 20 25
Day of menstrual cycle
Hormone levels
FSH Estrogen LH Progesterone
Figure 20–12 Correlation of

events in follicular development, ovu-
lation, hormonal interrelationships,
and the menstrual cycle. Note that the
levels of estrogen and luteinizing
hormone (LH) are highest at the time
of ovulation. FSH, follicle-stimulating
hormone.
blood as the coiled (helical) arteries are intermittently wound of the uterine lumen. These events commence
constricted. After 2 days or so, the coiled arteries the proliferative phase of the menstrual cycle.
become permanently constricted, reducing oxygen to
the functionalis layer, leading to a shutdown of the Proliferative (Follicular) Phase
glands, invasion by leukocytes, ischemia, and eventual (Days 4 to 14)
necrosis of the functionalis. Shortly thereafter, the
coiled arteries dilate once again; however, because these The proliferative phase of the menstrual cycle is
coiled arteries have been weakened by the previous characterized by a reepithelialization of the lining of the
events, they rupture. The disgorged blood removes endometrium and renewal of the functionalis.
patches of the functionalis to be discharged as a hem-
orrhagic discharge (menses), initiating menstruation The proliferative phase (also called the follicular phase
on day 1. because it occurs at the same time as the development
Although the entire functionalis layer of the of the ovarian follicles) begins when menstrual flow
endometrium is sloughed, it is not completely released ceases, on about day 4, and continues through day 14.
from the wall immediately; rather, this process contin- The proliferative phase is characterized by reepithelial-
ues for 3 to 4 days. During a normal menstrual period, ization of the lining of the endometrium; reconstruction
the approximate blood loss is 35 mL, although in some of the glands, connective tissue, and the coiled arteries
women it may be greater. of the lamina propria; and renewal of the functionalis.
Before and during the menstrual phase, the basalis During this phase, the functional layer becomes
layer of the endometrium continues to be vascularized much thicker (up to 2 to 3 mm) because the prolifera-
by its own straight arteries and thus remains viable. The tion of the cells in the base of the glands, whose blood
basal cells of the glands of the basalis begin to prolifer- supply remained intact, were unaffected during the
ate, and the newly formed cells migrate to the surface menstrual phase. As stated before, it is these cells that
to begin reepithelialization of the connective tissue are responsible for the formation of the epithelial lining
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of the uterus as well as for the establishment of new

glands in the functionalis. These tubular glands are
straight (not yet coiled), but their cells begin to accu-
mulate glycogen, as do the cells of the stroma that pro-
liferated to renew the stroma of the functionalis. The
coiled arteries that were lost in the menstrual phase are
replaced but are not tightly coiled and reach only two
thirds of the way into the functionalis.
By the 14th day of the menstrual cycle (ovulation), L
the functionalis layer of the endometrium has been fully
restored to its previous status with a full complement of
epithelium, glands, stroma, and coiled arteries. E
Secretory (Luteal) Phase L St

(Days 15 to 28)
The secretory phase of the menstrual cycle is
characterized by thickening of the endometrium as a
result of edema and accumulated glycogen secretions of
the highly coiled endometrial glands.
The secretory phase (or luteal phase) commences after

ovulation. During this phase, the endometrium contin-
ues to thicken as a result of edema and accumulated
glycogen secretions of the endometrial glands, which
become highly convoluted and branched. The secretory
products first accumulate in the basal region of the cyto- Figure 20–13 Light micrograph of the endometrium (E) of the
plasm of the cells constituting the endometrial glands. uterus in the luteal phase (×132). Note the lumina (L) of the glands
surrounded by stromal cells (St).
As more secretory product is manufactured, the secre-
tory granules move apically and are released into the
lumen of the gland. This glycogen-rich material will contractions of the smooth muscle of the oviduct (Fig.
nourish the conceptus before the formation of the 20-14). The nutrient-rich fluid produced by peg cells of
placenta. the mucosal epithelium nourishes the oocyte on its way
Most of the changes that result in the thickening of to the uterus.
the endometrium are attributed to the functionalis, Spermatozoa, introduced into the vagina during
although the lumina of the glands located in the basalis sexual intercourse, pass through the cervix, the uterine
are also filled with secretory product (Fig. 20-13). The lumen, and up the oviduct to the ampulla to encounter
coiled arteries of the functionalis attain full develop- the secondary oocyte. Fertilization usually occurs in the
ment, becoming more coiled and extending fully into ampulla (Fig. 20-15). At this time, the cells of the
the functional layer, by the 22nd day. Thus, at this point corona radiata still surround the zona pellucida and
in the secretory phase, the endometrium is about 5 mm the secondary oocyte.
thick. The ZP3 molecules of the zona pellucida have two
The secretory phase completes the cycle as the 28th regions: (1) the sperm receptor that recognizes integral
day approaches, prestaging the menstrual phase of a proteins of the sperm plasmalemma, and (2) the other
new menstrual cycle. region of the ZP3 molecule that binds to receptor pro-
teins located in the head of the sperm, triggering the
Fertilization, Implantation, and acrosome reaction. This reaction results in the release
Placental Development of the acrosomal enzymes into the zona pellucida.
Fertilization The liberated enzymes, especially the inner acrosomal
membrane–bound enzyme acrosin, digest the zona
Fertilization, the fusion of the sperm and the oocyte, pellucida, permitting the flagellar movement of the
occurs in the ampulla of the oviduct. spermatozoa to propel the sperm toward the oocyte.
Once the spermatozoon penetrates the entire width of
The oocyte and its attendant follicular cells are trans- the zona pellucida, it enters the perivitelline space,
ported down the oviduct by the beating of the cilia of located between the zona pellucida and the oocyte cell
the ciliated cells of the epithelial lining and by rhythmic membrane, and can reach the oocyte.
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3 days
8-cell stage
30 hours Zona pellucida

2-cell stage
Within uterus:
5–6 days
Blastocyst
Fertilization Zona pellucida gone
Ovary
6–7 days
Beginning of
implantation
2° Oocyte
Endometrium
Embryonic disk
Blastocoele
Trophoblast
14–15 days
Chorionic
cavity 12–13 days
Amniotic Amniotic cavity
cavity Blastocoele
Primitive
streak
14–15 days
Mesoderm Amniotic
cavity
Yolk sac
Maternal Remains of
blood vessel blastocoele
Yolk sac
Figure 20–14 Process of fertilization, zygote formation, morula and blastocyst development, and implantation.
The contact between the sperm and the oocyte is sperm receptors, in the zona pellucida, thus preventing
responsible for the cortical reaction, which prevents additional spermatozoa from reaching the oocyte.
polyspermy, the process by which more than a single At this time, entry of the sperm nucleus triggers the
sperm fuses with the egg. The cortical reaction has a secondary oocyte to resume and complete its second
fast and a slow component. The fast component meiotic division. This results in an unequal division of
involves a change in the resting membrane potential of the cytoplasm, forming two haploid cells, the ovum and
the oocyte plasma membrane that prevents contact the second polar body. The nucleus of the ovum
between the oocyte and another sperm. This alteration (female pronucleus) fuses with the nucleus of the
of the membrane potential lasts only a few minutes. The spermatozoon (male pronucleus), forming a zygote
slow component involves the release of the contents with the diploid number of chromosomes and thus com-
of numerous cortical granules located in the oocyte’s pleting the event of fertilization.
cytoplasm into the perivitelline space. Enzymes within The window of time between ovulation and fertiliza-
the cortical granules act to hydrolyze ZP3 molecules, the tion is about 24 hours. If fertilization does not occur
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Figure 20–15 Scanning electron micro-

graph of fertilization (×5700). A large number
of spermatozoa are trying to make their way
through the cells of the corona radiata, but
only a single spermatozoon will be able to fer-
tilize the egg. (From Phillips DM, Shalgi R,
Dekel N: Mammalian fertilization as seen
with the scanning electron microscope. Am J
Anat 174:357-372, 1985.)
during this period, the oocyte degenerates and is phago- The embryoblasts develop into the embryo, whereas
cytosed by macrophages. trophoblast cells give rise to the embryonic portion of
the placenta. Trophoblast cells proliferate rapidly,
Implantation forming an inner conglomeration of individual cells,
which are mitotically active and are known as cytotro-
Implantation is the process that occurs as the blastocyst phoblasts, and a thicker outer syncytium of cells that
becomes embedded in the uterine endometrium. do not undergo mitosis, called syncytiotrophoblasts.
The cytotrophoblasts proliferate, with the new
As the zygote continues its journey through the oviduct cells joining the syncytiotrophoblasts. As the syncy-
on its way to the uterus, it undergoes numerous mitotic tiotrophoblasts increase in number, they form vacuoles
divisions, becoming the spherical cluster of cells known that coalesce into large, labyrinthine spaces known as
as the morula (see Fig. 20-14). With further divisions lacunae. Continued growth of the syncytium erodes
and modifications, the morula is transformed into the the endometrium. This process permits deep penetra-
blastocyst, composed of a hollow ball of cells whose tion of the blastocyst into the wall of the endometrium,
lumen contains a somewhat viscous fluid and a few cells and by the 11th day of gestation the endometrial epithe-
at one pole. The peripheral cells are known as tro- lium seals over the implantation site.
phoblasts, and the cells trapped inside the blastocyst
are the embryoblasts. The blastocyst enters the Placenta Development
uterine cavity about 4 to 6 days after fertilization, and
on the 6th or 7th day it begins to embed itself into the The placenta is a vascular tissue derived from the
uterine wall, a process known as implantation. The uterine endometrium as well as from the developing
trophoblasts of the blastocyst stimulate the transforma- embryo.
tion of the star-shaped stromal cells of the uterine
endometrium into pale-staining decidual cells, whose Continued erosion of the highly vascular endometrium
stored glycogen probably provides nourishment for the by the syncytiotrophoblasts also erodes the maternal
developing embryo. blood vessels. The blood from these vessels empties into
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Decidua basalis
Chorion frondosum
Chorionic cavity
Uterine lumen
Decidua capsularis
Smooth chorion
(fetal portion
of placenta)
Chorion formation
Weeks 4-5
Decidua basalis
(maternal portion
of placenta)
Maternal
vein
Week 8
Chorionic villus
Fetal blood vessels
Intervillous space
containing maternal
Maternal blood
artery
Placental septum
Figure 20–16 Chorion and de- Decidua basalis Chorion

cidua formation; inset shows circula- (maternal portion (fetal portion
tion within the placenta. of placenta) of placenta)
the lacunae of the syncytiotrophoblasts that surround altered maternal tissue, called the decidua, is subdi-
the embryo. Thus, the maternal blood provides nour- vided into three regions:
ishment for the developing embryo. With further 䡲 The decidua capsularis, interposed between the
growth and development, the placenta begins to be uterine lumen and the developing embryo
formed, with the resultant separation between the 䡲 The decidua basalis, interposed between the devel-
blood of the developing embryo and that of the mother oping embryo and the myometrium
(maternal blood). From the remainder of the tro- 䡲 The decidua parietalis, which constitutes the
phoblast cells, the chorion develops and evolves into balance of the decidua
the chorionic plate, which gives rise to the chorionic
villi (Fig. 20-16). Initially, the entire embryo is surrounded by decidua
The developing trophoblasts induce changes in the in order to nourish it. The region of the chorion in
endometrium in their vicinity, altering it to begin the contact with the decidua capsularis forms short, insub-
formation of the maternal portion of the placenta. This stantial villi, thus remaining smooth-surfaced; this region
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of the chorion is known as the chorion laeve. The region that is delivered to and drained from the lacunae by
of the decidua capsularis, however, becomes highly maternal blood vessels of the decidua basalis.
vascularized by maternal blood vessels; it is in this Most of the villi are not anchored to the decidua
region that the placenta develops. The region of the basalis but are suspended in maternal blood of the
chorionic plate in contact with the decidua basalis forms lacunae, similar to roots of vegetables grown in hydro-
extensive chorionic villi, known as primary villi; thus, ponic environments; these are known as free villi. The
this region of the chorion is known as the chorion villi anchored to the decidua basalis are called anchor-
frondosum. ing villi. Capillaries of free and anchoring villi are near
The primary villi are composed of both syncytiotro- the surface of the villi and are separated from the mater-
phoblasts and cytotrophoblasts. With further develop- nal blood by a slight amount of connective tissue and
ment, extraembryonic mesenchymal cells enter the core the syncytiotrophoblasts covering the secondary villus.
of the primary villi, converting them into secondary Thus, maternal blood and fetal blood do not intermix;
villi (Fig. 20-17). The connective tissue of the second- instead, nutrients and oxygen from maternal blood
ary villi becomes vascularized by extensive capillary diffuse through the syncytiotrophoblasts, connective
beds, which are linked to the developing vascular supply tissue, and endothelial cells of the capillaries of the villi
of the embryo. to reach the fetal blood. These structures form the pla-
As development continues, the cytotrophoblast pop- cental barrier. Certain substances, such as water,
ulation decreases because these cells join the syncytium oxygen, carbon dioxide, small molecules, some proteins,
and contribute to its growth. The decidua basalis forms lipids, hormones, drugs, and some antibodies (espe-
large vascular spaces, lacunae, that are compartmen- cially immunoglobulin G), can penetrate the placental
talized into smaller regions by placental septa, exten- barrier, whereas most macromolecules cannot.
sions of the decidua. Secondary villi project into these In addition to being the site where nutritious sub-
vascular spaces and are surrounded by maternal blood stances, waste, and gases are exchanged between
maternal and fetal blood, the placenta (specifically
the syncytiotrophoblast) serves as an endocrine organ,
secreting hCG, chorionic thyrotropin, proges-
terone, estrogen, and chorionic somatomam-
motropin (a growth-promoting and lactogenic
hormone). Also, stromal connective tissue cells of the
decidua form the decidual cells, which enlarge and
synthesize prolactin and prostaglandins.
Ca CLINICAL CORRELATIONS
The blastocyst usually implants into the upper
one third of the anterior or posterior wall of the
uterus and it is in that location that the placenta
will begin to develop. Occasionally, in 1 out
of 200 pregnancies, implantation occurs lower
down in the uterus, near the cervix, where the
endometrium is much thinner and the connec-
IS tive tissue stroma is much denser. As the placenta
begins to develop and enlarge, it covers partially
or completely the opening of the cervix, making
normal, vaginal delivery an untenable option.
This condition is referred to as placenta previa
SK and usually necessitates the delivery of the baby
via a cesarean section.
Vagina
Figure 20–17 Light micrograph of cross sections of the chori-
onic villi of the placenta (×270). Observe the cytotrophoblasts and The vagina, a fibromuscular sheath, is composed of
syncytiotrophoblasts covering the chorionic villi. Ca, capillary; IS, three layers: mucosa, muscularis, and adventitia.
intervillous space; SK, syncytial knot.
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The vagina is a fibromuscular tubular structure 8 to Numerous sweat glands and sebaceous glands open on
9 cm in length connected to the uterus proximally and both surfaces.
to the vestibule of the external genitalia distally. The The labia minora, located medial to and slightly
vagina consists of three layers: mucosa, muscularis, deep to the labia majora, are the homologues of the ure-
and adventitia. thral surface of the penis in the male. The labia minora
The lumen of the vagina is lined by a thick stratified are two smaller folds of skin devoid of hair follicles
squamous nonkeratinized epithelium (150 to and adipose tissue. Their core is composed of a spongy
200 µm thick), although some of the superficial cells connective tissue containing elastic fibers arranged in
may contain keratohyalin. Langerhans cells in the networks. They contain numerous sebaceous glands
epithelium function in antigen presentation to T lym- and are richly supplied with blood vessels and nerve
phocytes housed in the inguinal lymph nodes. The endings.
epithelial cells are stimulated by estrogen to synthesize The cleft situated between the right and left labia
and store large deposits of glycogen, which is released minora is the vestibule, a space that receives secretions
into the lumen as the vaginal epithelial cells are of the glands of Bartholin, which are paired mucus-
sloughed. Naturally occurring vaginal bacterial flora secreting glands, and many small minor vestibular
metabolize the glycogen, forming lactic acid, which is glands. Also located in the vestibule are the orifices of
responsible for the low pH in the lumen of the vagina, the urethra and the vagina. In virgins, the orifice of the
especially at the midpoint of the menstrual cycle. The vagina is narrowed by a fold of epithelially enclosed
lowered pH also helps to restrict pathogenic invasion. fibrovascular tissue called the hymen.
The lamina propria of the vagina is composed The clitoris is located between the folds of the labia
of loose fibroelastic connective tissue containing a rich minora superiorly, where the two labia minora unite to
vascular supply in its deeper regions. It also contains form the prepuce over the top of the glans clitoridis.
numerous lymphocytes and neutrophils that reach the The clitoris, the female homologue of the penis, is
lumen by passing through intercellular spaces during covered by stratified squamous epithelium and is com-
certain periods in the menstrual cycle, where they par- posed of two erectile bodies containing numerous
ticipate in immune responses. Although the vagina does blood vessels and sensory nerves, including Meissner’s
not contain glands, there is an increase in vaginal fluid and pacinian corpuscles, which are sensitive during
during sexual stimulation, arousal, and intercourse that sexual arousal.
serves to lubricate its lining. This fluid is derived from
the transudate present in the lamina propria combined
with secretions from glands of the cervix. Mammary Glands
The muscularis layer of the vagina is composed of
smooth muscle cells arranged so that the mostly longi- The mammary glands are compound tubuloalveolar
tudinal bundles of the external surface intermingle with glands that consist of 15 to 20 lobes radiating out from
the more circularly arranged bundles near the lumen. the nipple and are separated from each other by
A sphincter muscle, composed of skeletal muscle fibers, adipose and collagenous connective tissue.
encircles the vagina at its external opening.
Dense, fibroelastic connective tissue constitutes the Mammary glands secrete milk, a fluid containing pro-
adventitia of the vagina, attaching it to surrounding teins, lipids, and lactose as well as lymphocytes and
structures. Contained within the adventitia is a rich monocytes, antibodies, minerals, and fat-soluble vita-
vascular supply with a vast venous plexus and nerve mins, to provide the proper nourishment for the
bundles derived from the pelvic splanchnic nerves. newborn.
The mammary glands develop in the same manner
and are of the same structure in both sexes until
External Genitalia puberty, when changes in the hormonal secretions in
females cause further development and structural
The external genitalia (vulva) are composed of the labia changes within the glands. Secretions of estrogen and
majora, labia minora, vestibule, and clitoris. progesterone from the ovaries (and later from the pla-
centa) and prolactin from the acidophils of the ante-
The labia majora are two folds of skin heavily endowed rior pituitary gland initiate development of lobules and
with adipose tissue and a thin layer of smooth muscle. terminal ductules. Full development of the ductal
The homologue of these structures in the male is the portion of the breast requires glucocorticoids and
scrotum, with the smooth muscle layer corresponding further activation by somatotropin.
to the dartos muscle of the scrotum. The labia majora Concomitant with these events is an increase in con-
are covered with coarse hair on their external surface nective tissue and adipose tissue within the stroma,
but are devoid of hair on their smooth inner surface. causing the gland to enlarge. Full development occurs
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at about 20 years of age, with minor cyclic changes smaller and without developed alveoli, which occur only
during each menstrual period, whereas major changes during pregnancy. Near the opening at the nipple,
occur during pregnancy and in lactation. After age 40 lactiferous ducts are lined by a stratified squamous
or so, the secretory portions as well as some of the ducts (keratinized) epithelium. The lactiferous sinus and the
and connective tissue elements of the breasts begin to lactiferous duct leading to it are lined by stratified
atrophy, and they continue this process throughout cuboidal epithelium, whereas the smaller ducts leading
menopause. to the lactiferous duct are lined by a simple columnar
The glands within the breasts are classified as com- epithelium. Stellate myoepithelial cells located between
pound tubuloalveolar glands, consisting of 15 to 20 the epithelium and the basal lamina also wrap around
lobes radiating out from the nipple and separated from the developing alveoli and become functional during
each other by adipose and collagenous connective pregnancy.
tissue. Each lobe is drained by its own lactiferous duct
leading directly to the nipple, where it opens onto its Lactating (Active)
surface. Before reaching the nipple, each of the ducts Mammary Glands
is dilated to form a lactiferous sinus for milk storage
and then narrows before passing through the nipple. During pregnancy, the terminal portions of the ducts
branch and grow and develop secretory units known as
Resting (Nonsecreting) alveoli.
Mammary Glands
Mammary glands are activated by elevated surges of
Alveoli are not developed in the resting mammary estrogen and progesterone during pregnancy to
gland. become lactating glands to provide milk for the
newborn. At this time, the terminal portions of the
Resting, or nonsecreting, mammary glands of nonpreg- ducts branch and grow and the alveoli develop and
nant women have the same basic architecture as the lac- mature (Fig. 20-18). As pregnancy progresses, the
tating (active) mammary gland, except that they are breasts enlarge as a result of hypertrophy of the glan-
INACTIVE BREAST LACTATING BREAST
Myoepithelial cell
Basal lamina
Adipose tissue Adipose tissue
Alveolar cell
Enlarged Milk lipids
Lactiferous secretory lobules
duct system Duct
Elaborate
duct system
Lactiferous
sinus
Milk
Opening
of sinus
Figure 20–18 Comparison of the glandular differences between an inactive and a lactating breast. Inset shows a longitudinal section of a
gland and duct of the active mammary gland.
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graph of an acinar cell from the lactat-
ing mammary gland of the rat (×9000).
Note the large lipid droplets (L), abun-
dant rough endoplasmic reticulum
(ER), and Golgi apparatus (G). F, folds
of the basal plasmalemma; m, mito-
chondria; MV, microvilli; Sg, secretory
granules; (From Clermont Y, Xia I,
Rambourg A, et al: Structure of the
Golgi apparatus in stimulated and non-
stimulated acinar cells of mammary
glands of the rat. Anat Rec 237:308-317,
1993.)
dular parenchyma and engorgement with colostrum,

a protein-rich fluid, in preparation for the newborn.
Within a few days after birth, when estrogen and pro-
gesterone secretions have subsided, prolactin, secreted
by acidophils of the anterior pituitary gland, activates Al
the secretion of milk, which replaces the colostrum.
The alveoli of the lactating (active) mammary glands
are composed of cuboidal cells partially surrounded by
a meshwork of myoepithelial cells. These secretory cells
possess abundant RER and mitochondria, several Golgi
complexes, many lipid droplets, and numerous vesicles
(Fig. 20-19) containing caseins (milk proteins) and
lactose. However, not all regions of the alveolus are in
the same stage of production, because different acini
display varying degrees of preparation for synthesis of
milk substances (Fig. 20-20).
The secretions of the alveolar cells are of two kinds:
lipids and proteins.
Lipids are stored as droplets within the cytoplasm. CT
They are released from the secretory cells, possibly by
the apocrine mode of exocytosis, whereby small
droplets coalesce to form larger and larger droplets that
move to the periphery of the cell. Once there, they
project as cytoplasmic blebs into the lumen; eventually,
the lipid droplets containing blebs are pinched off Figure 20–20 Light micrograph of the human mammary gland
(×132). Observe the crowded alveoli (Al), and note that various
and become part of the secretory product. Each bleb regions of the gland are in different stages of the secretory process.
then consists of a central lipid droplet surrounded CT, connective tissue.
by a narrow rim of cytoplasm and enclosed by a
plasmalemma.
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Proteins synthesized within these secretory cells are A) to provide nutrition and passive immunity to the
liberated from the cells by the merocrine mode of exo- newborn.
cytosis in much the same manner as would be expected Milk, usually produced by the 4th day after parturi-
of other cells that synthesize and release proteins into tion, is a fluid that contains minerals, electrolytes,
the extracellular space. carbohydrates (including lactose), immunoglobulins
(mostly immunoglobulin A), proteins (including caseins),
and lipids. Production of milk results from the stimuli of
Areola and Nipple sight, touch, handling of the newborn, and anticipation
The circular, heavily pigmented skin in the center of the of nursing, events that create a surge in prolactin
breast is the areola. It contains sweat glands and seba- release. Once initiated, milk production is continuous,
ceous glands at its margin as well as areolar glands (of with the milk being stored within the duct system.
Montgomery) that resemble both sweat and mammary Concomitant with the production of prolactin, oxy-
glands. In the center of the areola is the nipple, a pro- tocin is released from the posterior lobe of the pitu-
tuberance covered by stratified squamous epithelium itary. Oxytocin initiates the milk ejection reflex by
containing the terminal openings of the lactiferous inducing contractions of the myoepithelial cells around
ducts. In fair-skinned individuals, a pinkish color is the alveoli and the ducts, thus expelling the milk.
imparted to the nipple as a result of the color of blood
in the rich vascular supply within the long dermal papil-
lae that extend near its surface. During pregnancy, the CLINICAL CORRELATIONS
color becomes darker because of increased pigmenta-
tion of the areola and the nipple. Mothers who cannot breast-feed their infants
The core of the nipple is composed of dense colon a regular feeding schedule are inclined to
lagenous connective tissue with abundant elastic fibers suffer from poor lactation. This may motivate
connected to the surrounding skin or interlaced within a decision to discontinue nursing altogether,
the connective tissue and a rich component of smooth with the result that the infant is deprived of
muscle cells. The wrinkling of the skin on the nipple the passive immunity conferred by ingesting
results from the attachments of the elastic fibers. The antibodies from the mother.
abundant smooth muscle fibers are arranged in two Breast cancer, second only to lung cancer as
ways: circularly around the nipple and radiating longi- one of the major causes of cancer-related death
tudinally along the long axis of the nipple. The con- in women, may be of two different types: ductal
traction of these muscle fibers is responsible for carcinoma of the ductal cells and lobular car-
erection of the nipple. cinoma of the terminal ductules. Detection
Most of the sebaceous glands located around the lac- must be early, or the prognosis is poor because
tiferous ducts open onto the surface or sides of the the carcinoma may metastasize to the axillary
nipple, although some open into the lactiferous ducts lymph nodes and from there to the lungs, bone,
just before those ducts open onto the surface. and brain. At the recommendation of the
medical profession, early detection through self-
examination and mammography has helped to
Mammary Gland Secretions reduce breast cancer mortality rates. In the year
Prolactin is responsible for the production of milk by the
2005, approximately 270,000 women and 1700
mammary glands; oxytocin is responsible for the milk
men were diagnosed with breast cancer in the
United States and approximately 40,000 women
ejection reflex.
and 500 men died of breast cancer. There is an
Although the mammary gland is prepared to secrete inverse relationship between the age of the
milk even before birth, certain hormones prohibit this. woman and her risk of contracting the disease, in
However, when the placenta is detached in the adult that in 2005 1 out of 2200 women less than 30
female, prolactin from the anterior pituitary stimulates years of age contracted breast cancer, whereas 1
the production of milk, which reaches full capacity in a out 54 and 1 out of 23 women less than 50 and
few days. Before that, for the first 2 or 3 days after birth, 60 years of age, respectively, contracted breast
a protein-rich thick fluid called colostrum is secreted. cancer. Although breast cancer is more likely to
This high-protein secretion, rich in vitamin A, sodium, occur at an older age, younger women tend to
and chloride, also contains lymphocytes and monocytes, have more aggressive breast cancers.
minerals, lactalbumin, and antibodies (immunoglobulin
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21 䡲䡲䡲
Male Reproductive System
The male reproductive system consists of two testes General Structure and
suspended in the scrotum, a system of intratesticular Vascular Supply
and extratesticular genital ducts, associated glands,
and the male copulatory organ, the penis (Fig. 21-1). Connective tissue septa divide the testis into lobuli testis,
The testes are responsible for the formation of the male each of which houses one to four seminiferous tubules.
gametes, known as spermatozoa, as well as for the syn-
thesis, storage, and release of the male sex hormone, Each testis is surrounded by a capsule of dense, irregular
testosterone. collagenous connective tissue known as the tunica
The glands associated with the male reproductive albuginea. Immediately deep to this layer is a highly vas-
tract are the paired seminal vesicles, the single cularized loose connective tissue, the tunica vasculosa,
prostate gland, and the two bulbourethral glands which forms the vascular capsule of the testis. The poste-
(of Cowper). These glands form the noncellular rior aspect of the tunica albuginea is somewhat thickened,
portion of semen (spermatozoa suspended in the secre- forming the mediastinum testis, from which connective
tions of the accessory glands), which not only nourishes tissue septa radiate to subdivide each testis into approxi-
the spermatozoa but also provides a fluid vehicle for mately 250 pyramid-shaped intercommunicating com-
their delivery into the female reproductive tract. The partments known as the lobuli testis (Fig. 21-2).
penis has a dual function: It delivers semen to the Each lobule has one to four blindly ending seminif-
female reproductive tract during copulation and serves erous tubules, which are surrounded by a richly inner-
as the conduit of urine from the urinary bladder to vated and highly vascularized loose connective tissue
outside the body. derived from the tunica vasculosa. Dispersed through-
out this connective tissue are small conglomerations
of endocrine cells, the interstitial cells (of Leydig)
TESTES (see later), which are responsible for the synthesis of
testosterone.
The testes, located in the scrotum, are paired organs Spermatozoa are produced by the seminiferous
that produce spermatozoa and testosterone. epithelium of the seminiferous tubules. Spermatozoa
enter short straight ducts, tubuli recti, that connect the
Each testis of a mature male is an oval organ approxi- open end of each seminiferous tubule to the rete testis,
mately 4 cm long, 2 to 3 cm wide, and 3 cm thick. a system of labyrinthine spaces housed within the medi-
During embryogenesis, the testes develop retroperi- astinum testis. The spermatozoa leave the rete testis
toneally on the posterior wall of the abdominal cavity. through 10 to 20 short tubules, the ductuli efferentes,
As they descend into the scrotum, they carry with them which eventually fuse with the epididymis.
a portion of the peritoneum. This peritoneal outpouch- The vascular supply of each testis arises from the
ing, the tunica vaginalis, forms a serous cavity that abdominal aorta as the testicular artery, which
partially surrounds the anterolateral aspect of each descends with the testis into the scrotum, accompanying
testis, permitting it some degree of mobility within its the ductus deferens (vas deferens). The testicular
compartment in the scrotum. artery forms several branches before it pierces the
489
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490 䡲䡲䡲 Chapter 21 䡲 Male Reproductive System
Ductus (vas) deferens
Urinary bladder
Pubis
Corpus cavernosum
Corpus spongiosum
Penis
Seminal
Urethra
vesicle
Prostate
gland
Ejaculatory
duct
Glans penis
Anus
Scrotum
Bulbourethral Testis
gland Figure 21–1 The male reproduc-
Epididymis tive system.
Ductus (vas) Ductuli efferentes the temperature of the arterial blood, thus forming a
deferens countercurrent heat exchange system. In this
fashion, it helps keep the temperature of the testes a
few degrees lower than that of the remainder of the
Rete testis body. At this cooler temperature (95° F [35° C]), sper-
matozoa develop normally, whereas at body tempera-
Epididymis Tunica ture, spermatozoa that may develop are sterile. The
albuginea testes are maintained at a cooler temperature in the
Seminiferous
scrotum , thus aiding the cooling effect of the pampini-
tubules form plexus of veins.
Testicular
lobules
Septum
Hyperthermia has been identified as a factor in
Testis
male infertility, and it has been reported that
males who work with laptop computers held on
their laps for 1 hour of continuous use exhibited
Figure 21–2 The testis and epididymis. Lobules and their con- an increase in scrotal temperature by as much as
tents are not drawn to scale.
2.8° C. Although these studies are not conclu-
sive, it is suggested that boys and young men may
capsule of the testis to form the intratesticular vascular wish to limit the use of computers on their laps.
elements. The capillary beds of the testes are collected
into several veins, the pampiniform plexus of veins,
which are wrapped around the testicular artery. The artery,
veins, and ductus deferens together form the spermatic Seminiferous Tubules
cord, which passes through the inguinal canal, the pas-
Seminiferous tubules are composed of a thick
sageway from the abdominal cavity to the scrotum.
seminiferous epithelium surrounded by a thin connective
Blood in the pampiniform plexus of veins, which is
tissue, the tunica propria.
cooler than that in the testicular artery, acts to reduce
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Chapter 21 䡲 Male Reproductive System ■ ■ ■ 491
Seminiferous tubules are highly convoluted hollow TA

tubules, 30 to 70 cm long and 150 to 250 µm in diam-
eter, that are surrounded by extensive capillary beds.
About 1000 seminiferous tubules are present in the two TV
testes, for a total length of nearly 0.5 km (0.3 mile), ded-
icated to the production of spermatozoa.
The wall of the seminiferous tubule is composed of
a slender connective tissue layer, the tunica propria,
and a thick seminiferous epithelium. The tunica propria
and the seminiferous epithelium are separated from L
each other by a well-developed basal lamina. The con-
nective tissue comprises mostly interlaced, slender, type
I collagen fiber bundles housing several layers of fibro- S
blasts. In some animals, but not in humans, myoid
cells, similar to smooth muscle, are also present; the
cells impart contractility to the seminiferous tubules of
animals.
The seminiferous epithelium (or germinal epithe- BV
lium) is several cell layers thick (Figs. 21-3 and 21-4)
and is composed of two types of cells: Sertoli cells and
spermatogenic cells (Fig. 21-5; also see Fig. 21-4). The ST
latter cells are in various stages of maturation.
SE
Sertoli Cells
Sertoli cells support, protect, and nourish spermatogenic
cells; phagocytose cytoplasmic remnants of spermatids;
secrete androgen-binding protein, hormones, and a
nutritive medium; and establish the blood-testis barrier.
Figure 21–3 Light micrograph of the capsule of a monkey testis,
with cross-sectional profiles of blood vessels (BV), lumen (L), septa
Sertoli cells are tall, columnar cells whose lateral cell (S), seminiferous epithelium (SE), seminiferous tubules (ST), tunica
membranes possess complex infoldings, which make it albuginea (TA), and tunica vasculosa (TV) (×132).
Sz
Ad
SC Ap
SE
Figure 21–4 Seminiferous tubule

(×540). Note the seminiferous epi-
thelium (SE), pale spermatogonia
A (Ap), dark spermatogonia A
(Ad), spermatogonia B (B), Sertoli
cell (SC), and spermatozoa (Sz).
Ch021-X2945.qxd 15/8/06 2:53 PM Page 492
impossible to distinguish their lateral cell boundaries endoplasmic reticulum (RER) is limited. The cell also
using light microscopy. Their apical cell membranes are has numerous mitochondria, a well-developed Golgi
also highly folded and project into the lumina of the apparatus, and numerous vesicles that belong to the
seminiferous tubules. These cells have a basally located, endolysosomal complex. The cytoskeletal elements of
clear, oval nucleus with a large, centrally positioned Sertoli cells are also abundant, indicating that one of the
nucleolus (see Fig. 21-5). The cytoplasm has been functions of these cells is to provide structural support
shown to house inclusion products known as crystal- for the developing gametes.
loids of Charcot-Böttcher, the composition and func- The lateral cell membranes of adjacent Sertoli cells
tion of which are not known. form occluding junctions with each other, thus subdi-
Electron micrographs reveal that the cytoplasm of viding the lumen of the seminiferous tubule into two
Sertoli cells is replete with profiles of smooth endo- isolated, concentric compartments (Fig. 21-6; also see
plasmic reticulum (SER), but the amount of rough Fig. 21-5). The basal compartment is narrower, is
located basal to the zonulae occludentes, and surrounds
Lumen of
the wider adluminal compartment. Thus, the zonulae
seminiferous occludentes of these cells establish a blood-testis barrier
tubule that isolates the adluminal compartment from con-
Late nective tissue influences, thereby protecting the devel-
spermiogenesis oping gametes from the immune system. Because
Early spermatogenesis begins after puberty, the newly differ-
spermatids entiating germ cells, which have a different chromo-
compartment
some number as well as expressing different surface

Adluminal
Secondary
spermatocytes membrane receptors and molecules, would be consid-
ered “foreign cells” by the immune system. Were it not
Primary for the isolation of germ cells from the connective tissue
spermatocytes
compartments by the zonulae occludentes of the Sertoli
Nucleus of cells, an immune response would be mounted against
Sertoli cell
them.
Sertoli cells perform the following functions:
compartment
Spermatogonia
䡲 Physical and nutritional support of the developing
germ cells
Basal
䡲 Phagocytosis of cytoplasm eliminated during

Basal lamina
spermiogenesis
Fibroblast 䡲 Establishment of a blood-testis barrier by the forma-
tion of zonulae occludentes between adjacent Sertoli
Figure 21–5 Seminiferous epithelium. cells

graph of the basal compartmentof the
seminiferous epithelium (×15,000).
The testis has been perfused with an
electron-dense tracer (lanthanum
nitrate) to demonstrate that the
occluding junctions (arrows) between
adjacent Sertoli cells prevent the
tracer from entering the adluminal
compartment. (From Leeson TS,
Leeson CR, Papparo AA: Text/Atlas
of Histology. Philadelphia, WB
Saunders, 1988.)
Ch021-X2945.qxd 15/8/06 2:53 PM Page 493
䡲 Synthesis and release of androgen-binding protein Differentiation of Spermatogonia

(ABP), a macromolecule that facilitates an increase
in the concentration of testosterone in the seminifer- Spermatogonia (2n) are influenced by testosterone at
ous tubule by binding to it and preventing it from puberty to enter the cell cycle.
leaving the tubule
䡲 Synthesis and release (during embryogenesis) of Spermatogonia are small, diploid germ cells located in
antimüllerian hormone, which suppresses the for- the basal compartment of the seminiferous tubules (see
mation of the müllerian duct (precursor of the female Figs. 21-5 and 21-7). These cells lie on the basal lamina
reproductive system) and thus establishes the “male- and, subsequent to puberty, become influenced by
ness” of the developing embryo testosterone to enter the cell cycle. There are three cat-
䡲 Synthesis and secretion of inhibin, a hormone that egories of spermatogonia:
inhibits the release of follicle-stimulating hormone 䡲 Dark type A spermatogonia are small (12 µm in
(FSH) by the anterior pituitary diameter) dome-shaped cells. They have flattened,
䡲 Secretion of a fructose-rich medium that nourishes oval nuclei with abundant heterochromatin, im-
and facilitates the transport of spermatozoa to the parting a dense appearance to the nucleus. Dark
genital ducts type A spermatogonia are reserve cells that have
䡲 Synthesis and secretion of testicular transferrin, an not entered the cell cycle but may do so. Once
apoprotein that accepts iron from serum transferrin they undergo mitosis, they form additional dark
and conveys it to maturing gametes type A spermatogonia as well as pale type A
spermatogonia.
䡲 Pale type A spermatogonia are identical to the
Spermatogenic Cells dark type A cells, except that their nuclei have abun-
dant euchromatin, giving them a pale appearance.
The process of spermatogenesis, whereby spermatogonia
These cells have only a few organelles, including
give rise to spermatozoa, is divided into three phases:
mitochondria, a limited Golgi complex, some RER,
spermatocytogenesis, meiosis, and spermiogenesis.
and numerous free ribosomes. These cells are
Most of the cells composing the thick seminiferous induced by testosterone to proliferate and give rise,
epithelium are spermatogenic cells in various stages by mitosis, to additional pale type A spermatogonia
of maturation (see Fig. 21-5). Some of these cells, sper- and to type B spermatogonia.
䡲 Type B spermatogonia resemble pale type A sper-
matogonia, are located in the basal compartment,
whereas most of the developing cells—primary spermatogonia, but usually their nuclei are round rather
matocytes, secondary spermatocytes, spermatids, than flattened. These cells also divide mitotically to
and spermatozoa—occupy the adluminal compart- give rise to primary spermatocytes.
ment. Spermatogonia are diploid cells that undergo
mitotic division to form more spermatogonia as well as
primary spermatocytes, which migrate from the basal Meiotic Division of Spermatocytes
into the adluminal compartment. Primary spermato-
The first meiotic division of the primary spermatocyte,
cytes enter the first meiotic division to form second-
followed by the second meiotic division of the secondary
ary spermatocytes, which undergo the second meiotic
spermatocyte, reduces the chromosome number and
division to form haploid cells known as spermatids.
deoxyribonucleic acid (DNA) content to the haploid (n)
These haploid cells are transformed into spermatozoa
state in the spermatids.
(mature sperm) through shedding of much of their cyto-
plasm, rearrangement of their organelles, and formation As soon as primary spermatocytes are formed, they
of flagella. migrate from the basal compartment into the adlumi-
Various cell types that result from this process of cell nal compartment. As these cells migrate between adja-
maturation, called spermatogenesis, are diagrammed cent Sertoli cells, they form zonulae occludentes with
in Figure 21-7. The maturation process is divided into the Sertoli cells and thus help maintain the integrity
three phases: of the blood-testis barrier. Primary spermatocytes are
䡲 Spermatocytogenesis: Differentiation of spermato- the largest cells of the seminiferous epithelium (see
gonia into primary spermatocytes Fig. 21-5). They have large, vesicular-appearing nuclei
䡲 Meiosis: Reduction division whereby diploid primary whose chromosomes are in various stages of condensa-
spermatocytes reduce their chromosome completion. Shortly after their formation, primary spermato-
ment, forming haploid spermatids cytes duplicate their DNA to obtain a 4n DNA content;
䡲 Spermiogenesis: Transformation of spermatids into however, the chromosome number remains diploid
spermatozoa (sperm) (2n).
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A1 Spermatogonia
A2 Spermatogonia
A3 Spermatogonia
A4 Spermatogonia
Spermatogonia
B Spermatogonia
Primary spermatocytes
Secondary spermatocytes
Spermatids
Mature
sperm
Figure 21–7 Spermatogenesis, displaying the intercellular bridges that maintain the syncytium during differentiation and maturation.
(Modified from Ren X-D, Russell L: Clonal development of interconnected germ cells in the rat and its relationship to the segmental and
subsegmental organization of spermatogenesis. Am J Anat 192:127, 1991.)
During the first meiotic division, the DNA content Prophase I of the first meiotic division lasts for 22
is halved (to 2n DNA) in each daughter cell and the days and involves four stages:
chromosome number is reduced to haploid (n). During
the second meiotic division, the DNA content of each 䡲 Leptotene
new daughter cell is reduced to haploid (1n DNA), 䡲 Zygotene
whereas the chromosome number remains unaltered 䡲 Pachytene
(haploid). 䡲 Diakinesis
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The chromosomes of a primary spermatocyte begin Transformation of Spermatids

to condense, forming long threads during leptotene (Spermiogenesis)
and pairing with their homologues during zygotene.
Further condensation yields short, thick chromosomes, Spermatids discard much of their cytoplasm, rearrange
recognizable as tetrads, during pachytene. The their organelles, and form a flagellum to become
exchange of segments (crossing over) of homologous transformed into spermatozoa; this process of
chromosomes occurs during diakinesis; this random transformation is known as spermiogenesis.
genetic recombination results in the unique genome of
each gamete and contributes to the variation of the gene Spermatids are small, round haploid cells (8 µm in
pool. diameter). All the spermatids that are the progeny of a
During metaphase I, the paired homologous single pale type A spermatogonium are connected to
chromosomes line up at the equatorial plate. The one another by cytoplasmic bridges. They form small
members of each pair pull apart and then migrate to clusters and occupy a position near the lumen of the
opposite poles of the cell in anaphase I, and the daugh- seminiferous tubule. These cells have abundant RER,
ter cells separate (although a cytoplasmic bridge numerous mitochondria, and a well-developed Golgi
remains), forming two secondary spermatocytes during complex. During their transformation into spermato-
telophase I. zoa, they accumulate hydrolytic enzymes, rearrange and
Because the homologous chromosomes are segre- reduce the number of their organelles, form flagella and
gated during anaphase, the X and Y chromosomes associated skeletal apparatus, and shed some of their
are sorted into separate secondary spermatocytes, even- cytoplasm. This process of spermiogenesis is subdi-
tually forming spermatozoa that carry either X or Y vided into four phases (Figs. 21-8 and 21-9):
chromosomes. Thus, it is the spermatozoon that deter- 䡲 Golgi phase
mines the chromosomal (genetic) sex of the future 䡲 Cap phase
embryo. 䡲 Acrosomal phase
Secondary spermatocytes are relatively small 䡲 Maturation phase
cells, and because they are short-lived, they are not
readily seen in the seminiferous epithelium. These cells,
which contain 2n DNA, do not replicate their chromo- GOLGI PHASE
somes; they quickly enter the second meiotic division, During the Golgi phase of spermiogenesis, hydrolytic
forming two haploid (1n DNA) spermatids. enzymes are formed on the RER, modified in the Golgi
During mitosis of spermatogonia and meiosis of apparatus, and packaged by the trans Golgi network
spermatocytes, nuclear division (karyokinesis) is as small, membrane-bound preacrosomal granules.
accompanied by a modified cytokinesis. As each cell These small vesicles fuse with one another, forming an
divides to form two cells, a cytoplasmic bridge acrosomal vesicle. The hydrolytic enzymes in this
remains between them, holding the newly formed cells vesicle are visualized with the electron microscope as
tethered to each other (see Fig. 21-7). Because this an electron-dense material known as the acrosomal
incomplete division occurs over a number of mitotic granule. The acrosomal vesicle comes into contact
and meiotic events, it results in the formation of a syn- with and becomes bound to the nuclear envelope,
cytium of cells, a large number of spermatids that are thus establishing the anterior pole of the developing
connected to one another. This connection enables the spermatozoon.
spermatogenic cells to communicate with each other As the acrosomal vesicle is being formed, the centri-
and thus to synchronize their activities. oles leave the vicinity of the nucleus, and one of them
participates in the formation of the flagellar axoneme.
After the generation of the microtubules is initiated, the
centrioles return to the vicinity of the nucleus to assist
CLINICAL CORRELATIONS in the formation of the connecting piece, a structure
that will surround the centrioles (see later in the
The most common abnormality due to nondis- description of the spermatozoon).
junction of the XX homologues is known as Kline-
felter syndrome. Individuals afflicted with this
syndrome usually have XXY chromosomes (an CAP PHASE
extra X chromosome). They are typically infertile, During the cap phase, the acrosomal vesicle increases
are tall and thin, exhibit various degrees of mascu- in size, and its membrane partially surrounds the
line characteristics (including small testes), and nucleus (see Fig. 21-8). As this vesicle enlarges to its
are somewhat retarded mentally. final size, it becomes known as the acrosome (acroso-
mal cap).
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microtubules disassemble. Their place is assumed by

the annulus, an electron-dense, ring-like structure that
delineates the junction of the spermatozoon’s middle
piece with its principal piece (see Fig. 21-9). A mito-
chondrial sheath forms around the axoneme of the
middle piece of the tail of the spermatozoon.
During formation of the mitochondrial sheath and
elongation of the spermatid, nine columns of outer
dense fibers form around the axoneme. These dense
fibers are attached to the connecting piece formed
during the Golgi phase. After their establishment, the
dense fibers become surrounded by ribs, a series of
ring-like, dense structures known as the fibrous
sheath.
MATURATION PHASE
The maturation phase is characterized by the shedding
of spermatid cytoplasm. As the excess cytoplasm is
released, the syncytium is disrupted and individual
spermatozoa are liberated from the large cellular mass.
The cytoplasmic remnants are phagocytosed by Sertoli
cells, and the disengaged spermatozoa are released into
the lumen of the seminiferous tubule (spermiation).
Note that the newly formed spermatozoa are
immotile and cannot fertilize an oocyte. Spermatozoa
gain motility while passing through the epididymis.
Only after they enter the female reproductive system
do spermatozoa become capacitated (i.e., capable of
fertilization).
Structure of Spermatozoa
Spermatozoa are composed of a head, housing the
nucleus, and a tail that is divided into four regions:
Figure 21–8 Electron micrograph of the cap stage of a rodent
neck, middle piece, principal piece, and end piece.
spermatid (×18,000). AC, acrosome; G, Golgi apparatus; N, nucleus;
NE, nuclear envelope. (From Oshako S, Bunick D, Hess RA, et al:
Characterization of a testis specific protein localized in the endoplas- The spermatozoa (sperm), produced by spermatogene-
mic reticulum of spermatogenic cells. Anat Rec 238:335-348, 1994.) sis, are long cells (~65 µm). Each spermatozoon is com-
posed of a head, housing the nucleus, and a tail, which
accounts for most of its length (Fig. 21-10; also see
Fig. 21-9).
ACROSOMAL PHASE
HEAD OF THE SPERMATOZOON
The acrosomal phase is characterized by several alter-
ations in the morphology of the spermatid. The nucleus The flattened head of the spermatozoon is about 5 µm
becomes condensed, the cell elongates, and the mito- long and is surrounded by plasmalemma (see Fig. 21-
chondria shift location. 9). It is occupied by the condensed electron-dense
The chromosomes become tightly condensed and nucleus, containing only 1 member of the 23 pairs of
tightly packaged. As the chromosomal volume chromosomes (22 autosomes + the Y chromosome—or
decreases, the volume of the entire nucleus is also 22 autosomes + the X chromosome), and the acro-
reduced. Additionally, the nucleus becomes flattened some, which partially surrounds the anterior aspect of
and assumes its specific morphology. the nucleus. The acrosome comes into contact with the
Microtubules assemble to form a cylindrical struc- cell membrane of the spermatozoon anteriorly. It
ture, the manchette, which aids in the elongation of houses various enzymes, including neuraminidase,
the spermatid. As the elongating cytoplasm reaches the hyaluronidase, acid phosphatase, aryl sulfatase, and a
microtubules of the flagellar axoneme, the manchette trypsin-like protease known as acrosin.
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SPERMATID GOLGI PHASE ACROSOMAL EARLY MID

PHASE MATURATION MATURATION
PHASE PHASE
Flagellum
Nucleus
Acrosomal
Mitochondrion
granule
Nucleus
Acrosomal vesicle Acrosomal Nucleus
cap
End piece Principal piece
Annulus
Middle piece
Mitochondrion
Neck
Head
Figure 21–9 Spermiogenesis and
a mature spermatozoon.
Figure 21–10 Scanning elec-

tron micrograph of human sperma-
tozoa (×15,130). The entire
spermatozoon is shown, including
head region (HR), middle piece
(MP), principal piece (PP), and end
piece (EP) (×650). Inset, Head, neck
(NK), and middle piece (MP).
(From Kessel RG: Tissue and
Organs: A Text Atlas of Scanning
Electron Microscopy. San Francisco,
WH Freeman, 1979.)
Binding of a spermatozoon to the ZP3 molecule of TAIL OF THE SPERMATOZOON

the zona pellucida triggers the acrosomal reaction,
the release of the acrosomal enzymes that digest a path The tail of the spermatozoon is subdivided into
for the sperm to reach the oocyte, thereby facilitating four regions: neck, middle piece, principal piece,
the process of fertilization (see Chapter 20, Fig. 20-15). and end piece (see Fig. 21-9). The plasmalemma
The acrosomal reaction as well as the process of fertil- of the head is continuous with the tail’s plasma
ization is described in Chapter 20. membrane.
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The neck (~5 µm long) connects the head to the at 16-day intervals in the same stage of spermatogene-
remainder of the tail. It is composed of the cylindrical sis. Each 16-day interval is known as a cycle of the
arrangement of the nine columns of the connecting seminiferous epithelium, and the process of sper-
piece that encircles the two centrioles, one of which is matogenesis requires the passage of four cycles, or 64
usually fragmented. The posterior aspects of the colum- days. Examination of serial cross sections of a single
nar densities are continuous with the nine outer dense seminiferous tubule reveals that the same stage of the
fibers. seminiferous epithelium continues to reappear at spe-
The middle piece (~5 µm long) is located between cific distances along the length of the tubule. The dis-
the neck and the principal piece. It is characterized by tance between two identical stages of the seminiferous
the presence of the mitochondrial sheath, which encir- epithelium is called the wave of the seminiferous
cles the outer dense fibers and the centralmost epithelium. Thus, in humans there are six repeating
axoneme. The middle piece stops at the annulus, a waves of the seminiferous epithelium, corresponding to
ring-like, dense structure to which the plasmalemma the six stages.
adheres, thus preventing the mitochondrial sheath from
moving caudally into the tail. Also, two of the nine outer Interstitial Cells of Leydig
dense fibers terminate at the annulus; the remaining
seven continue into the principal piece. The interstitial cells of Leydig, scattered among
The principal piece (~45 µm long) is the longest connective tissue elements of the tunica vasculosa,
segment of the tail and extends from the annulus to the secrete testosterone.
end piece. The axoneme of the principal piece is con-
tinuous with that of the middle piece. Surrounding the The seminiferous tubules are embedded in the tunica
axoneme are the seven outer dense fibers that are con- vasculosa, a richly vascularized, loose connective tissue
tinuous with those of the middle piece and are sur- housing scattered fibroblasts, mast cells, and other
rounded, in turn, by the fibrous sheath. The principal cellular constituents normally present in loose connec-
piece tapers near its caudal extent, where both the outer tive tissue. Also dispersed throughout the tunica vas-
dense fibers and the fibrous sheath terminate, and is culosa are small collections of endocrine cells, the
continuous with the end piece. interstitial cells of Leydig, which produce the hormone
The end piece (~5 µm long) is composed of the testosterone.
central axoneme surrounded by plasmalemma. The The interstitial cells of Leydig are polyhedral and are
axoneme is disorganized in the last 0.5 to 1.0 µm, so approximately 15 µm in diameter. They have a single
that instead of the nine doublets and two singlets, nucleus, although occasionally they may be binucleate.
20 haphazardly arranged, individual microtubules are They are typical steroid-producing cells that have mito-
evident. chondria with tubular cristae, a large accumulation of
SER, and a well-developed Golgi apparatus (Fig. 21-
12). These cells also house some RER and numerous
CYCLE OF THE SEMINIFEROUS lipid droplets, but they contain no secretory vesicles,
EPITHELIUM because testosterone is probably released as soon as its
synthesis is complete. Lysosomes and peroxisomes are
The seminiferous epithelium displays 16-day cycles; four also evident, as are lipochrome pigments (especially in
cycles are required to complete spermatogenesis. older men). The cytoplasm also contains crystallized
proteins, the crystals of Reinke, a characteristic of
Because germ cells that arise from a single pale type human interstitial cells.
A spermatogonium are connected by cytoplasmic
bridges and constitute a syncytium, they can communi- Histophysiology of the Testes
cate with each other and synchronize their develop-
ment. Careful examination of the human seminiferous The principal functions of the testes are the production
epithelium reveals six possible characteristic associa- of spermatozoa and the synthesis and release of
tions of developing cell types, known as the six stages testosterone.
of spermatogenesis because they are undergoing
transformations to form spermatozoa (Fig. 21-11). Each The two testes form about 200 million spermatozoa
cross-sectional profile of a seminiferous tubule may be per day by a process that may be considered a holo-
subdivided into three or more wedgeshaped areas, each crine type of secretion. Sertoli cells of the seminiferous
displaying a different stage of spermatogenesis. epithelium also produce a fructose-rich fluid that acts
Studies following the fate of tritium-labeled thymi- to nourish and transport the newly formed spermatozoa
dine (3H-thymidine) injected into the testes of human from the lumen of the seminiferous tubule to the extrat-
volunteers have demonstrated that radioactivity appears esticular genital ducts.
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Six stages of spermatogenesis

within the seminiferous tubule
STAGE I STAGE II
Spermatozoa
Late spermatid
Early spermatid
Primary
spermatocyte
Sertoli cell
Spermatogonia
Basal lamina
STAGE III STAGE IV
Spermatid
Primary
spermatocyte
Sertoli cell
Spermatogonia
Basal lamina
STAGE V STAGE VI
Late spermatid
Primary
spermatocyte
Sertoli cell
Figure 21–11 The six stages of
spermatogenesis in the human semi- Spermatogonia
niferous tubule. (Redrawn from Cler-
mont Y: The cycle of the seminiferous
epithelium in man. Am J Anat 112:35- Basal lamina
52, 1963.)
Luteinizing hormone (LH), a gonadotropin released plasmic reticulum and mitochondria until testosterone,
from the anterior pituitary gland, binds to LH receptors the male hormone, is formed and is ultimately released
on the Leydig cells, activating adenylate cyclase to form by these cells (Fig. 21-13).
cyclic adenosine monophosphate (cAMP). Activation of Because blood testosterone levels are not sufficient
protein kinases of the Leydig cells by cAMP induces to initiate and maintain spermatogenesis, FSH, another
inactive cholesterol esterases to become active and anterior pituitary gonadotropin, induces Sertoli cells to
cleave free cholesterol from intracellular lipid droplets. synthesize and release androgen-binding protein
The first step in the pathway of testosterone synthesis (ABP) (Fig. 21-14). As its name implies, ABP binds
is also LH-sensitive, because LH activates cholesterol testosterone, thereby preventing the hormone from
desmolase, the enzyme that converts free cholesterol leaving the region of the seminiferous tubule and ele-
into pregnenolone. The various products of the syn- vating the testosterone levels in the local environment
thetic pathway are shuttled between the smooth endo- sufficiently to sustain spermatogenesis.
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Figure 21–12 Low-magnification

electron micrograph exhibits areas of
two human Leydig cells (×18,150).
Mitochondria are relatively uniform
in diameter, and even at low mag-
nification, stacked lamellae are an
evident form of the cristae (arrow-
head). (From Prince FP: Mitochon-
drial cristae diversity in human
Leydig cells: A revised look at cristae
morphology in these steroid-produc-
ing cells. Anat Rec 254:534-541,
1999.)
LH receptor Adenylate
cyclase
Leydig cell
Lipid droplet cAMP

ATP cAMP
+ PPi activates
Esterified
cholesterol
Protein
kinases
Plasma Free Acetyl activate
cholesterol cholesterol CoA
Nucleus Cholesterol
esterases
Mitochondrion cleave
Free
Pregnenolone SER cholesterol
Testosterone Figure 21–13 Testosterone synthesis

by the interstitial cells of Leydig. ATP,
adenosine triphosphate; cAMP, cyclic
adenosine monophosphate; CoA, coenzyme
To A; LH, luteinizing hormone; SER, smooth
bloodstream endoplasmic reticulum.
Release of LH is inhibited by increased levels of bound by ABP and thus can reduce the levels of
testosterone and dihydrotestosterone, whereas release spermatogenesis.
of FSH is inhibited by the hormone inhibin, pro- Testosterone is also required for the normal func-
duced by Sertoli cells (see Fig. 21-14). It is interesting tioning of the seminal vesicles, prostate, and bul-
to note that estrogens, female sex hormones, are also bourethral glands as well as for the appearance and
Ch021-X2945.qxd 15/8/06 2:53 PM Page 501
Hypothalamus
LHRH
Negative feedback Negative feedback of

of testosterone on inhibin on releasing
releasing of LHRH LHRH
(–)
LH stimulates synthesis
of male sex hormones (–)
by Leydig cells
Anterior pituitary
FSH stimulates Sertoli

cells to synthesize
androgen-binding
protein (ABP)
Sertoli
cells
Leydig cells
produce
testosterone
Figure 21–14 Hormonal control
of spermatogenesis. FSH, follicle- (ABP)
stimulating hormone; LH, luteiniz-
ing hormone; LHRH, luteinizing Blood
hormone–releasing hormone. (Adapted vessel
from Fawcett, DW: Bloom and
Fawcett’s A Textbook of Histology,
10th ed. Philadelphia, WB Saunders, Seminiferous
1975.) tubule
maintenance of the male secondary sexual characteris- Tubuli Recti

tics. The cells that require testosterone possess 5a-
reductase, the enzyme that converts testosterone to its The tubuli recti deliver spermatozoa from the
more active form, dihydrotestosterone. seminiferous tubules into the rete testis.
The tubuli recti are short, straight tubules that are con-
GENITAL DUCTS tinuous with the seminiferous tubules and deliver the
spermatozoa, formed by the seminiferous epithelium, to
The genital ducts may be subdivided into two cate- the rete testis. These short tubules are lined by Sertoli
gories: those located within the testes (intratesticular) cells in their first half, near the seminiferous tubule, and
and those located external to the testes (extratesticu- by a simple cuboidal epithelium in their second half,
lar) (Table 21-1). near the rete testis. The cuboidal cells have short, stubby
microvilli, and most possess a single flagellum.
Intratesticular Genital Ducts
Rete Testis
Intratesticular ducts include the tubuli recti and the rete
testis. Immature spermatozoa pass from the tubuli recti into
the rete testis, labyrinthine spaces lined by cuboidal
The genital ducts located within the testis connect the epithelium.
seminiferous tubules to the epididymis. These intrates-
ticular ducts are the tubuli recti and the rete testis (see The rete testis consists of labyrinthine spaces, lined by
Fig. 21-2). a simple cuboidal epithelium, within the mediastinum
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TABLE 21–1 Histological Features and Functions of Male Genital Ducts
Duct Epithelial Lining Supporting Tissues Function
Tubuli recti Sertoli cells in proximal half; Loose connective tissue Convey spermatoza from
simple cuboidal epithelium seminiferous tubules to
in distal half rete testis
Rete testis Simple cuboidal epithelium Vascular connective tissue Conveys spermatozoa
from tubuli recti to
ductuli efferentes
Ductuli Patches of nonciliated cuboidal Thin loose connective tissue Convey spermatozoa from
efferentes cells alternating with ciliated surrounded by thin layer of rete testis to epididymis
columnar cells circularly arranged smooth
muscle cells
Epididymis Pseudostratified epithelium Thin loose connective tissue Conveys spermatoza from
composed of short basal surrounded by layer of circularly ductuli efferentes to
cells and tall principal cells arranged smooth muscle cells ductus deferens
(with stereocilia)
Ductus (vas) Stereociliated pseudostratified Loose fibroelastic connective tissue; Delivers spermatozoa from
deferens columnar epithelium thick three-layered smooth muscle tail of epididymis to
coats; inner and outer longitudinal, ejaculatory duct
middle circular
Ejaculatory Simple columnar epithelium Subepithelial connective tissue Delivers spermatozoa and
duct folded, giving lumen irregular seminal fluid to prostatic
appearance; no smooth muscle urethra at colliculus
seminalis
testis. These cuboidal cells, which resemble those of the most of the luminal fluid elaborated by the Sertoli cells
tubuli recti, have numerous short microvilli with a single of the seminiferous tubule. The cilia of the columnar
flagellum (Fig. 21-15). cells probably move the spermatozoa toward the
epididymis.
Ductuli Efferentes The simple epithelium sits on a basal lamina that sep-
arates it from the thin, loose connective tissue wall of
The ductuli efferentes are interposed between the rete each ductule. The connective tissue is surrounded by a
testis and the epididymis. thin layer of smooth muscle whose cells are circularly
arrayed.
The 10 to 20 ductuli efferentes are short tubules that
drain spermatozoa from the rete testis and pierce the Extratesticular Genital Ducts
tunica albuginea of the testis to conduct the sperm to
the epididymis (see Fig. 21-2). Thus, the ductuli effer- The extratesticular genital ducts are the epididymis,
entes become confluent with the epididymis at this ductus deferens, and ejaculatory duct.
point.
The simple epithelial lining of the lumen of each The extratesticular genital ducts associated with each
ductule consists of patches of nonciliated cuboidal testis are the epididymis, the ductus deferens (vas def-
cells alternating with regions of ciliated columnar erens), and the ejaculatory duct (see Fig. 21-1). The epi-
cells. The successive clusters of short and tall epithelial didymis secretes numerous factors that, in an unknown
cells impart the characteristic festooned appearance to manner, facilitate maturation of spermatozoa. As noted
the lumina of the ductuli efferentes. The cuboidal cells previously, however, spermatozoa cannot fertilize a
are richly endowed with lysosomes, and their apical secondary oocyte until they undergo capacitation, a
plasmalemmae display numerous invaginations indica- process triggered by secretions produced in the female
tive of endocytosis. These cells are believed to resorb genital tract.
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epithelium of the bovine rete testis (×19,900). BL,
basal lamina; CF, collagen fibers; CI, cilium; ID,
interdigitation of the lateral plasmalemmae; JC, junc-
tional complexes; MC, monocellular cell; MF, myofi-
broblast; N, nucleus. (From Hees H, Wrobel KH, MF
Elmagd AA, Hees I: The mediastinum of the bovine
testis. Cell Tissue Res 255:29-39, 1989.)
Epididymis large accumulations of heterochromatin impart a dense

appearance to this structure. The sparse cytoplasm of
The epididymis, a highly convoluted tubule divided into a these cells is relatively clear, with a scarcity of
head, body, and tail, is continuous with the ductus deferens. organelles. It is believed that the basal cells function as
stem cells, regenerating themselves as well as the prin-
Each epididymis is a thin, long (4 to 6 m), highly con- cipal cells as the need arises.
voluted tubule that is folded into a space only 7 cm long The tall principal cells of the epithelium of the epi-
on the posterior aspect of the testis (see Fig. 21-2). The didymis have irregular, oval nuclei with one or two large
epididymis may be subdivided into three regions: head, nucleoli. These nuclei are much paler than those of the
body, and tail. The head, formed by the union of the 10 basal cells and are located basally within the cell.
to 20 ductuli efferentes, becomes highly coiled and con- The cytoplasm of the principal cell houses abundant
tinues as the equally highly coiled body. The distal RER located between the nucleus and the basal plas-
portion of the tail, which stores spermatozoa for a short malemma. The cytoplasm also has a large, supranu-
time, loses its convolutions as it becomes continuous clearly positioned Golgi complex, numerous profiles of
with the ductus deferens. apically located SER, endolysosomes, and multivesicular
The lumen of the epididymis is lined by a pseudo- bodies. The apical cell membranes of the principal cells
stratified epithelium composed of two cell types display a profusion of pinocytotic and coated vesicles at
(Fig. 21-16): the bases of the many stereocilia that project into the
䡲 Basal cells lumen of the epididymis. These long, branched, cellular
䡲 Principal cells extensions are clusters of nonmotile microvilli that
appear to form clumps as they adhere to one another.
The short basal cells of this epithelium are pyra- The principal cells resorb the luminal fluid, which is
midal to polyhedral. They have round nuclei in which endocytosed by pinocytotic vesicles and delivered to the
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from the tail of the epididymis to the ejaculatory duct

(see Figs. 21-1 and 21-2).
BC
The stereociliated pseudostratified columnar
epithelium of the ductus deferens is similar to that of
the epididymis, although the principal cells are shorter.
A basal lamina separates the epithelium from the
underlying loose fibroelastic connective tissue, which
has numerous folds, thus making the lumen appear
irregular. The thick smooth muscle coat surrounding
Ep the connective tissue is composed of three layers: inner
and outer longitudinal layers with an intervening middle
circular layer. The smooth muscle coat is invested by a
thin layer of loose fibroelastic connective tissue.
PC
SM CLINICAL CORRELATIONS
Because the ductus deferens has a muscular wall
1 mm thick, it is easily perceptible through the
skin of the scrotum as a dense, rolling tubule.
Vasectomy (surgical removal of part of the
ductus deferens) is performed via a small slit
through the scrotal sac, thus sterilizing the
person.
The dilated terminus of each ductus deferens, known

Figure 21–16 Light micrograph of the epididymis in a monkey
(×270). Basal cells (BC), epithelium (Ep), principal cells (PC), smooth as the ampulla, has a highly folded, thickened epithe-
muscle (SM). lium. As the ampulla approaches the prostate gland, it
is joined by the seminal vesicle. The continuation of the
junction of the ampulla with the seminal vesicle is called
the ejaculatory duct.
endolysosomes for disposal. Additionally, these cells
phagocytose remnants of cytoplasm that were not Ejaculatory Duct
removed by Sertoli cells. Principal cells also manufac- The ampulla of the ductus deferens joins the seminal
ture glycerophosphocholine, a glycoprotein that vesicle to form the ejaculatory duct, which then enters
inhibits spermatozoon capacitation, thus preventing the
the prostate gland and opens in the prostatic urethra.
spermatozoon from fertilizing a secondary oocyte until
the sperm enters the female genital tract. Each ejaculatory duct is a short, straight tubule that
The epithelium of the epididymis is separated by a enters the substance of and is surrounded by the
basal lamina from the underlying loose connective prostate gland (see Fig. 21-1). The ejaculatory duct
tissue. A layer of circularly arranged smooth muscle ends as it pierces the posterior aspect of the prostatic
cells surrounds the connective tissue layer. Peristaltic urethra at the colliculus seminalis. The lumen of the
contractions of this layer help conduct the spermato- ejaculatory duct is lined by a simple columnar epithe-
zoa to the ductus deferens. lium. The subepithelial connective tissue is folded, a
feature responsible for the irregular appearance of its
Ductus Deferens (Vas Deferens) lumen. The ejaculatory duct has no smooth muscle in
its wall.
The ductus deferens is a muscular tube that conveys
spermatozoa from the tail of the epididymis to the
ejaculatory duct. ACCESSORY GENITAL GLANDS
Each ductus deferens is a thick-walled muscular tube The male reproductive system has five accessory
with a small, irregular lumen that conveys spermatozoa glands: the paired seminal vesicles, the single prost-
Ch021-X2945.qxd 15/8/06 2:53 PM Page 505
ate gland, and the paired bulbourethral glands (see apparatus, numerous mitochondria, some lipid and
Fig. 21-1). lipochrome pigment droplets, and abundant secretory
granules. The height of the cells varies directly with
Seminal Vesicles blood testosterone levels. The subepithelial connective
tissue is fibroelastic and is surrounded by smooth
The paired seminal vesicles, located adjacent to the muscle cells, arranged as an inner circular layer and an
posterior wall of the prostate gland, secrete a viscous outer longitudinal layer. The smooth muscle coat is,
fluid that constitutes about 70% of the ejaculate. in turn, surrounded by a flimsy layer of fibroelastic con-
nective tissue.
The paired seminal vesicles are highly coiled tubular The seminal vesicles once were believed to store
structures about 15 cm long. They are located between spermatozoa, some of which are always present in the
the posterior aspect of the neck of the bladder and the lumen of this gland. It is now known that these glands
prostate gland and join the ampulla of the ductus def- produce a viscous, yellow fructose-rich seminal fluid
erens just above the prostate gland. that constitutes 70% of the volume of semen. Although
The mucosa of the seminal vesicles is highly convo- seminal fluid also contains amino acids, citrates,
luted, forming labyrinth-like cul-de-sacs that, in three prostaglandins, and proteins, fructose is its principal
dimensions, are observed to open into a central lumen. constituent, because it is the source of energy for sper-
The lumen is lined by a pseudostratified columnar matozoa. The characteristic pale yellow color of semen
epithelium composed of short basal cells and low is due to the lipochrome pigment released by the
columnar cells (Fig. 21-17). seminal vesicles.
Each columnar cell has numerous short microvilli
and a single flagellum projecting into the lumen of the Prostate Gland
gland. The cytoplasm of these cells displays RER, Golgi
The prostate gland, surrounding a portion of the
urethra, secretes acid phosphatase, fibrinolysin, and citric
acid directly into the lumen of the urethra.
The prostate gland, the largest of the accessory glands,

is pierced by the urethra and the ejaculatory ducts (Fig.
21-18). The slender capsule of the gland is composed
of a richly vascularized, dense, irregular collagenous
CC
Bladder
L
Prostate
Sz
Urethra
BC
Capsule
Ejaculatory ducts
Prostatic ducts
Mucosal glands
Submucosal glands
Main prostatic glands
Figure 21–17 Light micrograph of the monkey seminal vesicle

(×270). Basal cells (BC), columnar cells (CC), lumen (L), spermato-
zoa (Sz) . Figure 21–18 Human prostate gland.
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connective tissue interspersed with smooth muscle The lumina of the tubuloalveolar glands frequently
cells. The connective tissue stroma of the gland is house round to oval prostatic concretions (corpora
derived from the capsule and is, therefore, also amylacea), composed of calcified glycoproteins, whose
enriched by smooth muscle fibers in addition to their numbers increase with a person’s age (see Fig. 21-19).
normal connective tissue cells. The significance of these concretions is not understood.
The prostate gland, a conglomeration of 30 to 50 The prostatic secretion constitutes a part of semen.
individual compound tubuloalveolar glands, is It is a serous, white fluid rich in lipids, proteolytic
arranged in three discrete, concentric layers: enzymes, acid phosphatase, fibrinolysin, and citric acid.
The formation, synthesis, and release of the prostatic
䡲 Mucosal
secretions are regulated by dihydrotestosterone, the
䡲 Submucosal
active form of testosterone.
䡲 Main
Each tubuloalveolar gland has its own duct that
delivers the secretory product into the prostatic urethra.
The mucosal glands are closest to the urethra and
thus are the shortest of the glands. The submucosal
glands are peripheral to the mucosal glands and are
consequently larger than the mucosal glands. The
largest and most numerous of the glands are the periph-
eral-most main glands, which compose the bulk of the
prostate.
The components of the prostate gland are lined by a
simple to pseudostratified columnar epithelium
(Fig. 21-19), the cells of which are well endowed with
organelles responsible for the synthesis and packaging
of proteins. Hence, these cells have an abundant RER,
a large Golgi apparatus, numerous secretory granules
(Fig. 21-20), and many lysosomes.
Figure 21–20 Electron micrograph of the prostate gland in a

hamster. G, Golgi apparatus; M, microvilli; R, rough endoplasmic
reticulum. Bar = 5 µm. (From Toma JG, Buzzell GR: Fine structure
Figure 21–19 Light micrograph of the prostate gland of a of the ventral and dorsal lobes of the prostate in a young adult Syrian
monkey (×132). Note areas of prostatic concretion (arrows). hamster, Mesocricetus auratus. Am J Anat 181:132-140, 1988.)
Ch021-X2945.qxd 15/8/06 2:53 PM Page 507
erection of the penis. Just before ejaculation, secretions

CLINICAL CORRELATIONS from the prostate are discharged into the urethra, as are
the spermatozoa from the ampulla of the ductus defer-
As men age, the prostatic stroma and mucosal ens. The prostatic secretions apparently help the sper-
and submucosal glands begin to enlarge, a con- matozoa achieve motility. The final secretions arise
dition known as benign prostatic hypertro- from the seminal vesicles, which are responsible for a
phy. The enlarged prostate partially strangulates significant increase in the volume of the semen. Their
the lumen of the urethra, resulting in difficulties fructose-rich fluid is used by the spermatozoa for
with urination. Approximately 40% of men 50 energy.
years of age are afflicted with this condition; The ejaculate, known as semen, is about 3 mL in
the percentage increases to 95% in 80-year-old volume in humans and consists of secretions from the
men. accessory glands and 200 to 300 million spermatozoa.
The second most common form of cancer in
men is adenocarcinoma of the prostate. It
affects approximately 30% of men over 75 years PENIS
of age. Frequently, the cancer cells enter the cir-
culatory system and metastasize to bone. A The penis functions as an excretory organ for urine and
simple blood test to detect prostatic-specific as the male copulatory organ for the deposition of
antigen (PSA) has been developed that permits spermatozoa into the female reproductive tract.
early detection of prostatic adenocarcinoma.
Although tumor growth can be detected by The penis is composed of three columns of erec-
digital palpation through the rectum, a biopsy is tile tissue, each enclosed by its own dense, fibrous
required for confirmation. Surgery or radiother- connective tissue capsule, the tunica albuginea
apy are the usual treatments but they are not (Fig. 21-21).
without possible side effects such as impotence
and incontinence.
Penis
Bulbourethral Glands
The paired bulbourethral glands, located at the root of
the penis, secrete a slippery lubricating solution directly
into the urethra.
The bulbourethral glands (Cowper’s glands) are small

(3 to 5 mm in diameter) and are located at the root of
the penis, just at the beginning of the membranous
urethra (see Fig. 21-1). Their fibroelastic capsule con-
tains not only fibroblasts and smooth muscle cells but Superficial
also skeletal muscle fibers derived from the muscles of Deep dorsal dorsal vein
artery and
the urogenital diaphragm. Septa derived from the vein
capsule divide each gland into several lobules. The
epithelium of these compound tubuloalveolar glands Erectile
varies from simple cuboidal to simple columnar. tissue
The secretion produced by the bulbourethral glands
is a thick, slippery fluid containing galactose and sialic
acid that probably plays a role in lubricating the lumen
of the urethra. During the process of ejaculation, this Tunica
viscous fluid precedes the remainder of the semen. albuginea
Histophysiology of the Accessory Corpus

cavernosum
Genital Glands
Corpus Urethra
The bulbourethral glands secrete a viscous slippery fluid spongiosum
that lubricates the lining of the urethra. It is the first of
the glandular secretions to be released subsequent to Figure 21–21 The penis in cross section.
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Two of the columns of erectile tissue, the corpora Mechanisms of Erection,

cavernosa, are positioned dorsally; their tunicae albu- Ejaculation, and Detumescence
gineae are discontinuous in places, permitting commu-
nication between their erectile tissue. The third column Erection is controlled by the parasympathetic
of erectile tissue, the corpus spongiosum, is posi- nervous system; it is a result of sexual, tactile, olfactory,
tioned ventrally. Because the corpus spongiosum houses visual, auditory, and/or psychological stimulation.
the penile portion of the urethra, it is also called the Ejaculation is controlled by the sympathetic nervous
corpus cavernosum urethrae. The corpus spongiosum system.
ends distally in an enlarged, bulbous portion, the glans
penis (head of the penis). The tip of the glans penis is When the penis is flaccid, the vascular spaces of the
pierced by the end of the urethra as a vertical slit. erectile tissue contain little blood. In this condition,
The three corpora are surrounded by a common much of the arterial blood flow is diverted into arterio-
loose connective tissue sheath, but no hypodermis, and venous anastomoses that connect the branches of the
are covered by thin skin. The skin of the proximal deep and dorsal arteries of the penis to veins that deliver
portion of the penis has coarse pubic hairs and numer- their blood into the deep dorsal vein (Fig. 21-22A).
ous sweat and sebaceous glands. The distal portion of Thus, the blood flow bypasses the vascular spaces of the
the penis is hairless and has only a few sweat glands. erectile tissue.
Skin continues distal to the glans penis to form a Erection occurs when blood flow is shifted to the
retractable sheath, the prepuce, which is lined by a vascular spaces of the erectile tissues (the corpora cav-
mucous membrane, a moist, stratified squamous ernosa and, to a limited extent, the corpus spongiosum),
nonkeratinized epithelium. When an individual is cir- causing the penis to enlarge and become turgid (Fig.
cumcised, it is the prepuce that is removed. 21-22B). During erection, the tunica albuginea sur-
rounding the erectile tissues is stretched and decreases
Structure of Erectile Tissue in thickness from 2 to 0.5 mm.
The shift in blood flow that leads to erection is
Vascular spaces within the erectile tissues become controlled by the parasympathetic nervous system
engorged with blood, causing erection of the penis. following sexual stimulation (e.g., pleasurable tactile,
olfactory, visual, auditory, and psychological stimuli).
Erectile tissue of the penis contains numerous variably The parasympathetic impulses trigger local release
shaped, endothelially lined spaces that are separated of nitric oxide, which causes relaxation of smooth
from one another by trabeculae of connective tissue and muscles of the branches of the deep and dorsal arter-
smooth muscle cells. The vascular spaces of the corpora ies of the penis, increasing the flow of blood into the
cavernosa are larger centrally and smaller peripherally, organ. Simultaneously, the arteriovenous anastomoses
near the tunica albuginea. However, the vascular spaces undergo constriction, diverting the flow of blood into
of the corpus spongiosum are similar in size throughout the helical arteries of the erectile tissue. As these spaces
its extent. The trabeculae of the corpus spongiosum become engorged with blood, the penis enlarges and
contain more elastic fibers and fewer smooth muscle becomes turgid, and erection ensues. The veins of the
cells than those of the corpora cavernosa. penis become compressed, and the blood is trapped in
The erectile tissues of the corpora cavernosa receive the vascular spaces of the erectile tissue, thus main-
blood from branches of the deep and dorsal arteries taining the penis in an erect condition (see Fig. 21-22).
of the penis (see Fig. 21-21). These branches pene- Continued stimulation of the glans penis results in
trate the walls of the trabeculae of the erectile tissue ejaculation, the forceful expulsion of semen from the
and form either capillary plexuses, which supply some male genital ducts. Each ejaculate, which has a volume
blood flow into the vascular spaces, or coiled arteries of about 3 mL in humans, consists of secretions from
(helical arteries), which are important sources of the accessory genital glands and 200 to 300 million
blood to the vascular spaces during erection of the spermatozoa. Subsequent to erection, the bulboure-
penis. thral glands release a viscous fluid that lubricates the
Venous drainage occurs via three groups of veins, lining of the urethra. Just before ejaculation, the
which are drained by the deep dorsal vein (see Fig. prostate gland discharges its secretion into the urethra,
21-21). The three groups of veins arise from the base of and spermatozoa from the ampullae of the two ductus
the glans penis, from the dorsal aspect of the corpora deferentes are released into the ejaculatory ducts. The
cavernosa, and from the ventral aspect of the corpora prostatic secretion apparently helps the spermatozoa
cavernosa and the corpus spongiosum. Additionally, achieve motility. The final secretion added to semen is
some of the veins leave the erectile tissue at the root of a fructose-rich fluid, released from the seminal vesicles,
the penis and drain into the plexus of veins that drain that provides energy to the spermatozoa. This secretion
the prostate gland. forms much of the volume of the ejaculate.
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Flaccid penis Erect penis
Figure 21–22 Circulation in the

flaccid and erect penis. The arterio-
venous anastomosis (arrow) in the
flaccid penis is wide, diverting blood
flow into the venous drainage. In the
erect penis, the arteriovenous anas-
tomosis is constricted and blood
flow into the vascular spaces of the Blood circulating through Blood filling
erectile tissue is increased, causing corpora cavernosa corpora cavernosa
the penis to become turgid with
blood. (Adapted from Conti G: Acta Erectile tissue Erectile tissue
Anat 5:217, 1952.)
Ejaculation, unlike erection, is regulated by the sym-

CLINICAL CORRELATIONS pathetic nervous system. These impulses trigger the
following sequence of events:
A single ejaculate normally contains approxi-
mately 50 to 100 million spermatozoa per milli-
liter. A male whose sperm count is less than 20 1 Contraction of the smooth muscles of the genital
million spermatozoa per milliliter of ejaculate is ducts and accessory genital glands forces the semen
considered sterile. into the urethra.
The inability to achieve erection is known as 2 The sphincter muscle of the urinary bladder con-
impotence. Temporary erectile dysfunction can tracts, preventing the release of urine (or the entry
result from psychological factors or drugs (e.g., of semen into the bladder).
alcohol); whereas permanent impotence can be 3 The bulbospongiosus muscle, which surrounds the
caused by many factors, including lesions in cer- proximal end of the corpus spongiosum (bulb of the
tain regions of the brain and hypothalamus, as penis), undergoes powerful, rhythmic contractions,
well as spinal cord injuries, autonomic innerva- resulting in forceful expulsion of semen from the
tion malfunction, stroke, Parkinson’s disease, dia- urethra.
betes, multiple sclerosis, and even psychological
disorders. Ejaculation is followed by the cessation of parasym-
pathetic impulses to the vascular supply of the penis.
Ch021-X2945.qxd 15/8/06 2:53 PM Page 510
As a result, the arteriovenous shunt is reopened, blood drainage. As the blood leaves these vascular spaces,
flow through the deep and dorsal arteries of the penis the penis undergoes detumescence and becomes
is diminished, and the vascular spaces of the erectile flaccid.
tissues are slowly emptied of blood by the venous
The neurotransmitter nitric oxide (NO) released enzyme, phosphodiesterase (PDE), destroys the
by the endothelial cells of the sinusoids activate cGMP, permitting smooth muscle contraction to
guanlyate cyclase of smooth muscle cells to produce occur again; the sinusoids begin to be drained of
cyclic guanosine monophosphate (cGMP) from blood and the erection is terminated.
guanosine triphosphate (GTP), thus relaxing the the Although sildenafil (Viagra) was originally
smooth muscle cells. Relaxation of the smooth developed as a treatment for heart failure, it was
muscle cells permits the accumulation of blood in found to produce erections in many patients.
the sinusoids, and these enlarged vessels compress Further study showed that the medication blocked
the small return venous channels that drain the sinu- phosphodiesterase from inhibiting cGMP degrada-
soids, resulting in erection of the penis. tion, thus leading to erection.
After ejaculation or when the parasympathetic
impulses cease and cGMP levels dwindle, another
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22 䡲䡲䡲
Special Senses
Peripheral nerve terminals are of two structural types: within the head; this input is transmitted to the brain
(1) terminals of axons, which transmit impulses from the for processing into awareness of motion for corrective
central nervous system (CNS) to skeletal and smooth balancing.
muscles (motor endings) or to glands (secretory Interoceptors are specialized receptors that per-
endings), and (2) terminals of dendrites, called ceive sensory information from within organs of the
sensory endings or receptors, which perceive various body; therefore, the modality serving this function is the
stimuli and transmit this sensory input to the CNS. general visceral afferent modality.
These sensory receptors are classified into three types,
depending on the source of the stimulus, and are com- SPECIALIZED PERIPHERAL
ponents of the general or special somatic and visceral
afferent pathways: RECEPTORS
䡲 Exteroceptors Certain peripheral receptors, specialized to receive
䡲 Proprioceptors particular stimuli, include mechanoreceptors,
䡲 Interoceptors thermoreceptors, and nociceptors.
Exteroceptors, located near the body surface, are
The dendritic endings of certain sensory receptors,
specialized to perceive stimuli from the external envi-
located in various regions of the body, including
ronment. These receptors, sensitive to temperature,
muscles, tendons, skin, fascia, and joint capsules, are
touch, pressure, and pain, are components of the
specialized to receive particular stimuli. These adapta-
general somatic afferent pathways and are described
in the first part of this chapter. Other exteroceptors, spe- tions help the dendrite respond to a particular stimulus.
Thus, these receptors are classified into three types:
cialized for perceiving light (sense of vision) and sound
(sense of hearing), are components of the special 䡲 Mechanoreceptors, which respond to touch (Figs.
somatic afferent pathways (discussed later). Smell and 22-1 to 22-3)
taste stimuli are perceived by unique nerve endings in 䡲 Thermoreceptors, which respond to cold and
the viscera of the respiratory and digestive systems, warmth
respectively; these exteroceptors are classified as the 䡲 Nociceptors, which respond to pain due to mechan-
special visceral afferent modality. Receptors for ical stress, extremes of temperature differences, and
olfaction (sense of smell) are discussed in Chapter 15, chemical substances
and receptors for taste are discussed in Chapter 16.
Proprioceptors are specialized receptors located in Although these specialized receptors generally are
joint capsules, tendons, and intrafusal fibers within triggered only by a particular stimulus, any stimulus that
muscles (see Chapter 8). These general somatic is intense enough can trigger any receptor.
afferent receptors transmit sensory input to the CNS,
Mechanoreceptors
which is translated into information that relates to an
awareness of the body in space and in movement. Mechanoreceptors respond to mechanical stimuli that
Certain receptors of the vestibular (balance) mech- may deform the receptor or the tissues surrounding the
anism (see later), located within the inner ear, are spe- receptor. Stimuli that trigger the mechanoreceptors are
cialized for receiving stimuli related to motion vectors touch, stretch, vibrations, and pressure.
511
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512 䡲䡲䡲 Chapter 22 䡲 Special Senses
Nonencapsulated Fig. 22-1D). Additionally, peritricial nerve endings are

Mechanoreceptors wrapped around the base and shaft of hair follicles and
function in touch perception related to the deformation
Nonencapsulated mechanoreceptors are simple of the hairs. Moreover, some naked nerve endings func-
unmyelinated receptors present in the skin, connective tion as nociceptors or as thermoreceptors.
tissues, and surrounding hair follicles. Merkel’s disks are slightly more complex
mechanoreceptors (see Fig. 22-1A). Specialized for per-
Peritricial nerve endings, the simplest form of ceiving discriminatory touch, these receptors are com-
mechanoreceptors, are unmyelinated, lack Schwann posed of an expanded unmyelinated nerve terminal
cells, and are not covered by a connective tissue associated with Merkel cells, specialized epithelial
capsule. Such nerve endings are located in the epider- cells interspersed with keratinocytes in the stratum
mis of the skin, especially in regions of great sensitivity, basale of the skin (see Fig. 14-1). These receptors are
such as the face and the cornea of the eye, where they located mostly in nonhairy skin and regions of the body
respond to stimuli related to touch and pressure (see more sensitive to touch.
A B C
D E F
Figure 22–1 Various mechano-

receptors. A, Merkel’s disk. B, Meiss-
ner’s corpuscle. C, Pacinian corpuscle.
D, Peritricial (naked) nerve endings.
E, Ruffini’s corpuscle. F, Krause’s end
bulb. G, Muscle spindle. H, Golgi
G H tendon organ.
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Chapter 22 䡲 Special Senses ■ ■ ■ 513
OC
Ca
IC
NF
Figure 22–2 Pacinian corpus-

cles (×132). Ca, capsule; IC, inner
core; NF, nerve fiber; OC, outer
core.
NF
N
Ca
Figure 22–3 Meissner’s cor-

puscle (×540). Ca, capsule; N,
nuclei; NF, nerve fiber.
Encapsulated Mechanoreceptors papillae of the glabrous (nonhairy) portion of the fingers

and palms of the hands, where they account for about
Encapsulated mechanoreceptors exhibit characteristic half of the tactile receptors. They also are located in
structures and are present in specific locations. the eyelids, lips, tongue, nipples, and skin of the foot
and forearm. Meissner’s corpuscles, which measure 80
Meissner’s corpuscles (see Fig. 22-3) are encapsu- by 30 µm, are located in the dermal papillae, with their
lated mechanoreceptors specialized for tactile dis- long axes oriented perpendicular to the skin surface (see
crimination. These receptors are located in the dermal Fig. 22-1B). Each Meissner’s corpuscle is formed by
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three or four nerve terminals and their associated information also reaches the cerebellum and even
Schwann cells, all of which are encapsulated by con- the cerebral cortex, so that the individual may sense
nective tissue. Contained within the capsule are stacks muscle position. Golgi tendon organs and muscle spin-
of epithelioid cells, possibly modified Schwann cells or dles are discussed in Chapter 8.
fibroblasts, that serve to separate the branching nerve
terminals. Meissner’s corpuscles are especially sensitive Thermoreceptors
to edges and points and to movements of these objects.
Pacinian corpuscles, another example of the encap- Thermoreceptors, which respond to temperature
sulated mechanoreceptors, are located in the dermis and differences of about 2° C [35.6° F], are of three types:
hypodermis in the digits of the hands and in the breasts, warmth receptors, cold receptors, and temperature-
as well as in connective tissue of the joints, periosteum, sensitive nociceptors.
and the mesentery. These mechanoreceptors are spe-
cialized to perceive pressure, touch, and vibration. Although specific receptors have not been identified
Pacinian corpuscles are large, ovoid receptors 1 to 2 mm for warmth, it is assumed that these receptors are
long by 0.1 to 0.7 mm in diameter (see Figs. 22-1C and naked endings of small nonmyelinated nerve fibers that
22-2). Each receptor is composed of a single unmyeli- respond to temperature increases. Cold receptors are
nated fiber that courses the entire length of the derived from naked nerve endings of myelinated fibers
corpuscle. The core of the corpuscle contains the non- that branch and penetrate the epidermis. Because ther-
myelinated nerve terminal and its Schwann cells, sur- moreceptors are not activated by physical stimulation,
rounded by approximately 60 layers of modified they are believed to respond to differing rates of tem-
fibroblasts, each layer separated from the next by a small perature-dependent biochemical reactions.
fluid-filled space. An additional group of 30 less dense,
modified fibroblasts surround the core and are, in turn, Nociceptors
enveloped by connective tissue, forming the capsule Nociceptors are receptors sensitive to pain caused by
around the core. The arrangement of the cells in the mechanical stress, extremes of temperature, and
lamellae makes the histological section of a pacinian cor- cytokines such as bradykinin, serotonin, and histamine.
puscle resemble a sliced onion.
Ruffini’s endings (corpuscles) are encapsulated Nociceptors are responsible for pain perception. These
endings located in the dermis of the skin, nail beds, receptors are naked endings of myelinated nerve fibers
periodontal ligaments,and joint capsules. These large that branch freely in the dermis before entering the epi-
receptors, 1 mm long by 0.2 mm in diameter (see Fig. dermis. Nociceptors are divided into three groups: (1)
22-1E), are composed of branched, nonmyelinated ter- those that respond to mechanical stress or damage; (2)
minals interspersed with collagen fibers and surrounded those that respond to extremes in heat or cold; and
by four to five layers of modified fibroblasts. The con- (3) those that respond to chemical compounds such as
nective tissue capsule surrounding each of these recep- bradykinin, serotonin, and histamine.
tors is anchored at each end, increasing their sensibility
to stretching and pressure in the skin and in the joint
capsules. EYE
Krause’s end bulbs are spherical, encapsulated
nerve endings located in the papillary region of the The bulb of the eye is composed of three tunics: fibrous,
dermis, joints, conjunctiva, peritoneum, genital regions, vascular, and neural.
and the subendothelial connective tissues of the oral
and nasal cavities (see Fig. 22-1F). Originally, they were The eyes (orbs), approximately 24 mm in diameter, are
thought to be receptors sensitive to cold, but present located within the hollow bony orbits of the skull . They
evidence does not support this concept. Their function are the photosensory organs of the body. Light passes
is unknown. through the cornea, lens, and several refractory struc-
Both muscle spindles and Golgi tendon organs are tures of the orb; light is then focused by the lens on the
encapsulated mechanoreceptors involved in proprio- light-sensitive portion of the neural tunic of the eye, the
ception. Muscle spindles (see Fig. 22-1G) provide retina, which contains the photosensitive rods and
feedback concerning the changes in muscle length as cones. Through a series of several layers of nerve cells
well as the rate of alteration in the length of the muscle, and supporting cells, the visual information is transmit-
and Golgi tendon organs (see Fig. 22-1H) monitor ted by the optic nerve to the brain for processing.
the tension as well as the rate at which the tension is The eyes begin to develop from three different
being produced during movement. Information from sources at about the 4th week of embryonic develop-
these two sensory structures is processed mostly at the ment. Outgrowths of the forebrain, the future retina
unconscious levels within the spinal cord; however, the and optic nerve, are the first to be observed. As a result
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of continued growth of this structure, the surface ecto- (tear gland), which secretes lacrimal fluid (tears) that
derm is induced to develop into the lens and some of moistens the anterior surface of the eye. The lacrimal
the accessory structures of the anterior portion of the fluid moistens the eye and the inner surface of the
eye. Later in development, adjacent mesenchyme con- eyelids by passing through the conjunctiva, a trans-
denses to form the tunics and associated structures of parent membrane that covers and protects the anterior
the orb. surface of the eye.
The bulb of the eye is composed of three tunics, or
coats (Fig. 22-4): Tunica Fibrosa
䡲 A fibrous tunic, forming the tough outer coat of the The tunica fibrosa is composed of the sclera and the
eye cornea.
䡲 A vascular tunic, the pigmented and vascular
middle coat The external fibrous tunic of the eye, the tunica fibrosa,
䡲 A neural tunic, the retina, composing the innermost is divided into the sclera and the cornea (see Fig. 22-4).
coat The white, opaque sclera covers the posterior five
The fibrous tunic of the eye also receives insertions sixths of the orb, whereas the colorless, transparent
of the extrinsic muscles of the eye, which are respon- cornea covers the anterior one-sixth of the orb.
sible for coordinated movements of the eyes to gain
access to various visual fields. Smooth muscles located Sclera
within the orb accommodate focusing of the lens and
The white opaque sclera is composed of type I collagen
control the aperture of the pupil. Located outside the
fibers interlaced with elastic fibers.
orb, but still within the orbit, is the lacrimal gland
Ciliary body
Sclera
Ciliary process
Suspensory
ligament of lens Schlemm's canal
Extrinsic eye muscle
Conjunctiva Lens Posterior chamber
Ora serrata Anterior chamber
Sclera Cornea
Vitreous body Descemet's membrane
Hyaloid canal Endothelium
Fovea centralis
in macula
lutea Dilator muscle
of pupil
Sphincter muscle
of pupil
Optic nerve
Bulbar sheath
Cornea
Retina
Anterior chamber
Choroid Iris
Posterior chamber
Lens
Ciliary body
Figure 22–4 Anatomy of the eye (orb).

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The sclera, the white of the eye, is nearly devoid of replaces the cells that migrated to the wound. The
blood vessels. It is a tough, fibrous connective tissue corneal epithelium also functions in transferring water
layer, about 1 mm thick posteriorly, thinning at the and ions from the stroma into the conjunctival sac.
equator and then thickening again near its junction with Bowman’s membrane lies immediately deep to the
the cornea. It consists of interlacing type I collagen corneal epithelium. Electron micrographs reveal it to be
bundles alternating with networks of elastic fibers; this a fibrillar lamina, 6 to 30 µm thick, composed of type I
arrangement gives form to the orb, which is maintained collagen fibers arranged in an apparently random
by intraocular pressure from the aqueous humor fashion. It is believed that Bowman’s membrane is syn-
(located anterior to the lens) and the vitreous body thesized by both the corneal epithelium and cells of
(located posterior to the lens). the underlying stroma. Sensory nerve fibers pass through
Fibroblasts located in the connective tissue of the this structure to enter and terminate in the epithelium.
sclera are elongated, flat cells. Melanocytes are located The transparent stroma is the thickest layer of the
in deeper regions of the sclera. Tendons of the extraoc- cornea, constituting about 90% of its thickness. It is
ular muscles insert into the dense connective tissue composed of collagenous connective tissue, consisting
surface layer of the sclera, which is enveloped by the mostly of type I collagen fibers that are arranged in 200
capsule of Tenon, a fascial sheath that covers the optic to 250 lamellae, each about 2 µm in thickness. The col-
nerve and the orb as far anteriorly as the ciliary region. lagen fibers within each lamella are arranged parallel to
This sheath, which separates the orb from the perior- one another, but fiber orientation shifts in adjacent
bital fat, is connected to the sclera by a thin layer of loose lamellae. The collagen fibers are interspersed with thin
connective tissue called the episclera. The orb, along elastic fibers, embedded in ground substance contain-
with its various parts and attached extraocular muscles, ing mostly chondroitin sulfate and keratan sulfate.
moves in unison within the periorbital fat–filled bony orbit. Long, slender fibroblasts are also present among the
collagen fiber bundles. During inflammation, lympho-
Cornea cytes and neutrophils are also present in the stroma. At
the limbus (sclerocorneal junction) is a scleral sulcus
The cornea is the transparent bulging anterior sixth of whose inner aspect at the stroma is depressed and
the orb. houses endothelium-lined spaces, known as the tra-
becular meshwork, that lead to the canal of Schlemm.
The cornea is the transparent, avascular, and highly
The canal of Schlemm is the site of outflow of the
innervated anterior portion of the fibrous tunic that
aqueous humor from the anterior chamber of the eye
bulges out anteriorly from the orb. It is slightly thicker
into the venous system.
than the sclera and is composed of five histologically dis-
Descemet’s membrane is a thick basement mem-
tinct layers:
brane interposed between the stroma and the underly-
䡲 Corneal epithelium ing endothelium. Although this membrane is thin (5 µm
䡲 Bowman’s membrane at birth) and homogeneous in younger persons, electron
䡲 Stroma microscopy has demonstrated that it becomes thicker
䡲 Descemet’s membrane (17 µm) and has cross-striations and hexagonal fiber
䡲 Corneal endothelium patterns in older adults.
The corneal endothelium, which lines the internal
The corneal epithelium, the continuation of the (posterior) surface of the cornea, is a simple squamous
conjunctiva (a mucous membrane covering the anterior epithelium. It is responsible for synthesis of proteins
sclera and lining the internal surface of the eyelids), is that are necessary for secreting and maintaining
a stratified, squamous, nonkeratinized epithelium, com- Descemet’s membrane. These cells exhibit numerous
posed of five to seven layers of cells, that covers the pinocytotic vesicles, and their membranes have sodium
anterior surface of the cornea. The larger superficial pumps that transport sodium ions (Na+) into the anterior
cells have microvilli and exhibit zonulae occludentes. chamber; these ions are passively followed by chloride
The remaining cells constituting the corneal epithelium ions (Cl−) and water. Thus, excess fluid within the stroma
interdigitate with and form desmosomal contacts with is resorbed by the endothelium, keeping the stroma rel-
one another. Their cytoplasm contains the usual array atively dehydrated, a factor that contributes to main-
of organelles along with intermediate filaments. The taining the refractive quality of the cornea.
corneal epithelium is highly innervated by numerous
free nerve endings. Mitotic figures are observed mostly Tunica Vasculosa
near the periphery of the cornea, with a turnover rate
of approximately 7 days. Damage to the cornea is The vascular middle tunic of the eye, the tunica vascu-
repaired rapidly as cells migrate to the defect to cover losa (uvea), is composed of three parts: (1) the choroid,
the injured region. Subsequently, mitotic activity (2) the ciliary body, and (3) the iris (see Fig. 22-4).
Ch022-X2945.qxd 12/8/06 3:45 PM Page 517
Choroid the lens capsule, forming the suspensory ligaments of

the lens, which anchor the lens in place.
The choroid, the pigmented posterior portion of the The ciliary processes are covered by the same two
middle vascular tunic, is loosely attached to the sclera layers of epithelium that cover the ciliary body. The
and separated from the retina by Bruch’s membrane. inner nonpigmented layer has many interdigitations and
infoldings; its cells transport a protein-poor plasma fil-
The choroid is the well-vascularized, pigmented layer trate, the aqueous humor, into the posterior chamber
of the posterior wall of the orb that is loosely attached of the eye. The aqueous humor flows from the poste-
to the tunica fibrosa. It is composed of loose connective rior chamber into the anterior chamber by passing
tissue containing numerous fibroblasts and other con- through the pupillary aperture between the iris and
nective tissue cells, and it is richly supplied with blood the lens. The aqueous humor exits the anterior chamber
vessels. The black color of the choroid is due to the by passing into the trabecular meshwork near the
myriad of melanocytes present in it. Because of the limbus and, finally, as stated previously, into the canal
abundance of small blood vessels in the inner surface of of Schlemm, which leads directly into the venous
the choroid, that region is known as the choriocapil- system. Aqueous humor provides nutrients and oxygen
lary layer and is responsible for providing nutrients to for the lens and the cornea.
the retina. The choroid is separated from the retina by The bulk of the ciliary body is composed of three
Bruch’s membrane, a membrane 1 to 4 µm thick com- bundles of smooth muscle cells called the ciliary
posed of a network of elastic fibers located in the central muscle. One bundle, because of its orientation,
region and sandwiched on both sides by collagen fiber stretches the choroid, thus altering the opening of the
layers. The outer aspect of each collagen fiber layer is canal of Schlemm for drainage of the aqueous humor.
covered by a basal lamina that belongs to capillaries on The remaining two muscle bundles, attached at the
one side and the pigment epithelium of the retina on scleral spur, function in reducing tension on the
the other side. zonulae. Contractions of this muscle, mediated by
parasympathetic fibers of the oculomotor nerve (cranial
Ciliary Body nerve [CN] III), stretch the choroid body, thereby
releasing tension on the suspensory ligaments of the
The ciliary body is a wedge-shaped portion of the lens. As a result, the lens becomes thicker and more
choroid located in the lumen of the orb between the iris convex. This action permits focusing on nearby objects,
and the vitreous body and projecting toward the lens. a process called accommodation. Relaxation of all
three muscle bundles increases tension on the zonule,
The ciliary body, the wedge-shaped extension of the thereby flattening the lens enabling focusing on distant
choroid that rings the inner wall of the eye at the level objects. Constant adjustments between various degrees
of the lens, occupies the space between the ora serrata of contraction and relaxation are required to permit
of the retina (the junction between and anterior and focusing on objects distant, intermediate, and close.
posterior portions of the retina) and the iris. One
surface of the ciliary body abuts the sclera at the scle-
rocorneal junction, another surface abuts the vitreous CLINICAL CORRELATIONS
body, whereas the medial surface projects toward the
lens, forming short, finger-like projections known as Glaucoma is a condition resulting from pro-
ciliary processes. longed increased intraocular pressure caused by
The ciliary body is composed of loose connective the failure of drainage of the aqueous humor
tissue containing numerous elastic fibers, blood vessels, from the anterior chamber of the eye. It is one
and melanocytes. Its inner surface is lined by the pars of the world’s leading causes of blindness. In
ciliaris of the retina, a pigmented layer of the retina chronic glaucoma, the most common condi-
that is composed of two cell layers. The outer cell layer, tion, the continued increasing pressure causes
which faces the lumen of the orb, is a nonpigmented progressive damage to the eye, particularly in the
columnar epithelium (nonpigmented ciliary epithe- retina; if left untreated, blindness results.
lium), whereas the inner cell layer is composed of a
pigmented simple columnar epithelium (pigmented
ciliary epithelium), which is rich in melanin.
The anterior one third of the ciliary body has about Iris
70 ciliary processes, which radiate out from a central
The iris, the colored anterior extension of the choroid,
core of connective tissue containing abundant fenes-
is a contractile diaphragm that controls the pupillary
trated capillaries. Fibers, composed of fibrillin (zonule
aperture.
fibers), radiate from the ciliary processes to insert into
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The iris, the anteriormost extension of the choroid, lies

between the posterior and anterior chambers of the
Ca
eye, completely covering the lens except at the pupil-
lary aperture (pupil). The iris is thickest in the
middle, thinning toward its junction with the ciliary
body and at the rim of the pupil. The anterior surface
consists of two concentric rings: the pupillary zone,
lying nearest the pupil, and the wider ciliary zone. The
anterior surface of the iris is irregular, with trenches
extending into it; it also contains contraction furrows,
which are easily distinguished when the pupil is dilated.
An incomplete layer of pigmented cells and fibroblasts
covers the anterior surface of the iris. Deep to this layer
is a stroma of poorly vascularized connective tissue con-
taining numerous fibroblasts and melanocytes, which
gives way to a well-vascularized, loose connective tissue
zone.
The posterior surface of the iris is smooth and is
covered by the continuation of the two layers of retinal
epithelium that cover the ciliary body. The surface
facing the lens is composed of heavily pigmented cells,
which block the light from passing through the iris
except at the pupil. The epithelial cells facing the Figure 22–5 Light micrograph of the lens (×132). Note the
simple cuboidal epithelium (arrow) on the anterior surface and the
stroma of the iris have extensions that form the dilator capsule (Ca) covering the epithelium.
pupillae muscle. Hence, this muscle is myoepithelial
in nature. Another muscle, the sphincter pupillae
muscle, is located in a concentric ring around the pupil.
Contractions of these smooth muscles alter the diame-
ter of the pupil. The diameter of the pupil changes The lens capsule is a basal lamina, 10 to 20 µm
inversely to the amount of light entering it. Thus, bright thick, containing mostly type IV collagen and glycopro-
light causes constriction of pupillary diameter, whereas tein that covers the epithelial cells and envelops the
dim light dilates it. Pupil diameter is the result of the entire lens. This elastic, transparent, homogeneous
the functions of the two intrinsic muscles contained structure, which refracts light, is thickest anteriorly.
within the iris. The dilator pupillae muscle, innervated The subcapsular epithelium is located only on the
by the sympathetic nervous system, dilates the pupil; anterior and lateral surfaces of the lens, immediately
the sphincter pupillae muscle, innervated by parasym- deep to the lens capsule (Fig. 22-5). It is composed
pathetic fibers of the oculomotor nerve (CN III), con- of a single layer of cuboidal cells, which communicate
stricts the pupil. with each other via gap junctions. The apices of
The abundant population of melanocytes in the these cells are directed toward the lens fibers and inter-
epithelium and stroma of the iris not only blocks the digitate with them, especially in the vicinity of the
passage of light into the eye (except at the pupil) but equator, where they are elongated and are columnar in
also imparts color to the eyes. The eyes are dark when shape.
the number of melanocytes is high, and they are blue The bulk of the lens is composed of approximately
when the number of melanocytes is low. 2000 long cells known as lens fibers. These cells lie
immediately deep to the subcapsular epithelium and
Lens lens capsule (Fig. 22-6). The cells of the subcapsular
epithelium give rise to these highly differentiated,
The lens, the transparent biconvex disk located directly hexagonal cells, the lens fibers, which lose their nuclei
behind the pupil, focuses light rays on the retina. and organelles and continue elongating until they reach
a length of 7 to 10 µm. This process of elongation,
The lens of the eye is a flexible, biconvex, trans- known as maturation, continues throughout the life of
parent disk composed of epithelial cells and their secre- the individual. Eventually these long, hexagonal cells
tory products. The lens consists of three parts: lens become filled with crystallins, which are lens proteins
capsule, subcapsular epithelium, and lens fibers (see whose presence increases the refractory index of the
Fig. 22-4). lens fibers.
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micrograph of the posterior surface of
the lens (×28). C, ciliary body; L, lens; Z,
zonula fibers. (From Leeson TS, Lee
CR, Paparo AA: Text/Atlas of Histology.
amount of electrolytes, collagen fibers, and hyaluronic

CLINICAL CORRELATIONS acid. It adheres to the retina over its entire surface, espe-
cially at the ora serrata. Occasional macrophages and
Presbyopia is the inability of the eye to focus on small cells called hyalocytes are observed at the periph-
near objects (accommodation) and is caused by ery of the vitreous body; these are believed to synthesize
an age-related decrease in the elasticity of the collagen and hyaluronic acid. The fluid-filled hyaloid
lens. As a result, the lens cannot become spher- canal, a narrow channel that was occupied by the hyaloid
ical for exact focusing. This condition can be cor- artery in the fetus, extends through the entire vitreous
rected with eyeglasses. body from the posterior aspect of the lens to the optic disk.
Cataract is usually also an age-related condi-
tion in which the lens becomes opaque, thus
impairing vision. This condition may be due to
an accumulation of pigment or other substances CLINICAL CORRELATIONS
as well as to excessive exposure to ultraviolet
radiation. Although cataracts do not usually Eye floaters (vitreous opacities)—specks, clouds,
respond to medication and eventually lead to cobwebs, and so forth—that persons appear to
blindness, the opaque lens may be excised and see in front of their eyes represent small debris
replaced with a corrective lens. that is floating in the vitreous body, caused by its
dehydration. These objects cast shadows on the
retina that are translated by the brain as images
in front of the eyes. Although most of the time
these floaters naturally resolve, some persons
Vitreous Body find their presence disruptive, especially when
The vitreous body is a transparent, refractile gel that fills they are reading or driving. Specialized laser
the cavity of the eye (vitreous cavity) behind the lens. It treatments can obliterate the floaters.
is composed mostly (99%) of water containing a minute
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Retina (Neural Tunic) The optic disk, located on the posterior wall of the
orb, is the exit site of the optic nerve. Because it contains
The retina, composed of 10 layers, possesses specialized no photoreceptor cells, it is insensitive to light and is
receptors, called rods and cones, that are responsible for therefore called the “blind spot” of the retina. Approx-
photoreception. imately 2.5 mm lateral to the optic disk is a yellow-
pigmented zone in the retinal wall called the macula
The retina, the third and innermost tunic of the eye, is lutea (yellow spot). Located in the center of this spot is
its neural portion, which contains the photoreceptor an oval depression, the fovea centralis, where visual
cells, known as rods and cones (Figs. 22-7, 22-8, and 22- acuity is greatest (see Fig 22-4). The fovea is a special-
9; also see Fig. 22-4). The retina develops from the optic ized area of the retina containing only cones, which are
cup, an evagination of the diencephalon, which gives packed tightly as the other layers of the retina are
rise to the primary optic vesicle. Later in development, pushed aside. As distance from the fovea increases, the
this structure invaginates to form a bilaminar, second- number of cones decreases and the number of rods
ary optic vesicle from which the retina develops, increases.
whereas the stalk of the optic cup becomes the optic The portion of the retina that functions in photore-
nerve. ception lines (faces) the inner surface of the choroid
The retina is formed of an outer pigmented layer
that develops from the outer wall of the optic cup. The
neural portion of the retina develops from the inner Pigmented
layer of the optic cup and is called the retina proper. epithelium
The pigmented layer of the retina covers the entire Rod
internal surface of the orb, reflecting over the ciliary photoreceptor
body and the posterior wall of the iris, whereas the
Outer limiting
retina proper stops at the ora serrata. The cells com- membrane
posing the retina proper constitute a highly differenti-
ated extension of the brain. Cone
photoreceptor
Cone cell nuclei
Rod cell nucleus
Cone pedicle
Rod spherule
Horizontal cell
Direction of light path

1 Bipolar cell
2 Nuclei of
3 Müller cell
Body of
4 Müller cell
Amacrine cell
5
6 Ganglion cells
Optic nerve
7 fibers
8
9
Inner
10 limiting
Light from lens membrane
Figure 22–7 Light micrograph of the retina with its described
ten layers (×270). (1) Pigment epithelium, (2) lamina of rods and
cones, (3) external (outer) limiting membrane, (4) outer nuclear layer, Figure 22–8 Cellular layers of the retina. The space observed
(5) outer plexiform layer, (6) inner nuclear layer, (7) inner plexiform between the pigmented layer and the remainder of the retina is an
layer, (8) ganglion cell layer, (9) optic nerve fiber layer, (10) inner lim- artifact of development and does not exist in the adult except during
iting membrane. detachment of the retina.
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8 Ganglion cell layer

9 Optic nerve fiber layer
10 Inner limiting membrane.
Pigment Epithelium
OS OS
The pigment epithelium, derived from the outer layer
of the optic cup, is composed of cuboidal to columnar
cells (14 µm wide and 10 to 14 µm tall) whose nuclei
are located basally. The cells are attached to Bruch’s
membrane, which is located between the choroid and
C
the pigment cells. Mitochondria are especially abun-
BB IS dant in the cytoplasm near the numerous cell invagina-
Ce
tions with Bruch’s membrane, suggesting transport in
M this region. Desmosomes, zonulae occludentes, and
IS zonulae adherentes are present on the lateral cell mem-
branes, forming the blood-retina barrier. Moreover,
gap junctions on the lateral cell membranes permit
intercellular communication. The cell apices exhibit
microvilli and sleeve-like structures that surround and
isolate the tips of the individual photoreceptor cells.
The most distinctive feature of the pigment cells is
their abundance of melanin granules, which these cells
NR synthesize and store in their apical portions. The apical
NR cytoplasm also contains residual bodies housing phago-
cytosed tips shed by the rods. Additionally, smooth
endoplasmic reticulum (SER), rough endoplasmic
reticulum (RER), and Golgi apparatus are abundant in
the cytoplasm.
The pigmented epithelium has several functions.
Pigmented epithelial cells absorb light after it has
SR SR SV passed through and stimulated the photoreceptors, thus
SV preventing reflections from the tunics, which would
impair focus. These pigmented cells continually phago-
cytose spent membranous disks from the tips of the
photoreceptor rods. Pigment epithelial cells also play an
ROD CONE
active role in vision by esterifying vitamin A derivatives
Figure 22–9 Morphology of a rod and a cone. BB, basal body; in their SER.
C, connecting stalk; Ce, centriole; IS, inner segment; M, mitochon-
dria; NR, nuclear region; OS, outer segment; SR, synaptic region;
SV, synaptic vesicles. (Modified from Lentz TL: Cell Fine Structure:
An Atlas of Drawings of Whole-Cell Structure. Philadelphia, WB CLINICAL CORRELATIONS
Saunders, 1971.)
Because the sleeve-like extensions of the pigment
epithelial cells merely surround the photorecep-
layer from the optic disk to the ora serrata and is com- tor rod and cone tips, sudden hard jolts may
posed of 10 distinct layers (see Figs. 22-7 and 22-8). disengage them, resulting in detachment of
From outside, adjacent to the choroid, to inside, where the retina, a common cause of partial blindness.
they are continuous with the optic nerve, these layers The condition can be corrected surgically by
are as follows: “spot welding” the two structures back together.
1 Pigment epithelium However, if this condition is left unattended, the
2 Layer of rods and cones rods and cones die because they will have lost
3 External (outer) limiting membrane the metabolic support normally provided by the
4 Outer nuclear layer pigment epithelium. Their death leaves a blind
5 Outer plexiform layer spot in the visual field corresponding to the area
6 Inner nuclear layer where the photoreceptors were lost.
7 Inner plexiform layer
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Layer of Rods and Cones basal to the mitochondria is rich in microtubules,

polysomes, SER, RER, and Golgi complexes. Proteins
The optical portion of the retina houses two distinct produced in the inner segment migrate to the outer
types of photoreceptor cells called rods and cones. Both segment, where they become incorporated into the
rods and cells are polaarized cells whose apical portions, disks. The disks gradually migrate to the apical end of
known as the outer segments, are specialized den- the outer segment and are eventually shed into the
drites. The outer segments of the rods and cones are sheaths of the pigment cells, where they will be phago-
surrounded by pigmented epithelial cells (see Fig. 22- cytosed. The length of time from protein incorporation,
8). The bases of the rod and cone cells form synapses through migration, and finally to shedding is less than 2
with the underlying cells of the bipolar layer. There are weeks. The process of photoreception is as follows:
approximately 100 to 120 million rods and 6 million
cones. Rods are specialized receptors for perceiving 1 Photoreception by rods begins with absorption
objects in dim light, whereas cones are specialized of light by the light-sensitive photopigment rho-
receptors for perceiving objects in bright light recep- dopsin, composed of the transmembrane protein
tion. Cones are further adapted for color vision, opsin bound to cis retinal, the aldehyde form of
whereas rods perceive only light. Rods and cones are vitamin A.
unevenly distributed in the retina, in that cones are 2 Absorption of light causes isomerization of the
highly concentrated in the fovea; thus, this is the area retinal moiety into all-trans retinal, which then
of the retina where high-acuity vision occurs. dissociates from opsin.
3 This bleaching yields activated opsin, which facili-
tates binding of guanosine triphosphate (GTP) to
Rods the α-subunit of transducin, a trimeric G protein.
4 The resulting GTP-Ga activates cyclic guanosine
Rods are the photoreceptors of the retina specialized for monophosphate (cGMP) phosphodiesterase, an
perceiving dim light. enzyme that catalyzes the breakdown of 3′,5′-
cGMP.
Rods, which are activated in dim light only, are so sen- 5 The decreasing cytosolic cGMP concentration
sitive that they can produce a signal from a single results in closure of Na+ channels in the plasma
photon of light. However, they cannot mediate signals membrane of the rod so that Na+ cannot leave the
in bright light, and they cannot sense color. Rods are cell, and the rod becomes hyperpolarized.
elongated cells (50 µm long by 3 µm in diameter) ori- 6 Hyperpolarization of the rod results in the inhibi-
ented parallel to one another but perpendicular to the tion of neurotransmitter release into the
retina. These are composed of an outer segment, an synapse with the bipolar cells.
inner segment, a nuclear region, and a synaptic region 7 During the next dark phase, the level of cGMP is
(see Fig. 22-9). regenerated, the Na+ channels are reopened, and
The outer segment of the rod, its dendritic end, the Na+ flow resumes as before.
presents several hundred flattened membranous lamel- 8 The all-trans retinal remaining from the break-
lae oriented perpendicular to its long axis (Fig. 22-10; down diffuses and is carried to the retinal pigment
also see Fig. 22-9). Each lamella represents an invagi- epithelium via retinal binding proteins.
nation of the plasmalemma, which is detached from the 9 The all-trans retinal is recycled to its 11-cis
cell surface, thus forming a disk. Each disk is composed retinal form.
of two membranes separated from each other by an 8- 10 Finally, cis retinal is returned to the rod, where it is
nm space. The membranes contain rhodopsin (visual once again bound to opsin to form rhodopsin.
purple), a light-sensitive pigment. Because the outer
segment is longer in rods than in cones, rods contain When the rod is not activated by light, cGMP main-
more rhodopsin, respond more slowly than cones, and tains open Na+ channels in the plasmalemmae of rod
have the capacity to collectively summate the reception. cells. During the dark phase, sodium ions are pumped
The inner segment of the rod is separated from out of the inner segment and enter the outer segment
the outer segment by a constriction called the con- of the rods through sodium-gated ion channels. The
necting stalk. Passing through the connecting stalk presence of sodium ions in the outer segment results in
and into the outer segment of the rod is a modified the release of neurotransmitter substance into the
cilium (lacking the central singlet microtubules) that synapse with the bipolar cells.
arises from a basal body located at the apical end of the The signal is not induced by depolarization, as it is
inner segment. Congregated near the interface with the in most cells; rather, light-induced hyperpolarization
connecting stalk are abundant mitochondria and cyto- causes the signal to be transmitted through the various
plasmic glycogen granules, both necessary for the pro- cell layers to the ganglion cells, where the signal gen-
duction of energy for the visual process. The cytoplasm erates an action potential along the axons to the brain.
Ch022-X2945.qxd 12/8/06 3:46 PM Page 523
A B
C D
Figure 22–10 Electron micrographs of rods from the eye of a frog and cones from the eye of a squirrel. A, Disks in the outer segment
(arrowheads) and mitochondria (m) in the inner segment of the rod of a frog (×16,200). Note the cilium (arrow) connecting the inner and outer
segments. B, Higher magnification of the disks in the outer segment of the rod of a frog (×76,500). C, Junction of the outer and inner segments
of the cone of a squirrel (arrowheads, disks in the outer segment). m, mitochondria. (×28,800). D, Higher magnification of the disks in the outer
segment of a squirrel eye showing continuity of the lamellae with the plasmalemma (arrowheads). (×82,800). (From Leeson TS, Leeson CR,
Paparo AA: Text-Atlas of Histology. Philadelphia, WB Saunders, 1988.)
Cones There are three types of cones, each containing a dif-

ferent variety of the photopigment iodopsin. Each
Cones are specialized photoreceptors of the retina for variety of iodopsin has a maximum sensitivity to one of
perceiving bright light and color. three colors of the spectrum—red, green, and blue–and
the difference resides in the opsins rather than in the
Although the mode of function of the cones is similar 11-cis retinal.
to that of rods, cones are activated in bright light and Cones are elongated cells (60 µm long by 1.5 µm
produce greater visual acuity compared with rods. in diameter), being longer and narrower at the fovea
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External (Outer)
Limiting Membrane
Although the term external limiting membrane is still
used in descriptions of the layers of the retina, this
structure is not a membrane. Instead, electron micro-
graphs have revealed that this “layer” is a region of
zonulae adherentes between Müller cells (modified
neuroglial cells) and the photoreceptors. Distal to this,
microvilli of the Müller cells project into the interstices
R between the inner segments of the rods and cones.
Z Outer Nuclear Layer

4
3
The outer nuclear layer consists of a zone occupied
mainly by the nuclei of the rods and cones. In histolog-
C
ical sections, the nuclei of rods are smaller, more
rounded, and more darkly stained than the nuclei of
cones.
Outer Plexiform Layer

Axodendritic synapses between the photoreceptor
cells and dendrites of bipolar and horizontal cells are
MV located in the outer plexiform layer. There are two types
of synapses in this layer: flat synapses, which display the
usual synaptic histology, and invaginated synapses.
Invaginated synapses are unique, in that they consist of
a dendrite of a single bipolar cell and a dendrite from
each of two horizontal cells, thus making a triad.
Figure 22–11 Scanning electron micrograph of the retina in a Located within this invaginated synaptic region is a
monkey in a displaying cones (C) and a few rods (R) (×5800). MV, ribbon-like lamella (synaptic ribbon) containing neu-
microvilli belonging to the Müller cells; Z, inner segments; 3, exter- rotransmitter. It is believed that this structure captures
nal (outer) limiting membrane; 4, outer nuclear layer. (From Borwein
B, Borwein D, Medeiros J, McGowan J: The ultrastructure of monkey and assists in distributing the neurotransmitter.
foveal photoreceptors, with special reference to the structure, shape,
size, and spacing of the foveal cones. Am J Anat 159:125-146, 1980.) Inner Nuclear Layer
The nuclei of bipolar, horizontal, amacrine, and Müller
cells compose the inner nuclear layer.
centralis. Their structure is similar to that of rods with
Bipolar neurons are interposed between photorecep-
the following few exceptions (Fig. 22-11; also see Figs.
tor cells and ganglion cells. These neurons may be con-
22-9B and 22-10):
tacted by many rods (10 near the macula to as many as
䡲 Their apical terminal (outer segment) is shaped more 100 near the ora serrata), thus permitting summation of
like a cone than a rod. the signals, which is especially useful in low light inten-
䡲 The disks of cones, although composed of lamellae of sity. Cones, however, do not converge, at least near the
the plasmalemma, are attached to the plasma mem- fovea; instead each cone synapses with several bipolar
brane, unlike the lamellae of the rods, which are sep- cells, thus further enhancing visual acuity. Axons of the
arated from the plasma membrane. bipolar cells synapse with dendrites of the ganglion
䡲 Protein produced in the inner segment of cones is cells.
inserted into the disks throughout the entire outer Horizontal cells located in this layer synapse with
segment; in the rods, it is concentrated in the most the synaptic junctions between the photoreceptor cells
distal region of the outer segment. and the bipolar cells. These cells function to modulate
䡲 Unlike rods, cones are sensitive to color and provide the synaptic activity.
greater visual acuity. Amacrine cells are located at the inner limits of this
䡲 Recycling of the cone photopigment does not require layer. Their dendrites all exit from one area of the cell
the retina pigment cells for the processing. and terminate on synaptic complexes between bipolar
Ch022-X2945.qxd 12/8/06 3:46 PM Page 525
cells and ganglion cells. They also synapse on inter- A transparent mucous membrane, known as the con-
plexiform cells that are interspersed with bipolar cell junctiva, lines the inner surface of the eyelids (palpe-
bodies. Amacrine cells function as a feedback mecha- bral conjunctiva) and covers the sclera of the anterior
nism by transferring neuronal information derived from portion of the eye (bulbar conjunctiva). The con-
the bipolar cell-ganglion synaptic complex to interplex- junctiva is composed of a stratified columnar epithelium
iform cells, whose axons communicate with bipolar and that contains goblet cells overlying a basal lamina and a
horizontal cells. lamina propria composed of loose connective tissue.
Müller cells are neuroglial cells that extend Secretions of the goblet cells become a part of the tear
between the vitreous body and the inner segments of film, which aids in lubricating and protecting the
the rods and cones, where Müller cells end by forming epithelium of the anterior aspect of the eye. At the cor-
zonulae adherentes with the photoreceptor cells repre- neoscleral junction, where the cornea begins, the con-
sented by the external limiting membrane. Microvilli junctiva continues as the stratified squamous corneal
extend from the apical surface. Thus, Müller cells func- epithelium and is devoid of goblet cells.
tion as supporting cells for the neural retina.
Inner Plexiform Layer

The processes of amacrine, bipolar, and ganglion cells CLINICAL CORRELATIONS
are intermingled in the inner plexiform layer. Axoden- Conjunctivitis is an inflammation of the con-
dritic synapses between the axons of bipolar cells and junctiva usually associated with hyperemia and
the dendrites of ganglion cells and amacrine cells also a discharge. It may be caused by a number of
are located here. As in the outer plexiform layer, there bacterial agents, viruses, allergens, and parasitic
are two types of synapses in this layer: flat and invagi- organisms. Some forms of conjunctivitis are
nated. Invaginated synapses consist of an axon of a extremely contagious, are damaging to the eye,
single bipolar cell and two dendrites of either amacrine and may cause blindness if untreated.
cells or ganglion cells or one dendrite from each of the
two different cells, thus making a dyad. Also located
within this synapse is a shortened version of the synap-
tic ribbon, which contains neurotransmitter.
Eyelids
Ganglion Cell Layer
Eyelids, covered externally by skin and internally by the
Cell bodies of large multipolar neurons of the ganglion conjunctiva, provide a protective barrier for the anterior
cells, up to 30 µm in diameter, are located in the gan- surface of the eye.
glion cell layer. The axons of these neurons pass to the
brain. Hyperpolarization of the rods and cones activates The eyelids are formed as folds of skin that cover the
these ganglion cells, which then generate an action anterior surface of the developing eye. Accordingly,
potential that is passed by their axons to the brain via stratified squamous epithelium of skin covers their
the visual relay system. external surface; at the palpebral fissure, palpebral
conjunctiva covers their inner surface. The eyelids are
Optic Nerve Fiber Layer supported by a framework of tarsal plates. Sweat
glands are located in the skin of the eyelids, as are fine
Nerve fibers are formed of unmyelinated axons of the hairs and sebaceous glands. The dermis of the eyelids
ganglion cells in the optic nerve fiber layer. These axons is generally thinner than in most skin, contains numer-
become myelinated as the nerve pierces the sclera. ous elastic fibers, and is without fat. The margins of the
eyelids contain eyelashes arranged in rows of three or
Inner Limiting Membrane four, but they are without arrector pili muscles.
Basal laminae of the Müller cells compose the inner Modified sweat glands, called glands of Moll, form
limiting membrane. a simple spiral before opening into the eyelash follicles.
Meibomian glands, modified sebaceous glands
Accessory Structures of the Eye located in the tarsus of each lid, open on the free edge
of the lids. The oily substance secreted by these glands
Conjunctiva becomes incorporated into the tear film and impedes
evaporation of the tears. Other smaller, modified seba-
The conjunctiva is the mucous membrane lining the
ceous glands, the glands of Zeis, are associated with
eyelids and reflecting onto the sclera of the anterior
the eyelashes and secrete their product into the eyelash
surface of the eye.
follicles.
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Lacrimal Apparatus the external ear, (2) the middle ear (tympanic cavity),
and (3) the inner ear (Fig. 22-12).
The lacrimal apparatus keeps the anterior surface of the Sound waves received by the external ear are trans-
eye lubricated with tears, thus preventing dehydration lated into mechanical vibrations by the tympanic mem-
of the cornea. brane (eardrum). These vibrations then are amplified by
the bony ossicles in the middle ear (tympanic cavity)
The lacrimal apparatus consists of: and transferred to the fluid medium of the inner ear
䡲 The lacrimal gland, which secretes the lacrimal fluid at the oval window. The inner ear, a perilymph-filled
(tears) bony labyrinth in which is suspended a membranous
䡲 The lacrimal canaliculi, which carry the lacrimal fluid labyrinth, regulates hearing (the cochlear portion) and
away from the surface of the eye maintains balance (the vestibular portion). Sensory
䡲 The lacrimal sac, a dilated portion of the duct system input into the entire vestibulocochlear apparatus is
䡲 The nasolacrimal duct, which delivers the lacrimal transmitted to the brain by the two divisions of the
fluid to the nasal cavity vestibulocochlear nerve (CN VIII).
The lacrimal gland lies in the lacrimal fossa located
in the superolateral aspect of the orbit. It lies outside External Ear
the conjunctival sac, although it communicates with the The external ear comprises the auricle, the external
sac via 6 to 12 secretory ducts, which open into the sac auditory meatus, and the tympanic membrane.
at the lateral portion of the superior conjunctival fornix.
The gland is a serous, compound tubuloalveolar gland The external ear is composed of the auricle (pinna), the
that resembles the parotid gland. Myoepithelial cells external auditory meatus, and the tympanic membrane
completely surround its secretory acini. (see Fig. 22-12). The auricle develops from parts of the
Lacrimal fluid (tears) is composed mostly of water. first and second branchial arches. Its general shape,
This sterile fluid, containing the antibacterial agent size, and specific contours are usually distinctive in each
lysozyme, passes through the secretory ducts to enter person, with familial similarities. The pinna is composed
the conjunctival sac. The upper eyelids, by blinking, of an irregularly shaped plate of elastic cartilage covered
wash the tears over the anterior portion of the sclera by thin skin that adheres tightly to the cartilage. The
and cornea, thus keeping them moist and protected cartilage of the pinna is continuous with the cartilage
from dehydration. The lacrimal fluid is wiped in a lining the cartilaginous portion of the external auditory
medial direction and enters the lacrimal punctum, an meatus.
aperture located in each of the medial margins of the The external auditory meatus is the canal that
upper and lower eyelids. The punctum of each eyelid extends from the pinna into the temporal bone to the
leads directly to lacrimal canaliculi, which join into a external surface of the tympanic membrane. Its super-
common conduit that leads to the lacrimal sac. The ficial portion is composed of elastic cartilage, which is
walls of the lacrimal canaliculi are lined by stratified continuous with the cartilage of the pinna. Temporal
squamous epithelium. bone replaces the cartilage as support within the inner
The lacrimal sac is the dilated superior portion of two thirds of the canal. The external auditory meatus is
the nasolacrimal duct. It is lined by pseudostratified cil- covered with skin containing hair follicles, sebaceous
iated columnar epithelium. glands, and modified sweat glands known as cerumi-
The inferior continuation of the lacrimal sac is the nous glands, which produce a waxy material called
nasolacrimal duct, also lined by pseudostratified cerumen (earwax). Hair and the sticky wax help
ciliated columnar epithelium. This duct carries the prevent objects from penetrating deep into the meatus.
lacrimal fluid into the inferior meatus located in the The tympanic membrane covers the deepest end
floor of the nasal cavity. of the external auditory meatus. It represents the
closing plate between the first pharyngeal groove and
the first pharyngeal pouch, where ectoderm, meso-
EAR (VESTIBULOCOCHLEAR derm, and endoderm are in close proximity. The exter-
APPARATUS) nal surface of the tympanic membrane is covered by a
thin epidermis derived from ectoderm, whereas its
The ear, the organ of hearing and balance, is composed internal surface is composed of a simple squamous to
of three regions: the outer ear, the middle ear, and the cuboidal epithelium derived from endoderm. A thin
inner ear. layer of mesodermal elements, including collagen
fibers, elastic fibers, and fibroblasts, is interposed
The ear, the organ of hearing as well as the organ of between the two epithelial layers of the tympanic mem-
equilibrium, or balance, is divisible into three parts: (1) brane. This membrane receives sound waves transmit-
Ch022-X2945.qxd 12/8/06 3:46 PM Page 527
Superior semicircular canal
Posterior semicircular canal
Lateral semicircular canal
Facial nerve (VII)
Acoustic nerve (VIII)
Cochlea
Middle ear cavity
Malleus Auditory tube

Tympanum
Incus
External auditory meatus
Stapes
Figure 22–12 Anatomy of the ear.
ted to it by air through the external auditory meatus, many mucous glands whose ducts open into the lumen
which cause it to vibrate. In this fashion, the sound of the tympanic cavity. Additionally, goblet cells and
waves are converted into mechanical energy that is lymphoid tissue are found in the vicinity of the pharyn-
transmitted to the bony ossicles in the middle ear. geal opening.
During swallowing, blowing the nose, and yawning,
Middle Ear the orifice of the auditory tube at the pharynx opens,
permitting an equalization of air pressure in the tym-
The middle ear (tympanic cavity) houses the three bony panic cavity with that in the external auditory meatus,
ossicles: the malleus, the incus, and the stapes. which is located on the opposite side of the tympanic
membrane. This is why swallowing, blowing one’s nose,
The middle ear, or tympanic cavity, is an air-filled or yawning relieves the “ear pressure” that occurs
space located in the petrous portion of the temporal during rapid descent when one is flying in an airplane.
bone. This space communicates posteriorly with the Located within the medial wall of the tympanic
mastoid air cells and anteriorly, via the auditory tube cavity are the oval window and the round window,
(eustachian tube), with the pharynx (see Fig. 22-12). which connect the middle ear cavity to the inner ear.
The three bony ossicles are housed in this space, span- These two windows are formed by membrane-covered
ning the distance between the tympanic membrane and voids in the bony wall. The bony ossicles, the malleus,
the membrane at the oval window. incus, and stapes are articulated in series by synovial
The tympanic cavity is lined by simple squamous joints lined with simple squamous epithelium. The
epithelium, which is continuous with the internal lining malleus is attached to the tympanic membrane, with the
of the tympanic membrane. In its deepest two thirds, incus interposed between it and the stapes, which in
however, the bone of the tympanic cavity gives way to turn is attached to the oval window. Two small skeletal
cartilage as it approaches the auditory tube. Similarly, muscles, the tensor tympani and the stapedius, mod-
its epithelial covering becomes a pseudostratified cili- ulate movements of the tympanic membrane and the
ated columnar epithelium as it approaches the auditory bony ossicles to prevent damage from loud sounds.
tube. The lamina propria over the bony wall adheres to Vibrations of the tympanic membrane set the ossicles
it tightly and does not contain glands, but the lamina into motion, and because of their lever action, the oscil-
propria overlying the cartilaginous portion contains lations are magnified to vibrate the membrane of the
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oval window, thus setting the fluid medium of the Semicircular canals:
Superior
cochlear division of the inner ear into motion. Posterior
Lateral
Inner Ear Ampulla
Recess for utricle
The inner ear is composed of the bony labyrinth, an Recess for saccule
irregular, hollowed-out cavity located within the petrous
portion of the temporal bone, and the membranous
labyrinth, which is suspended within the bony
labyrinth (Fig. 22-13). A
Bony Labyrinth
Vestibule
The bony labyrinth has three components: the Oval
semicircular canals, the vestibule, and the cochlea. window
Round window
Cochlea
The bony labyrinth is lined with endosteum and is sep- BONY
arated from the membranous labyrinth by the peri-
lymphatic space. This space is filled with a clear fluid Semicircular duct:
Endolymphatic
called the perilymph, within which the membranous Superior
sac
Posterior
labyrinth is suspended. The central region of the bony Lateral
labyrinth is known as the vestibule. Cochlear duct
The three semicircular canals (superior, poste-
rior, and lateral) are oriented at 90 degrees to one
another (see Fig. 22-13). One end of each canal is
B
enlarged; this expanded region is called the ampulla.
All three semicircular canals arise and return to the
vestibule, but one end of each of two of the canals shares
an opening to the vestibule; consequently, there are only Utricle
five orifices to the vestibule. Suspended within the Saccule
canals are the semicircular ducts, which are regionally Ductus
reuniens
named continuations of the membranous labyrinth.
MEMBRANOUS
The vestibule is the central portion of the bony
labyrinth located between the anteriorly placed cochlea
and the posteriorly placed semicircular canals. Its lateral Cristae ampullares of
semicircular
wall contains the oval window (fenestra vestibuli), ducts:
covered by a membrane to which the footplate of the Superior
stapes is attached, and the round window (fenestra Lateral
Posterior
cochleae), covered only by a membrane. The vestibule
also houses specialized regions of the membranous
labyrinth (the utricle and the saccule). C
The cochlea arises as a hollow bony spiral that turns
upon itself, like a snail shell, two and one-half times
around a central bony column, the modiolus. The Organ of Corti
modiolus projects into the spiraled cochlea with a shelf Macula of utricle
of bone called the osseous spiral lamina, through Macula of saccule
which traverse blood vessels and the spiral ganglion, SENSORY
the cochlear division of the vestibulocochlear nerve.
Figure 22–13 Cochlea of the inner ear. A, Anatomy of bony
Membranous Labyrinth labyrinth. B, Anatomy of the membranous labyrinth. C, Sensory
labyrinth.
The membranous labyrinth is filled with endolymph and
possesses the following specialized areas: the saccule
and utricle, the semicircular ducts, and the cochlear duct.
The membranous labyrinth is composed of an epithe-

lium derived from the embryonic ectoderm, which
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invades the developing temporal bone and gives rise to The maculae are thickened areas of the epithelium,
two small sacs, the saccule and utricle, as well as to 2 to 3 mm in diameter. They are composed of two types
the semicircular ducts and the cochlear duct (see of neuroepithelial cells called type I and type II
Fig. 22-13). Circulating through the entire membra- hair cells, as well as of supporting cells that sit on a
nous labyrinth is endolymph, a viscous fluid that basal lamina (Figs 22-14 and 22-15). Nerve fibers from
resembles extracellular fluid in its ionic composition the vestibular division of the vestibulocochlear nerve
(i.e., it is sodium-poor but potassium-rich). supply the neuroepithelial cells.
Thin strands of connective tissue attached to the Each type I or type II hair cell has a single kinocil-
endosteum of the bony labyrinth pass through the peri- ium and 50 to 100 stereocilia arranged in rows accord-
lymph to be inserted into the membranous labyrinth. In ing to length, with the longest (10 µm) being nearest
addition to anchoring the membranous labyrinth to the the kinocilium.
bony labyrinth, these connective tissue strands carry Type I hair cells are plump cells with a rounded
blood vessels that nourish the epithelia of the membra- base that narrows toward the neck (see Fig. 22-15).
nous labyrinth. Their cytoplasm contains occasional RER, a supranu-
clear Golgi complex, and numerous small vesicles. Each
Saccule and Utricle stereocilium, which is anchored in a dense terminal
web, is a long microvillus with a core of many actin fil-
The saccule and utricle, sac-like structures lying in the aments cross-linked by fimbrin. The filamentous core
vestibule, contain neuroepithelial cells that are imparts rigidity to the stereocilia, so that bending can
specialized to sense position of the head and linear occur only in the neck region, near their site of origin
movement. from the apical plasma membrane.
Type II hair cells are similar to type I hair cells with
The saccule and utricle are connected to each other by regard to the stereocilia and kinocilium, but their shape
a small duct, the ductus utriculosaccularis. Addition- is more columnar and their cytoplasm contains a larger
ally, small ducts from each join to form the endolym- Golgi complex and more vesicles (see Fig. 22-15).
phatic duct, whose dilated blind end is known as the Supporting cells of the maculae, which are inter-
endolymphatic sac. Another small duct, the ductus posed between both types of hair cells, have a few
reuniens, joins the saccule with the duct of the cochlea microvilli. Thick junctional complexes bind these cells
(see Fig. 22-13). to each other and to the hair cells. They exhibit a well-
The walls of the saccule and utricle are composed of developed Golgi complex and secretory granules, sug-
a thin outer vascular layer of connective tissue and an gesting that they may help maintain the hair cells or may
inner layer of simple squamous to low cuboidal epithe- contribute to the production of endolymph.
lium. Specialized regions of the saccule and utricle act Innervation of the hair cells is derived from the
as receptors for sensing orientation of the head relative vestibular division of the vestibulocochlear nerve. The
to gravity and acceleration, respectively. These recep- rounded bases of the type I hair cells are almost entirely
tors are called the macula of the saccule and the surrounded by a cup-shaped afferent nerve fiber. Type
macula of the utricle. II hair cells exhibit many afferent fibers synapsing on
The maculae of the saccule and utricle are located so the basal area of the cell. Structures resembling synap-
that they are perpendicular to each other (i.e., the macula tic ribbons are present near the bases of type I and
of the saccule is located predominantly in the wall, thus type II hair cells. The synaptic ribbons of the type II
detecting linear vertical acceleration, whereas the macula hair cells probably function in synapses with efferent
of the utricle is located mostly in the floor, thus detecting nerves, which are thought to be responsible for increas-
linear horizontal acceleration). The epithelium of the ing the efficiency of synaptic release.
nonreceptor regions of the saccule and utricle is com- The stereocilia of the neuroepithelial hair cells are
posed of light and dark cells. Light cells have a few covered by and embedded in a thick, gelatinous glyco-
microvilli, and their cytoplasm contains a few pinocytotic protein mass, the otolithic membrane. The surface
vesicles, ribosomes, and only a small number of mito- region of this membrane contains small calcium car-
chondria. The cytoplasm of the dark cells, however, con- bonate crystals known as otoliths or otoconia (see
tains an abundance of coated vesicles, smooth vesicles, Figs. 22-14 and 22-15).
and lipid droplets as well as numerous elongated mito-
chondria located in compartments formed by infoldings Semicircular Ducts
of the basal plasma membrane. Nuclei of the dark cells
Each of the three semicircular ducts contains an
are irregular in shape and are often located apically.
expanded region, the ampulla, where specialized
Although the function of these two cell types is not
receptors (neuroepithelial hair cells) sense linear and
known, it is thought that light cells play a role in absorp-
angular movement.
tion and that dark cells control endolymph composition.
Ch022-X2945.qxd 12/8/06 3:46 PM Page 530
Otoliths
Otolithic
membrane
Kinocilium
Stereocilium
Supporting cells
Nerve fibers
Cross section through

Otolithic membrane macula of utricle
Endolymph
Otoliths
Figure 22–14 Hair cells and

supporting cells in the macula of the
utricle.
Each semicircular duct, a continuation of the membra- labyrinth. The cochlear duct is a wedge-shaped recep-
nous labyrinth arising from the utricle, is housed within tor organ housed in the bony cochlea and surrounded
its semicircular canal and thus conforms to its shape. on two sides by perilymph but separated from it by two
Each of the three ducts is dilated at its lateral end (near membranes (Figs. 22-17 and 22-18). The roof of the
the utricle). These expanded regions, called the ampul- scala media (cochlear duct) is the vestibular (Reiss-
lae, contain the cristae ampullares, which are spe- ner’s) membrane, whereas the floor of the scala media
cialized receptor areas. Each crista ampullaris is is the basilar membrane. The perilymph-filled com-
composed of a ridge whose free surface is covered by partment lying above the vestibular membrane is called
sensory epithelium consisting of neuroepithelial hair the scala vestibuli, whereas the perilymph-filled com-
cells and supporting cells (Fig. 22-16). The support- partment lying below the basilar membrane is the scala
ing cells sit on the basal lamina, whereas the hair cells tympani. These two compartments communicate at
do not; rather, the hair cells are cradled between the the helicotrema, near the apex of the cochlea.
supporting cells. The neuroepithelial cells, also known The vestibular membrane is composed of two
as type I and type II hair cells, exhibit the same mor- layers of squamous epithelia separated from each other
phology as the hair cells of the maculae (discussed by a basal lamina. The inner layer is the lining cells of
earlier). The cupula, a gelatinous glycoprotein mass the scala media, and the outer layer is the lining cells of
overlying the cristae ampulares, is similar to the the scala vestibuli. Numerous tight junctions seal both
otolithic membrane in structure and function, but it is layers of cells, thus ensuring a high ionic gradient across
cone-shaped and does not contain otoliths. the membrane. The basilar membrane, extending
from the spiral lamina at the modiolus to the lateral
Cochlear Duct and Organ of Corti wall, supports the organ of Corti and is composed of two
zones: the zona arcuata and the zona pectinata. The
The cochlear duct and its organ of Corti are responsible zona arcuata is thinner, lies more medial, and supports
for the mechanism of hearing. the organ of Corti. The zona pectinata is similar to a
fibrous meshwork containing a few fibroblasts.
The cochlear duct, a diverticulum of the saccule, is The lateral wall of the cochlear duct, extending
another regionally named portion of the membranous between the vestibular membrane and the spiral
Ch022-X2945.qxd 12/8/06 3:46 PM Page 531
Otolith
Hairs
Hairs (stereocilia) Kinocilium
(stereocilia) Kinocilium
Microtubules
Figure 22–15 The morphol-

ogy of type I and type II neuroep-
ithelial (hair) cells of the maculae of Afferent Afferent
the saccule and utricle. (From nerve nerve ending
Lentz TL: Cell Fine Structure: An calyx Afferent
Atlas of Drawings of Whole-Cell nerve ending
Structure. Philadelphia, WB Saun-
ders, 1971.) TYPE I HAIR CELL TYPE II HAIR CELL
Endolymph in
semicircular
duct
Cupula
Afferent
nerve
fibers
Type I Type II
hair hair
cell cell
Crista
Figure 22–16 The hair cells ampullaris of the Supporting
and supporting cells in one of the posterior semicircular cell
cristae ampullares of the semicircular duct
canals.
Ch022-X2945.qxd 12/8/06 3:46 PM Page 532
Osseous spiral lamina

Spiral ganglion
Cochlear duct
Scala vestibuli in cochlea
Reissner’s
membrane
Scala
media Scala
tympani
Stria
vascularis
Spiral
prominence
Organ
of Corti
Tectorial
membrane
Inner hair cell

Outer hair cell
Inner phalangeal cell
Outer phalangeal cell
Hensen’s cell
Cells of Claudius Inner pillar cell

Cells of Böttcher
Inner spiral cell
Basilar Cochlear nerve
Cochlear nerve
membrane Outer pillar cell
Figure 22–17 Organ of Corti.
prominence, is covered by a pseudostratified epithelium diate cells. Basal cells also have cellular processes that
called the stria vascularis. Unlike most epithelia, it ascend around the bases of the marginal cells, forming
contains an intraepithelial plexus of capillaries. cup-like structures that isolate and support the marginal
Although the stria vascularis is reported to be composed cells. Intraepithelial capillaries are positioned in
of three cell types—basal, intermediate, and mar- such a fashion that they are surrounded by the basal
ginal cells—the three types closely resemble one processes of the marginal cells and the ascending
another in electron micrographs. processes of the basal and intermediate cells.
Dark-staining marginal cells have abundant Although it has been suggested that a number of cells
microvilli on their free surfaces. Their dense cytoplasm in the membranous labyrinth, including those of the
contains numerous mitochondria and small vesicles. stria vascularis, may be responsible for the production
Labyrinthine, narrow cell processes containing elon- of endolymph, the true nature of its origin remains
gated mitochondria are abundant on the basilar portion unclear. Maintenance of the ionic composition of the
of the cells. endolymph may be a function of the marginal cells of
Light-staining basal cells and intermediate cells the the stria vascularis.
have less dense cytoplasm containing only a few mito- The spiral prominence is also located on the infe-
chondria. Both have cytoplasmic processes that radiate rior portion of the lateral wall of the cochlear duct. It is
out from the cell surfaces to interdigitate with the cell a small protuberance that juts out from the periosteum
processes of the marginal cells and with other interme- of the cochlea into the cochlear duct throughout its
Ch022-X2945.qxd 12/8/06 3:46 PM Page 533
panic lip of the limbus, a continuation of the basilar

membrane. Numerous perforations in the tympanic lip
accommodate branches of the cochlear division of the
vestibulocochlear nerve (acoustic nerve). Interdental
cells located within the body of the spiral limbus
secrete the tectorial membrane, a proteoglycan-rich
gelatinous mass containing numerous fine keratin-like
filaments, that overlies the organ of Corti. Stereocilia
of specialized receptor hair cells of the organ of
Corti are embedded in the tectorial membrane (see
CD Fig. 22-17).
VM
The organ of Corti, the specialized receptor organ
for hearing, lies on the basilar membrane and is com-
BM posed of neuroepithelial hair cells and several types of
SV
supporting cells. Although the supporting cells of the
organ of Corti have different characteristics, they all
originate on the basilar membrane and contain bundles
of microtubules and microfilaments, and their apical
surfaces are all interconnected at the free surface of the
ANF organ of Corti. Supporting cells include pillar cells,
phalangeal cells, border cells, and cells of Hensen
(see Figs. 22-17 and 22-18).
ST SUPPORTING CELLS OF THE ORGAN

OF CORTI
The supporting cells of the organ of Corti are the inner

and outer pillar cells, the inner and outer phalangeal
cells, the border cells, the cells of Hensen, and the cells
of Böttcher.
Figure 22–18 Light micrograph of the organ of Corti sitting on Inner and outer pillar cells are tall cells with wide
the basilar membrane (BM) within the cochlea (×180). The cochlear
duct (CD), containing endolymph, is limited by the vestibular mem- bases and apical ends; thus, they are shaped like an
brane (VM) and the BM. The scala vestibuli (SV) and the scala elongated “I.” They are attached to the basilar mem-
tympani (ST) contain perilymph. Observe the spiral ganglion and the brane, and each one arises from a broad base. The
vestibulocochlear (acoustic) nerve fibers (ANF) coming from the hair central portions of both inner and outer pillar cells are
cells of the organ of Corti.
deflected to form the walls of the inner tunnel, where
the inner pillar cells form the medial wall of the tunnel
and the outer pillar cells form the lateral wall of the
entire length. The basal cells of the stria vascularis are tunnel. At their apices, both inner and outer pillar cells
continuous with the vascular layer of cells covering the are again in contact with each other. Their cytoplasm
prominence. Inferiorly, these cells are reflected into contains bundles of microfilaments and microtubules.
the spiral sulcus, where they become cuboidal. Other Inner pillar cells outnumber outer pillar cells, with
cells of this layer continue onto the basilar lamina as the three inner pillar cells usually abutting two outer pillar
cells of Claudius, which overlie the smaller cells of cells. The pillar cells support the hair cells of the organ
Böttcher (see Fig. 22-17). The latter cells are located of Corti.
only in the basilar turns of the cochlea. The function of Outer phalangeal cells are tall columnar cells that
the cells of Claudius and Böttcher is unknown. are attached to the basilar membrane. Their apical por-
At the narrowest portion of the cochlear duct, where tions are cup-shaped to support the basilar portions of
the vestibular and basilar membranes meet, periosteum the outer hair cells along with bundles of efferent and
covering the spiral lamina bulges out into the scala afferent nerve fibers, which pass between them on
media, forming the limbus of the spiral lamina. Part their way to the hair cells. Because their cup-shaped
of the limbus projects over the internal spiral sulcus apices cradle the hair cells, the outer phalangeal cells
(tunnel). The upper portion of the limbus is the do not reach the free surface of the organ of Corti.
vestibular lip, and the lower portion is called the tym- However, originating from the lateral aspect of each of
Ch022-X2945.qxd 12/8/06 3:46 PM Page 534
these cells is a small phalangeal process that extends contains abundant RER, and their mitochondria are
to the reticular lamina. Microtubules and microfila- located basally. The cytoplasm of those cells just
ments within the phalangeal process add to its rigidity. beneath the lateral walls contains a cortical lattice,
The distal, flattened end of the phalangeal process is in composed of 5- to 7-nm filaments cross-linked by
contact with its cradled hair cell and an adjacent hair thinner filaments, that appears to support the cell
cell. There is a fluid-filled gap around unsupported and resist deformation. Afferent and efferent fibers
regions of the outer hair cells. This space is called the synapse on the basilar portion of the hair cells. Extend-
space of Nuel, and it communicates with the inner ing from the apical surface of the outer hair cells are as
tunnel. many as 100 stereocilia organized in the shape of the
Inner phalangeal cells are located deep to the letter “W.” These stereocilia vary in length and are
inner pillar cells; unlike the outer phalangeal cells, arranged in ordered gradation. Like inner hair cells,
they completely surround the inner hair cells they outer hair cells do not have a kinocilium but do have a
support. basal body.
Border cells delineate the inner border of the organ
of Corti. They are slender cells that support the inner Vestibular Function
aspects of the organ of Corti.
Cells of Hensen define the outer border of the The vestibular function is the sense of position in space
organ of Corti. These tall cells are located between the and during movement.
outer phalangeal cells and the shorter cells of Claudius,
which rest on the underlying cells of Böttcher. The sense of position in space and during movement
All of these cells support the outer aspects of the is essential to activate and deactivate certain muscles
organ of Corti (see Fig. 22-17). that function in accommodating the body for balance.
The sensory mechanism for this function is the vestibu-
NEUROEPITHELIAL CELLS (HAIR lar apparatus, which is located in the inner ear. This
CELLS) OF THE ORGAN OF CORTI apparatus comprises the utricle, saccule, and semicircular
ducts.
There are two types of neuroepithelial cells in the organ Stereocilia of neuroepithelial hair cells located in the
of Corti: inner hair cells and outer hair cells. ampullae of the utricle and saccule are embedded in the
otolithic membrane. Linear movements of the head
Neuroepithelial hair cells are specialized for transduc- cause displacement of the endolymph, which disturbs
ing impulses for the organ of hearing. Depending on the positioning of the otoliths within the otolithic mem-
their locations, these cells are called inner hair cells and brane and, consequently, the membrane itself, thereby
outer hair cells. bending the stereocilia of the hair cells. Movements of
Inner hair cells, a single row of cells supported by the stereocilia are transduced into action potentials,
inner phalangeal cells, extend the inner limit of the which are conducted by synapses to the vestibular divi-
entire length of the organ of Corti. Inner hair cells are sion of the vestibulocochlear nerve for transmittal to the
short and exhibit a centrally located nucleus, numerous brain.
mitochondria (especially beneath the terminal web), Circular movements of the head are sensed by
RER and SER, and small vesicles. The basal aspect of receptor sites in the semicircular ducts housed within
these cells also contains microtubules. Their apical the semicircular canals. Stereocilia of the neuroep-
surface contains 50 to 60 stereocilia arranged in a “V” ithelial hair cells of the cristae ampullares are em-
shape. The core of the stereocilia contains microfila- bedded in the cupula. Movements of the endolymph
ments, cross-linked with fimbrin, as in the type I hair within the semicircular ducts disturb the orientation
cells of the vestibular labyrinth. The microfilaments of of the cupula, which subsequently distorts the stereo-
the stereocilia merge with those of the terminal web. cilia of the hair cells. This mechanical stimulus is
Although a kinocilium is not present in inner hair cells, transduced to an electrical impulse, which is trans-
a basal body and centriole are both evident in the apical ferred by synapse to branches of the vestibular division
region of these cells. The basal aspects of these cells of the vestibulocochlear nerve for transmission to the
synapse with afferent fibers of the cochlear division of brain.
the vestibulocochlear nerve. Information concerning the linear and circular
Outer hair cells, supported by outer phalangeal movements of the head, recognized by receptors of the
cells, are located near the outer limit of the organ of inner ear, is transmitted to the brain via the vestibular
Corti and are arranged in rows of three (or four) along division of the vestibulocochlear nerve. There, it is
the entire length of this organ (see Fig. 22-17). The interpreted, and adjustments to the balance are initi-
outer hair cells are elongated cylindrical cells whose ated by activation of specific muscle masses responsible
nuclei are located near their bases. Their cytoplasm for posture.
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Schematic cutaway of
vestibule and cochlea with
cochlear duct:
2 Wave returns via

Figure 22–19 Schematic dia- scala tympani and
gram showing how vibrations of resonates with a
the footplate of the stapes move specific section of
the membrane on the oval window. cochlear duct
This action produces a pressure
in the perilymph, located in the scala
vestibuli. At the helicotrema, where
the scala vestibuli and scala tympani
communicate, the pressure wave
within the perilymph of the scala
tympani sets the basilar membrane
and the organ of Corti, sitting on it, 1 Vibration
into motion. This causes a shearing pressure starts
motion on the hair cells of the basilar at oval window,
membrane, which is transduced into passes into
an electric current and in turn is scala vestibuli
4 Reduced wave 3 Vibration of basilar
transmitted by a synapse to the dissipated by membrane of duct
cochlear division of the vestibulo- Round window round window stimulates specific
cochlear nerve for conduction to the hair cells in organ
brain for processing. of Corti
Because of a mechanical advantage rendered by

CLINICAL CORRELATIONS the articulations of the three bony ossicles, the mechan-
ical energy is amplified about 20 times when it reaches
Meniere’s Disease is a disorder characterized the footplate of the stapes, where it impinges on the
by hearing loss resulting from excess fluid membrane of the fenestra vestibuli (oval window).
accumulation in the endolymphatic duct. Other Movements of the oval window membrane initiate pres-
symptoms include vertigo, tinnitus, nausea, and sure waves in the perilymph within the scala vestibuli.
vomiting. Some drugs can relieve vertigo and Because fluid (in this instance, perilymph) is incom-
nausea. However, in severe cases the vestibular pressible, the wave is passed through the scala vestibuli,
division nerve may have to be severed, and the through the helicotrema, and into the scala tympani.
semicircular canals and cochlea may have to be The pressure wave in the perilymph of the scala
surgically removed. tympani causes the basilar membrane to vibrate.
Because the organ of Corti is firmly attached to the
basilar membrane, a rocking motion within the basilar
membrane is translated into a shearing motion on the
Cochlear Functions stereocilia of the hair cells that are embedded in the
overlying rigid tectorial membrane. When the shearing
The cochlea functions in the perception of sound. force produces a deflection of the stereocilia toward the
taller stereocilia, the cell becomes depolarized, thus
Sound waves collected by the external ear pass into the generating an impulse that is transmitted via the affer-
external auditory meatus and are received by the tym- ent nerve fibers of the cochear division of the vestibu-
panic membrane, which is set into motion. The tympanic locochear nerve (Fig. 22-19).
membrane converts sound waves into mechanical energy. How differences in sound frequency or pitch are dis-
Vibrations of the tympanic membrane set the malleus, tinguished is not understood. It has long been thought
and consequently the remaining two ossicles, into that the basilar membrane, which becomes longer with
motion. each turn of the cochlea, vibrates at different frequen-
Ch022-X2945.qxd 12/8/06 3:46 PM Page 536
cies relative to its width. Therefore, low-frequency length of their stereocilia and consequently altering the
sounds would be detected near the apex of the cochlea, shear force between the tectorial membrane and the
whereas high-frequency sounds would be detected near basilar membrane, thus “tuning” the basilar membrane.
the base of the cochlea. Evidence suggests that outer This action then alters the response of the sound-
hair cells contain the necessary machinery to react detecting inner hair cells, affecting their reaction to dif-
rapidly to efferent input, causing them to vary the ferent frequencies.
Conductive deafness may be caused by any con- tube. Fluid buildup in the middle ear cavity dampens
dition that impedes the conduction of the sound the tympanic membrane, thus constricting the move-
waves from the external ear through the middle ear ments of the bony ossicles. Antibiotics are the usual
and into the organ of Corti of the inner ear. Condi- treatment.
tions that can lead to conductive deafness include Nerve deafness usually results from a disease
the presence of foreign bodies, otitis media, and process that interrupts transmission of the nerve
otosclerosis (fixation of the footplate of the stapes impulse. The interruption may be located anywhere
in the oval window). in the cochlear division of the acoustic nerve, from
Otitis media is a common infection of the middle the organ of Corti to the brain. Disease processes
ear cavity in young children. It usually develops from that can lead to nerve deafness include rubella,
a respiratory infection that involves the auditory tumors of the nerve, and nerve degeneration.
Index-X2945.qxd 12/8/06 3:48 PM Page 537
䡲䡲䡲
Index
Note: Page numbers followed by the letter b refer to boxed material; those followed by the letter f refer to figures, and those followed by t
refer to tables.
A Acetylcholine (Continued) Actin monomer, 43f

receptors for, 171 Actin ring, of osteoclast, 141
α-actin, 43, 45f pancreatic, 419 Action potential
α-actinin suprarenal release of, 324 cycle of, 200
in cytoskeleton, 44t, 45f Acetylcholinesterase, 171 mechanism of, 198–200, 200f
in epithelium, 99 Acid hydrolases, 35 of cardiac muscle, 178–179
in skeletal muscle, 164, 165t Acidophil(s), in pituitary gland, 308, 308f, of skeletal muscle, 171, 178
in smooth muscle, 182 309f Activated cells, in immune response,
A antigens, 224, 224t Acidophilic components, 2 276
A bands Acidosis, 432b Activated macrophages, 123
in cardiac muscle, 178f Acinar cells Activation
in skeletal muscle, 160, 161f, 162, 162f mammary, 487f of B cells, 280
α cells, 420, 421, 421t pancreatic, 418–419, 418f, 419f of lymphoid cells, 285
α-chains Acinar glands, 107, 107f Activation gate, 199
in tropocollagen, 73, 75, 76t Acinus(i) Active catalytic subunits, of A-kinase, 22
synthesis of, 75, 77f hepatic (liver, portal), 426 Active sites
α-globulins, 221t in sebaceous glands, 339 of synapse, 201
α-granules, of platelets, 233, 233f, 236t of mixed glands, 104, 104f on axon terminal, 170
A-kinase, 22 of multicellular exocrine glands, 107, 109f on G-actin, 166
α-melanocyte-stimulating hormone (α- of Rappaport, 426 Active transport, 17, 18f, 19
MSH), 310 of salivary gland, 104f, 107, 109f, primary, by Na+-K+ pump, 19
α-motor neurons, 169, 173, 174f 413–414, 414f secondary, by coupled carrier proteins,
A-site, ribosomal, 22 pancreatic, 418, 418f, 419f 20
α-tubulin, 43f Acne, 339b Activin, ovarian, 466, 468, 472, 473t
Abluminal plasmalemma, of capillaries, Acoustic (vestibulocochlear) nerve, 527f, Acute myeloblastic leukemia, 246b
263, 264 528, 529, 531f, 535, 535f Acute myelogenous leukemia, 66b
ABO blood group system, 224, 224t Acquired immunodeficiency syndrome Adaptin, 31
Absorption (AIDS), 196b, 287b Adaptive immune system, 273, 276
by colon, 409 Acromegaly, 154b Addison’s disease, 322b, 332b
by small intestine, 405–406, 407f Acrosin, 480, 496 Adducin, 224
Absorption cavities, of bone, 152 Acrosomal cap, 495, 496f Adenocarcinoma, 102b
Accessional teeth (molars), 368, 373 Acrosomal granule, 495, 497f of prostate, 507b
Accessory genital glands, 490f, 504–507 Acrosomal phase, of spermiogenesis, 496, Adenohypophysis, 304, 306–310
Accessory structures, of eye, 515f, 497f Adenoid, 299
525–526 Acrosomal reaction, 480, 497 Adenoma(s)
Accommodation, 517, 519b Acrosomal vesicle, 495, 497f benign pleomorphic, 417b
Acellular cementum, 370 Acrosome, 495, 496f pituitary, 311b
Acetyl coenzyme A (acetyl CoA), 36, 40, Actin-binding proteins, 43, 44t Adenosine diphosphate (ADP)
173b Actin filaments and clot formation, 233
Acetylcholine as vesicle pathway, 31 in active transport, 19
as neurotransmitter, 203, 204t bundles of, 43–44 in muscle contraction, 168, 168f
in autonomic nervous system, 208 in cytokinesis, 65 Adenosine triphosphate (ATP)
in gallbladder, 436 in cytoplasm, 42, 43, 43f, 44, 44t, 45f binding to heavy merosin, 165
in HCl secretion, 396 in eccrine sweat glands, 338 in active transport, 19
in lacrimal gland, 184 in epithelial microvilli, 90–91, 93f, 94f in chromaffin cells, 323
in signaling, 20 in erythrocyte cell membrane, 224, 224f in mitochondria, 39f, 40
in skeletal muscle contraction, 170–171 in skeletal muscle, 161, 164f, 166–167 in muscle contraction, 167, 168, 168f
in smooth muscle synapses, 182 in zonulae adherentes, 99 in signaling, 20
537
538 䡲䡲䡲 Index
Adenylate cyclase Alimentary canal, 381–411. See also Anchoring fibrils, 76t, 82f, 83f
in fat release, 117 Digestive system. in dermis, 334
in hepatocytes, 428 defined, 381 Anchoring filaments, 83f
in mast cells, 120 diffuse neuroendocrine system cells and lymphatic, 270, 270f
in signaling, 20, 21–22 hormones of, 390–391, 392t, 393f Anchoring junctions, 94
Adhesion molecules esophagus in, 383–395, 394t Anchoring plaques, of lamina reticularis,
and capillaries, 265 histology of, 381–382, 382f, 394t–395t 81f–83f
cell adhesion (CAMs), 201 innervation of, 382–383 Anchoring proteins, 99
Adhesive glycoproteins, 72 large intestine in, 395t, 407–411 Anchoring villi, 484
in connective tissue, 111 small intestine in, 394t–395t, 398–406 Androgen(s), 312t, 321
Adipose cells (adipocytes), 115–117, stomach in, 385–397, 394t in follicular development, 470
116f Alkaline phosphatase, 138b weak, 322
brown (multilocular), 115, 116, 118f, All-or-none law, 167 Androgen-binding protein (ABP), 493, 499,
128–129 All-trans retinal, 522 501f
histogenesis of, 129 Alport’s syndrome, 442b Androstenedione, 312t, 321, 322, 468
in cytoplasm, 41 Alveolar bone proper, 375, 376 Anemia, 224b
in loose connective tissue, 126 Alveolar capillary network, 355f, 358f iron deficiency, 243b
obesity related to, 129b Alveolar cells, 360, 360f–362f pernicious, 389b
storage and release of fat by, 116–117, Alveolar ducts, 346t, 357, 357f–359f sickle cell, 223b
119f Alveolar elastin network, 355f Anencephaly, 186b
structure of, 112f, 115, 117f Alveolar glands, 107, 107f Aneuploidy, 56b
tumors of, 129b Alveolar macrophages, 359f, 361, 361b, Aneurysm, 256b, 257b
white (unilocular), 115–116, 117f, 362f, 363 Angina pectoris, 269b
127–128 Alveolar pores (of Kohn), 359f, 360 Angiotensin
Aditus, laryngeal, 351 Alveolar sacs, 347t, 357, 358f functions of, 457, 457t
Adluminal compartment, of seminiferous Alveolus(i) in blood pressure regulation, 258
tubules, 492, 492f of lung, 347t, 357, 358f, 359f, 360 in chronic essential hypertension, 457b
Adluminal plasmalemma, of capillaries, of mammary glands, 486, 486f, 487, 487f in corticosteroid synthesis, 320
263, 264 of tooth, 368, 368f, 369f, 375–376 in juxtaglomerular cells, 450, 457, 457t
ADP. See Adenosine diphosphate (ADP). Amacrine cells, in retina, 520f, 524–525 in urine formation, 457
Adrenal glands. See Suprarenal (adrenal) Ameloblasts, 369, 373, 373f tunica intima and, 252
glands. Amino acid(s) Angiotensin-converting enzyme (ACE)
Adrenocorticosteroids, 312t, 318, 319, 320, derivatives of, in hormones, 303 angiotensin II produced by, 258
321–322 sulfation and phosphorylation of, 30f in juxtaglomerular cells, 450, 457, 457t
effect on thymus, 290 D-Amino acid oxidase, 36 in tunica intima, 252
Adrenocorticotropic hormone (ACTH, Amino sugar, 69, 71t Angiotensinogen
corticotropin), 307t, 309, 312t, 318, Amino-terminal regions, 280 in blood pressure regulation, 258
320, 322b Aminoacyl tRNA, 24 in urine formation, 457
Adult hemoglobin, 223 Amniotic cavity, 481f Ankyrin, 223, 224, 224f
Adventitia. See Tunica adventitia. Amphipathic molecule, 13 Annulate lamella, 41
Adventitial reticular cells, of bone marrow, Ampulla(e) Annulus(i)
237, 237b of ductus deferens, 504 of annulate lamella, 41
Aerobic energy system, 168 of oviducts, 474 of spermatozoon, 496, 497f
Afferent component, of peripheral nervous of semicircular canal, 528, 528f, 530 Annulus fibrosus, 136, 136b, 269
system, 185, 206 of Vater, 434 Anode, in electron microscopy, 4f, 9
Afferent fibers, 206 Amylase, salivary, 367, 416 Anterior chamber, of eye, 515f
Afferent lymphatic vessels, 270, 290, Anabolic steroids, 321 Anterograde reaction, to nerve injury, 216,
291f Anagen phase, of hair growth, 342 217–218
Afferent neurons, 193 Anal canal, 395t, 409–410 Anterograde transport, 29, 31
Afferent pathways Anal columns, 410 axonal, 191, 192
somatic, 511 Anal glands, 410 Anti-Rh agglutinins, 225b
visceral, 511 Anal mucosa, 410 Antibody(ies), 276, 277–278, 279t
Aggrecans, 70f, 71, 72f Anal sinuses, 410 constant (Fc) regions of, 32
in bone, 137 Anal sphincter muscle, 410 membrane-bound, 277, 279t
in cartilage, 134 Anal valves, 410 production of, by plasma cells, 232
in connective tissue, 113 Anamnestic response, 277 reaginic, 279t
Aging Anaphase, of cell cycle secretory, 279t
cartilage degeneration and, 134b meiotic, 66f, 67 structure of, 278, 278f
nucleolus and, 61b in spermatocytes, 495 Antibody-dependent cellular cytotoxicity,
Agranulocytes, 225, 226t, 231–232, mitotic, 63f, 64–65, 64f 275, 279t
232f Anaphase II, of cell cycle, 67f, 68 Antibody labeling, direct and indirect, 5,
Albinism, 332b Anaphylactic reaction, 118, 120, 120f 5f, 6f
Albumin, in blood, 220, 221t Anaphylactic shock, 122b, 230b Anticodon, 24, 59
Albuminuria, 445b Anaphylaxis Antidiuresis, 456f
Alcoholics, liver disorders in, 429b slow-reacting substance of, 230 Antidiuretic hormone (ADH), 307t, 310, 311
Aldosterone, 312t, 320 systemic, 122b as neurotransmitter, 203
and distal convoluted tubule, 449 Anastomosis, arteriovenous, 263 in blood pressure regulation, 258
in urine formation, 457 in penis, 508 in urine formation, 456f, 458
Index ■ ■ ■ 539
Antigen(s) Arrector pili muscles, 328f, 329, 335, Autonomic innervation, of salivary glands,
antibodies against, 232 341–342 416
binding of, 118, 120f Arterial blood pressure, 258, 259b Autonomic nervous system, 185, 207–210,
cytokine release due to, 276 Arteriolae rectae, 453, 453f 209f
lipid, 283 Arterioles, 254t, 256–257, 256f, 257f Autophagosomes, 35–36
thymic-independent, 280 glomerular, 440, 441f, 453, 457 Autoradiography, 5–6, 7f, 8f
Antigen-presenting cells (APCs), 284, 284t hepatic, 425 Autosomes, 55
in activation of cytotoxic T-cells, 285, of splenic pulp, 294f, 295 Axoaxonic synapse, 200
286f sheathed, 294f, 295, 298f Axodendritic synapse(s), 200, 201f–203f,
Langerhans cells as, 332 terminal, 263 212f
macrophages as, 231, 276 Arteriosclerosis, 259b in retina, 524, 525
Antigenic determinant, 276 Arteriovenous anastomosis (AVA), 263 Axolemma, 190
Antigenicity, 276b in penis, 508 Axon(s), 190–192, 191f, 192f
Antimicrobial peptides, 274 Artery(ies), 253–258. See also specific type defined, 186, 188f
Antimüllerian hormone, 493 of artery. hypothalamic, 306
Antiport transport, 18f, 19 blood pressure regulation in, 258 myelinated, 191, 191f, 192f, 196
Antral follicles, 465f, 467t, 468–469, 468f, classification of, 253–257, 254t, 255f in neuromuscular junction, 169, 171f
469t defined, 251, 253 of olfactory cell, 348
Antrum, 465f, 468 disorders of, 259b of parasympathetic nerves, 210
Anus, 410 elastic (conducting), 253–254, 254t, 255f type Ib, 175
Aorta, 253, 318 muscular (distributing), 254t, 255–256, unmyelinated, 191, 192f, 197
aneurysm of, 256b 255f Axon hillock, 188, 188f, 190
Aortic bodies, 258 specialized sensory structures in, Axon reaction, 216–218, 217f
Aortic valve, 268 257–258 Axon terminals, 170, 186–187, 202f, 203f
Apical canaliculi, 447 structure of, 252f, 253 Axonal transport, 191–192, 191b
Apical domain, of epithelium, 90–92, tunics of, 251–253, 252f Axoneme, 91, 92, 95f
91f–96f Articular cartilage, 156, 156f flagellar, 495, 497f, 498
Apical foramen, of tooth, 368, 368f, 369f Articular cavity, 156f Axoplasm, 191
Apical light zone, of lymphoid nodule, Aryl sulfatase, mast cell release of, 117, Axosomatic synapse, 200, 201f
292 120f, 121t Azures, 219
Apocrine glands, 105, 105f Aspartate, 203 Azurophilic granules
mammary, 487 Aspirin, and ulcers, 398b of basophils, 230
sweat, 338 Asthma, 122b, 356b of eosinophils, 229
Apoptosis Astral rays, 64 of monocytes, 231
granzyme-induced, 286 Astrocytes, 193, 194f, 195 of neutrophils, 225, 228f
mechanism of, 68 Astrocytomas, 192b
of hemopoietic cells, 241 Asymmetric synapse, 202 B
of myometrial muscle, 477 Atherosclerosis, 259b, 269b
Appendices epiploicae, 409 ATP. See Adenosine triphosphate (ATP). β-actin, 43
Appendicitis, 411b ATP synthase, 39f, 40 B antigens, 224, 224t
Appendix, 395t, 410–411 ATPase dynein, 92 B-cell receptors, 277, 278
Appositional growth Atresia, of oogonia, 464 β cells, 420, 421t, 422b, 423t
of bone, 151 Atretic follicles, 471 β-globulins, 221t
of hyaline cartilage, 132 Atrial muscle cell, 175, 177f B lymphoblast, 239t
Appositional stage, of odontogenesis, 374 Atrial natriuretic peptide (ANP), 175, 177f, B lymphocytes (B cells), 231–232, 278, 280
APUD cells. See Diffuse neuroendocrine 268, 269f activation of, 280
system (DNES) cells. Atriopeptin, 268 B7 molecule, 285, 286f
Aquaporins, 19, 90, 458, 459t Atrioventricular (AV) bundle, 267f, 268 effector cells of, 232
Aqueous humor, 517 Atrioventricular (AV) node, 267f, 268 features of, 226t
Arachidonic acid Atrioventricular (AV) valves, 267 formation of, 112f, 239t, 247, 249
basophils and, 230 Atrium(a) functions of, 231–232, 278, 280
in mast cell mediator synthesis, 117, 120 alveolar, 357 immunocompetent, 247, 278, 280
Arachnoid layer, 212f, 213 of heart, 267, 267f in small intestine, 404, 405f
Arachnoid trabecular cells, 213 Attachment plaques, 102, 103f interaction between T-helper cells and,
Arachnoid villi, 213 Auditory meatus, external, 526, 527f 285, 285f
Arcuate arteries Auditory tube, 527, 527f memory cells of, 232, 280, 285, 292, 293
of endometrium, 476, 477f Auerbach plexus vs. T cells, 280
of kidneys, 439f, 453 myenteric, 382, 383, 402 β particles, of glycogen, 430
of myometrium, 477, 477f of parasympathetic nervous system, 186, β-tubulin, 43f
Arcuate veins, 439f, 453, 454 210 Balance mechanism, 511, 534–535
Area cribrosa, 437 Auricle (pinna), 526–527, 527f BALT (bronchus-associated lymphoid
Areola, 488 Autocrine signaling, 20, 104 tissue), 299
Areolar connective tissue, 126, 126b Autografts, 153b Band 3 protein, 221, 223, 224, 224f
Areolar glands (of Montgomery), 488 Autoimmune diseases, 237b, 276b, 277b Band 4.1 protein, 224, 224f
Argentaffin and argyrophilic cells. See Autologous transplant, 240b Barbiturates, tolerance to, 433b
Diffuse neuroendocrine system Autonomic fibers, of periodontal ligament, Baroreceptors, 257
(DNES) cells. 375 Barr body, 55, 225
Aromatase, 468, 472 Autonomic ganglia, 208, 210, 211f Barrett’s syndrome, 385b
540 䡲䡲䡲 Index
Bartholin glands, 485 Bile duct(s) Bolus, 367

Basal body, of cilium, 92, 95f common, 382f, 419, 434 Bone(s), 136–156. See also Osteoblasts;
Basal cell(s) interlobular, 424f, 427 Osteoclast(s).
of cochlear duct, 532 Bile salts, 430, 430b, 432f calcification of, 151
of epididymis, 503 Bilirubin, 297, 430–431, 432f calcium level maintenance by, 154
of nasal cavity, 347–348, 348f Bilirubin glucuronide, 430, 432f cancellous (spongy), 143, 144f
of taste buds, 378, 379f Biogenic amines, 203, 204t cells of, 137–142
of trachea, 352f, 353 Bipolar neurons, 189f, 192–193 classification of, 142–143
Basal cell carcinoma, 335b in retina, 520f, 524 compact, 143, 144f, 147
Basal compartment, of seminiferous Birbeck granules, 332 haversian canal systems of, 144f,
tubules, 492, 492f Bisphosphonates, 155b 145–146, 145f, 152
Basal lamina, 79–80, 81f–83f Bladder, 437, 461–462, 461f lamellar systems of, 143–145, 144f
of capillary, 260, 261f, 262f Bladder cancer, 66b decalcified sections of, 136
of glomerulus, 441–442, 443f, 445b Blastocele, 481f defined, 136
of kidney, 439 Blastocysts, 481f, 482 flat, 143
of muscle, 158 Bleaching, in photoreception, 522 formation of
of renal corpuscle, 441f Bleeding disorders, 237b alkaline phosphatase in, 138b
of seminiferous tubules, 491 Blood, 219–236 endochondral, 131, 147–150,
of spleen, 296 coagulation of, 219 147f–150f, 148t
of thyroid, 313 defined, 219 intramembranous, 131, 146–147, 146f,
Basal light zone, of lymphoid nodule, formed element(s) of, 220–236 147f
292 agranulocytes as, 225, 226t, 231–232, functions of, 136
Basal surface specializations, of epithelium, 232f gross observation of, 143, 144f
102, 103f basophils as, 220f, 222f, 226t, 230, ground sections of, 136
Basal zone, of osteoclast, 141 230b growth of
Basalis layer, of endometrium, 476, 477f eosinophils as, 220f, 222f, 226t, in length, 149f, 150–151
Basement membrane, 79–80, 81f 228–230, 230b in width, 151
of skin, 328f, 329 erythrocytes as, 220–225, 222f, 223f histogenesis of, 146
Basilar membrane, of cochlear duct, 530, formation of. See Hemopoiesis. histophysiology of, 154–155
532f, 535, 536 granulocytes as, 225–230, 226t, hormonal effects on, 154, 154b, 155b
Basket cells, of salivary gland, 414, 414f 227f–229f hyaline cartilage model of, 147, 147f,
Basolateral domain, of epithelium, 92, leukocytes as, 225–232 148, 148t, 149f
94–102 lymphocytes as, 220f, 222f, 226t, in joints, 156, 156f
Basophil(s) 231–233, 232 inorganic component of, 137
features of, 226t macrophages as, 231 irregular, 143
formation of, 239t, 240f, 243 monocytes as, 220f, 222f, 226t, long, 143
functions of, 125, 230 230–231 matrix of, 137, 143, 146
granules of, 226t, 230 neutrophils as, 220f, 222f, 225, 226t, microscopic observations of, 143–146
in anaphylactic shock, 230b 227–228 nutritional effects on, 155, 155b, 155t
in pituitary gland, 308–309, 308f platelets as, 220f, 222f, 233–236, organic component of, 137
origin of, 112f 234f–236f, 236t, 236b osteocytes of, 112f, 136, 136f, 137f, 138,
structure of, 220f, 222f, 230 functions of, 219 139f, 140
vs. mast cells, 117 plasma of, 219, 220, 221t osteoprogenitor cells of, 136f, 137
Basophilic components, 2 proteins in, 220, 221t, 432, 432f primary (immature), 143
Basophilic erythroblast, 239t, 240f, 246t staining of, 219 remodeling of, 140, 151–152
Basophilic metamyelocyte, 239t, 240f volume of, 219 repair of, 152–153, 153b, 153f
Basophilic myelocyte, 239t, 240f Blood-brain barrier, 195, 213–214, 214b resorption of, 142, 142f
Basophilic stab cell, 239t, 240f Blood cells secondary (mature), 143
Bell stage, of odontogenesis, 370f, formation of. See Hemopoiesis. sesamoid, 143
373–374, 373f, 374f red. See Erythrocyte(s). short, 143
Bellini ducts, 437, 439, 451 white. See Leukocyte(s). structure of, 142–156
Benign pleomorphic adenoma, 417b Blood clot, 233–235, 235f, 236 types of, 143–146
Benign prostatic hypertrophy, 507b Blood clotting disorders, 237b Bone graft, 153b
Beta oxidation, 36 Blood-CSF barrier, 215 Bone-lining cells, 140
Bicarbonate ions (HCO −3) Blood-gas barrier, 360f, 363 Bone marrow, 236–249
in gas exchange, 363 Blood group system, 224–225, 224t B lymphocytes and, 231
in HCl production, 397 Blood islands, 238 defined, 136, 236
secretion of, by colon, 409 Blood pressure, arterial, 258–259, 259b in hemopoiesis, 237–249
Bicuspid valve, 267, 268b Blood supply. See Vascular supply. postnatal, 238–249, 238f, 239t
Bile Blood-thymus barrier, 290 prenatal, 237–238
functions of, 413 Blood vessels red, 236, 237b
heme in, 297 arteries as, 251, 253–258, 254t, structure of, 236–237, 237f
manufacture of, 425, 429, 430–431, 255f–257f transplantation of, 240b
432f capillaries as, 259–265, 260f, 262f yellow, 236, 237b
storage, concentration, and release of, general structure of, 251–253, 252f Bone morphogenetic protein, 138
435–436 nerve supply to, 253 in odontogenesis, 373
Bile acids, 430 tunics of, 251–253, 252f Bone sialoprotein, 137, 138, 151
Bile canaliculi, 424f, 425, 428, 429f veins as, 265–267, 265t, 266f Bony labyrinth, 528–534, 528f
Index ■ ■ ■ 541
Bony ossicles, 527, 527f, 535 Brush border cAMP. See Cyclic adenosine
Bony union, 153b of proximal tubule, 90 monophosphate (cAMP).
Border cell(s), of organ of Corti, 534 of renal corpuscle, 441f cAMP response elements (CREs), 22
Border cell layer, of meninges, 211, 213 of small intestine, 399 Canal of Schlemm, 515f, 516
Böttcher’s cells, 532f, 533 Brush cells Canaliculus(i)
Botulinum toxin of gallbladder, 434, 435f apical, 447
type A (“botox”), 173b of respiratory epithelium, 352f, 353 bile, 424f, 425, 428, 429f
type B, 201 Bud stage, of odontogenesis, 372, 372f in cementum, 370
Botulism, 173b Buffy coat, 219 in eccrine sweat glands, 338
Bouin’s fluid, 1 Bulb, of eye, 515 lacrimal, 526
Bouton terminal, 187, 201 Bulbar conjunctiva, 525 of bone, 140, 143
Boutons en passage, 201 Bulbar sheath, of eye, 515f of parietal cells, 389, 390f
Bowman’s capsule, 439f, 440, 442, 443f, Bulbourethral glands, 489, 490f, 507 pancreatic, 418f
444f, 445 Bundle branch, 267f Canals of Hering, 427
Bowman’s (olfactory) glands, 347, 347f, Bundle of His, 267f, 268 Cancellous bone, 143, 144f
348f, 349 Bursa of Fabricius, 247, 280 Cancer. See also specific type.
Bowman’s membrane, 516 Burst-forming units-erythrocyte (BFU-E), adenocarcinoma as, 102b
Bowman’s space, 440, 441f, 445, 445f, 450f 241 benign pleomorphic adenoma as, 417b
Bradykinin(s) cervical carcinoma as, 478b
and capillary permeability, 264 C dermatologic, 335b
in inflammatory response, 121 gastric carcinoma as, 398b
mast cell release of, 117, 121t C-kinase, 22 meningioma as, 213b
salivary glands and, 416 C protein, 162, 165t metastasis of, to lymph nodes, 271b, 293b
Brain. See also Central Nervous System C-reactive protein (CRP), 259b neurologic, 192b
(CNS); Nervous System. C-rings, tracheal, 351, 354 of bladder, 66b
blood-brain barrier and, 195, 213–214, Cadherins, 94, 98f, 99 of breast, 488b
214b Cajal, interstitial cells of, 382 pancreatic, 420b
cerebellar cortex of, 215–216, 216f Calcification pituitary adenoma as, 213b
cerebral cortex of, 215 of bone, 151 prostatic, 507b
cerebrospinal fluid in, 214–215, 215b, zone of, 151 Cancer chemotherapy, and cell cycle, 66b
215t Calcified cartilage/calcified bone complex, Cap phase, of spermiogenesis, 495, 496f
choroid plexus of, 214, 214f 147f, 148t, 149, 150f, 151 Cap stage, of odontogenesis, 372–373, 372f
congenital malformations of, 186b Calcitonin Cap Z, in skeletal muscle, 164, 165t
demyelination disorders of, 199b functions of, 311, 312t Capacitation, of spermatozoa, 475, 496, 502
development of, 185–186 in blood calcium regulation, 154 Capillaries, 259–265, 260f, 262f
gray matter of, 210 in bone resorption, 142 blood flow regulation in, 263
meninges of, 214, 214f in parafollicular cells, 316 classification of, 259, 260f, 261–263, 262f
neurotransmitter disorders of, 204b parathyroid hormone and, 316 continuous, 259, 260f, 262, 262f
swelling of, 215b Calcium (Ca2+) of blood-brain barrier, 214
tumors of, 192b as second messenger, 20, 22, 304 of interalveolar septum, 360, 363
vasomotor center in, 258 blood level of, maintenance of, 154, 317 of lungs, 365
“Brain sand,” 325 control of, in muscles, 180t of muscle, 157
Breast(s) in cardiac muscle organelles, 178, 179b, of pia mater, 213
areola and nipple of, 488 180t of thymus, 290
cancer of, 488b in signaling, 22 defined, 251, 253
mammary glands of, 485–488, 486f, 487f parathyroid hormone and, 154, 317 general structure of, 259–261, 260f–262f
Breast-feeding, 488b Calcium-calmodulin-dependent protein histophysiology of, 263–265, 264f
Breathing, 345, 364 kinase (CaM-kinase), 22 intraepithelial, in cochlear duct, 532
Broad ligament, of uterus, 463, 464f Calcium hydroxyapatite lymphatic, 270–271, 270f
Bronchial arteries, 365 in bone, 137, 151 renal, 441, 442f, 443f, 453, 453f, 454f
Bronchial tree, 346t, 354–357, 355f in cementum, 370 sinusoidal (discontinuous), 259, 262f, 263
Bronchial veins, 365 in dentin, 370 Capillary bed, regulation of blood flow into,
Bronchioles in enamel, 368–369 263, 264f
primary, 346t, 355–357, 355f Calcium ion channels, voltage-gated, 201 Capillary plexus
respiratory, 346t, 357, 357f Calcium release channels, voltage-gated, hypophyseal, 305, 306, 306f
terminal, 346t, 356–357 167 peribiliary, 425
Bronchopulmonary segment, 354, 364 Calcium-sodium channels, 178 Capping proteins, 43
Bronchus(i) Caldesmon, 181 Capsule
lobar, 354 Callus Bowman’s, 439f, 440, 442, 443f, 444f, 445
primary (extrapulmonary), 346t, 354 external, 153 Glisson’s, 423
secondary and tertiary (intrapulmonary), internal, 152, 153f of gland, 107
346t, 354 Calmodulin of joint, 156
Bronchus-associated lymphoid tissue in epithelial microvilli, 90–91 of kidney, 437, 438f
(BALT), 299 in signaling, 22 of lens, 518
Brown adipose tissue, 115, 116, 118f, in smooth muscle, 182 of liver (Glisson’s), 423
128–129 Calmodulin-calcium complex, 182 of lymph node, 291, 291f
Bruch’s membrane, 517, 521 Calvaria, 143, 147 of Meissner corpuscles, 513f, 514
Brunner’s glands, 401–402, 401f, 403 Calyx(ces), renal, 437, 438f, 459–460 of pacinian corpuscle, 513f
542 䡲䡲䡲 Index
Capsule (Continued) Cartilage (Continued) Cell cycle (Continued)

of palatine tonsils, 299 fibrocartilage as, 131, 132f, 133t, metaphase of
of prostate gland, 505, 505f 135–136, 136f meiotic, 66f, 67
of spleen, 294, 294f, 295f formation of, in bone repair, 153 mitotic, 64, 64f
of Tenon, 516 hyaline, 131–134, 133t mitosis in, 62, 62f–64f
Capsule cells, 210 as model for bone formation, 147, prometaphase of, 63f, 64, 64f
Carbaminohemoglobin, 222 147f, 148, 148t, 149f prophase of
Carbamylhemoglobin, 222 cells in, 133–134, 133f meiotic, 66f, 67
Carbohydrate metabolism, in liver, degeneration and regeneration of, 134b mitotic, 63–64, 64f
431–433, 432f histogenesis and growth of, 132, 133f S (synthetic) phase of, 61f, 62
Carbon dioxide histophysiology of, 134, 135t telophase of
exchange of, 363–364 hormone and vitamin effects on, 134, meiotic, 66f, 67
release of, 358f 135t mitotic, 64f, 65–66, 65f
uptake of, 358f in joints, 156, 156f Cell death, programmed. See Apoptosis.
Carbon monoxide matrix of, 132f, 134 Cell-free zone, of dental pulp, 371
as neurotransmitter, 203 types of, 131, 132f, 133t Cell-mediated cytotoxicity, antibody-
poisoning due to, 223b structure of, 131, 132f dependent, 275, 279t
Carbon monoxyhemoglobin, 223b water in, 134 Cell-mediated immune response, 232, 276
Carbonic anhydrase, 220, 363, 397, 419 zone of reserve, 150 Cell membrane, 11–22
Carcinoma(s), 102b Cartilage rings (C-rings), 351, 354 carrier proteins in, 17, 19–20
adenocarcinoma as, 102b Caspases, 68 cell signaling in, 20–22
of prostate, 507b Catabolic steroids, 321 cell-surface receptors in, 21–22, 21f
basal cell, 335b Catagen phase, of hair growth, 342 channel proteins in, 17–19
cervical, 478b Catalase, 36, 226, 228 fluid mosaic model of, 14, 16f
ductal, 488b Catalytic receptors, 304 functions of, 11
gastric, 398b Cataract, 519b glycocalyx of, 16
in situ, 478b Catecholamines, 312t, 322, 324 integral (transmembrane) proteins in,
invasive, 478b Catenin, 99 13–14, 16f
lobular, 488b Cathode, in electron microscopy, 4f, 9 ion channels in, 17–19
squamous cell, 335b Caveolae, 182 membrane trafficking of, 32, 33f
Cardia, 385, 393, 394t Cavities, dental, 369b membrane transport proteins in, 16–19,
Cardiac hypertrophy, 179b CD molecules (CD markers), 280, 281t 18f
Cardiac muscle, 175–179, 176f, 177f CDI molecules, 283 molecular composition of, 12–16, 16f,
characteristics of, 159f, 180t CD3 marker, 281t 17f
contraction of, 175, 180t CD4 marker, 280, 281t, 282, 285, 286f, multipass proteins in, 14, 19
intercalated disks of, 175, 176f, 177, 287, 287b, 287f of erythrocyte, 223–224, 224f
178f–179f CD8 marker, 280, 281t, 286, 286f peripheral proteins in, 13, 14, 16f
organelles of, 177–179 CD28 marker, 281t, 285, 286f signaling molecules in, 14, 20–21
regeneration of, 183 CD40 marker, 281t structure of, 12, 14f–16f
Cardiac skeleton, 269 Cecum, 407 Cell-rich zone, of dental pulp, 371
Cardiac stomach, 385, 393, 394t Celiac ganglion, 209f Cell signaling, 20–22
Cardiodilatin, 268 Cell(s). See also Cytoplasm; specific cells. Cell-surface fibronectin, 73
Cardiolipin, 39 defined, 11 Cell-surface receptors, 20, 21–22, 21f, 303
Cardionatrin, 268 general characteristics of, 11, 12f, 13f Cellular cementum, 370
Cardiovascular system, 251–271 of Böttcher, 532f, 533 Cementing line, 137f, 145
arteries in, 253–258, 254t, 255f–257f of Claudius, 532f, 533 Cementoblasts, 370, 374
blood vessel structure in, 251–253, of Hensen, 534 Cementocytes, 370
252f protein synthetic and packaging Cementum, 368f, 369f, 370, 370f, 374
capillaries in, 259–265, 260f, 262f machinery of, 22–32 Central artery, of spleen, 294f, 295
heart in, 251, 267–269, 267f Cell adhesion molecules (CAMs), 201 Central canal, 211
pulmonary circuit in, 251 Cell adhesive glycoproteins, 72 Central channel, 263, 264f
systemic circuit in, 251 Cell body, neuronal, 186, 186f, 187–190, Central longitudinal vein, 236
veins in, 265–267, 265t, 266f 187f Central memory T cells (TCMs), 281
Cargo receptors, 32–33 parasympathetic, 210 Central nervous system (CNS), 210–216.
Cargo vesicles, 28, 29 somatic, 207 See also Brain; Nervous system.
Caries, 369b Cell coat, 15 blood-brain barrier in, 195, 213–214, 214b
Carotid artery, right common, 253 Cell cycle, 61–68, 61f cerebellar cortex in, 215–216, 216f
Carotid body, 257–258 anaphase of cerebral cortex in, 215
Carotid sinus, 257 meiotic, 66f, 67, 68 cerebrospinal fluid in, 196, 214–215,
Carpopedal spasms, 318b mitotic, 63f, 64–65, 64f 215b, 215t
Carrier-mediated diffusion, 18f cancer chemotherapy and, 66b choroid plexus in, 214, 214f
Carrier proteins, 17, 19–20 cytokinesis in, 62, 65–66, 65f, 68 congenital malformations of, 186b
Cartilage, 131–136, 132f, 133t defined, 61 defined, 185
articular, 156, 156f G0, (outside, stable) phase of, 61 development of, 185–186
cells of, 133–134, 133f G1 (gap) phase of, 61–62, 61f meninges in, 211, 212f, 213b
elastic, 131, 132f, 133t, 134–135, 135f G2 phase of, 61f, 62 neurotransmitter disorders of, 204b
epiphyseal plate of, 143 interphase of, 61–62, 61f, 64f regeneration in, 218
extracellular matrix of, 131 meiosis in, 66–68, 66f, 67f, 68b tumors of, 192b
Index ■ ■ ■ 543
Central sheath, of cilia, 91 Chondrocytes cis retinal, 522

Central vein, of liver, 425, 425f defined, 131 Cistern, of endoplasmic reticulum, 23
Centrioles in bone lengthening, 150 Cisterna(e)
in G1 phase, 61 in endochondral bone formation, 148, hypolemmal, 187
in mitosis, 63 148t, 150 of Golgi apparatus, 27
of cytoskeleton, 14f, 43f, 48 in epiphyseal plate zones, 150–151 of sarcoplasmic reticulum, 160, 162f, 167
of neuron, 187 of elastic cartilage, 135, 135f perinuclear, 49, 52f
Centroacinar cells, 418, 418f, 419, of fibrocartilage, 135, 136f Cisterna chyli, 271
419f of hyaline cartilage, 132, 133–134, 133f Cisternal maturation, 31–32
Centroblasts, of lymphoid nodule, 292 origin of, 112f Clara cells, 355–356, 356f
Centrocytes, 292 Chondrogenic cells, 132, 133, 133f, 134b Class II-associated invariant protein
Centromere, 63 Chondroitin sulfate (CLIP), 283, 284
Centrosome, 29, 45, 49, 63 in bone, 137 Class switching, 280
Cephalic phase, of HCl secretion, 396 in extracellular matrix, 70, 71t Classical liver lobule, 423, 425, 425f
Cerebellar cortex, 215–216, 216f mast cell release of, 117, 120f, 121t Clathrin, 28
Cerebellar islands, 216 Chondronectin, 73, 113, 134 Clathrin basket, 31
Cerebral cortex, 215 Choriocapillary layer, 517 Clathrin-coated vesicle, 31, 31f, 32, 33f
Cerebrospinal fluid (CSF), 214–215, 215b, Chorion, 483, 483f Clathrin-mediated endocytosis, 201
215t Chorion frondosum, 483f, 484 Clathrin triskelions, 30f, 31, 31f, 32, 33f
blood-CSF barrier and, 215 Chorion laeve, 484 Claudins, 94
ependymal cells and, 196 Chorionic cavity, 481f, 483f Claudius cells, 532f, 533
vs. serum, 215t Chorionic plate, 483 Clear cells
Cerumen, 526 Chorionic somatomammotropin, 484 of eccrine sweat gland, 337–338, 337f
Ceruminous glands, 338, 526 Chorionic thyrotropin, 484 of gallbladder, 434, 435f
Cervical carcinoma, 478b Chorionic villi, 483, 483f, 484, 484f parafollicular, of thyroid, 154, 313, 313f,
Cervical ganglia, 209f Choroid, ocular, 515f, 517 316
Cervical glands, 478 Choroid plexus, 196, 214, 214f Clear zone, of osteoclast, 141
Cervical loop, of tooth, 372 Chromaffin cells, 322–323, 322f, 323f Clearing, in tissue preparation, 2
Cervix Chromatids, 66 Clefts of Schmidt-Lanterman, 196–197
of tooth, 368, 369f sister, 63, 63f, 64–65 Clitoris, 485
uterine, 464f, 478 Chromatin, 52, 55–61, 55f Clonal anergy, 277
cGMP (cyclic guanosine monophosphate), defined, 49 Clonal deletion, 277
18, 20, 304 nucleolus-associated, 60 Clonal expansion, 276–277
Chain-terminator site, 58 packaging of, 52, 55f Clone(s), 232, 276–277, 278
Channel proteins, 17–19 sex, 55–56 Closed circulation theory, of spleen, 295,
Charcot-Böttcher, crystal of, 42, 492 Chromatin assembly factor 1 (CAF-1), 52 295f
Checkpoints, 62 Chromatolysis, 218 Clostridium difficile, 409b
Chemical synapse, 200 Chromogranins, 323 Clot formation, 233–235, 235f, 236
Chemiosmotic theory, 40 Chromophils, 308–309, 308f Clotting disorders, 237b
Chemokines, 274 Chromophobes, 308f, 310 Clotting factors, 237b
Chemoreceptors, 258 Chromosomes, 52, 55–60, 56f Clotting proteins, 221t
Chemotherapy, demyelination due to, abnormalities of, 56b, 68b, 495b Club hairs, 342
199b Chyle, 406 Cluster of differentiation proteins (CD
Chiasmata, 67 Chylomicrons, 116, 221t, 406, 431 molecules, CD markers). See CD
Chief cells Chyme, 385, 396 entries.
of parathyroid, 317, 317f Cilia, of epithelium, 91–92, 95f, 96f Coagulation, 219, 233–235, 235f, 236
of stomach, 386f, 387f, 390, 391f Ciliary body, 515f, 517 Coagulation disorders, 237b
Chloride, in HCl production, 397 Ciliary ganglion, 209f, 211f Coagulation factors, 234
Chloride pump, in Henle’s loop, 456 Ciliary muscle, 517 Coat protein subunit, 31
Chloride shift, 221, 363 Ciliary processes, 515f, 517 Coatomer I (COP I), 28, 30f, 31
Choana, 345 Ciliary zone, 518 Coatomer II (COP II), 28, 30f, 31
Cholangioles, 427 Ciliated cells Cochlea, 527f, 528, 528f, 532f
Cholecystokinin, 392t, 419, 435 of ductuli efferentes, 502 functions of, 535–536, 535f
Cholelithiasis, 436b of endometrium, 476 Cochlear duct, 528f, 530, 532–534, 532f,
Cholera, pancreatic, 422b of larynx, 351 533f
Cholera toxin, 405b of oviducts, 475, 476f Cochlear nerve, 532f
Cholesterol of paranasal sinuses, 350 Codon(s), 24, 57
corticosteroid synthesis from, 318, of trachea, 353, 353f start, 24, 57, 58
319 olfactory, 347f, 348, 348f stop, 25, 57
in cell membrane, 13, 16f Circular deoxyribonucleic acid (cDNA), 40 Colchicine, 46b, 56, 66b
level of, and heart disease, 259b Circular movements, 534 Collagen, release of, by capillaries, 264
Cholesterol desmolase, 499 Circulation. See Cardiovascular system; Collagen fibers, 73–78
Cholesterol esterase, 499, 500f Lymphatic vascular system; Vascular degradation of, 78f
Cholesterol stones, 436b supply. fibril-forming, 73, 74f, 76t
Choline acetyl transferase, 171 Circumanal glands, 410 hemidesmosomes and, 102
Cholinergic splanchnic nerves, 322 Circumvallate papilla, 377f, 378 in bone, 137, 145
Chondrification centers, 132 Cirrhosis, 429b in cartilage, 131, 133t, 134
Chondroblasts, 112f, 132, 133, 133f cis Golgi network, 27, 28, 29f, 30 in cementum, 370
544 䡲䡲䡲 Index
Collagen fibers (Continued) Composite bodies, 361 Contact sites, mitochondrial membranes,
in connective tissue, 113, 113f, 126 Compound glands, 106, 107f 39
in dentin, 370 tubuloalveolar, 486 Continuous capillaries. See Capillaries,
in dermis, 334 Compound microscope, 2, 4f continuous.
in Golgi tendon organs, 175 Concentric cell layers, in tunica media, Continuous conduction, 206
in periodontal ligament, 375 252 Contractile bundles, 43
structure and function of, 73–78, 74f, Concentric lamellae, of bone, 145f Contractile ring, 65–66
75f, 76t Condenser lens, 2, 4f Contraction(s)
synthesis of, 75–78, 77f Condensing vesicles, 31 of cardiac muscle, 175, 180t
types of, 73, 74f, 75, 75f, 76t, 113, 113f Conducting arteries, 253–254, 254t, 255f of skeletal muscle, 160–161, 167–169,
wavy, 175 Conducting portion, of respiratory system, 168f, 180t
white fibers as, 73 345–357, 346t of small intestine, 405
wound healing and, 75b Conduction, of nerve impulses, 198–204, of smooth muscle, 180t, 181, 182, 184f
Collagenase, 142 199f, 200f of uterus, 477
Collateral branches, of axons, 188f, 190 continuous, 206 Cord type glands, 107, 109
Collateral ganglia, 210 saltatory, 206 Core
Collecting tubules, 451–452, 459t Conduction system, of heart, 267f, 268, of dental pulp, 371
cortical, 446f, 451 268f of Meissner corpuscles, 514
loss of water and urea from filtrate in, Conduction velocity, 206, 206t Core promoter, 57
458 Conductive deafness, 536b Corium. See Dermis.
medullary, 446f, 451 Cones, 520f, 523–524, 523f, 524f Cornea, 515f, 516, 525
papillary, 437, 439, 451 Confocal microscopy, 7, 8f, 9f Corona
structure of, 438f–439f, 446f, 451f, 452f, Conjunctiva, 515, 515f, 525 of lymphoid nodules, 292
459t Conjunctivitis, 525b of spleen, 294f
Collecting veins, of liver, 425 Connecting piece, of spermatozoon, 495, Corona radiata, 465f, 468, 482f
Colliculus seminalis, 504 498 Coronary arteries, 253
Colloid, in thyroid, 313, 313f Connecting stalk, of rod, 522 Coronary heart disease, 259b, 269b
Colloid osmotic pressure, 220 Connective tissue, 111–129 Coronary vessels, atherosclerosis of, 269b
Colon, 395t, 407, 408b, 408f, 409, 409f, adipose, 127–129, 129b Corpora amylacea, 506
410f adipose cells in, 112f, 113f, 115–117, Corpora arenacea, 325
Colony-forming unit-erythrocyte (CFU-E), 116f–119f Corpus albicans, 465f, 471
241 cellular components of, 114–125 Corpus cavernosum, 507f, 508
Colony-forming unit-granulocyte (CFU-G), classification of, 125–129, 126t Corpus cavernosum urethrae, 508
243 defined, 111 Corpus hemorrhagicum, 470
Colony-forming unit-granulocyte, dense, 126–129, 127f, 128f Corpus luteum, 465f, 470–471, 470f, 473
erythrocyte, monocyte, megakaryocyte embryonic, 125–126, 126t degeneration of, 470–471
(CFU-GEMM), 238, 239, 239t, 243 extracellular matrix of, 111, 113–114 of menstruation, 470, 474
Colony-forming unit-granulocyte- fibers in, 113–114 of pregnancy, 470–471, 474
macrophage (CFU-GM), 243 fibroblasts as, 112f, 114, 114b, 115f Corpus spongiosum, 507f, 508
Colony-forming unit-lymphocyte (CFU- fixed cells of, 114–123 Cortex
Ly), 238, 239, 239t, 247, 249 functions of, 111 cerebellar, 215–216, 216f
Colony-forming unit-macrophage (CFU- in muscles, 180t cerebral, 215
M), 243, 246 leukocytes in, 124–125 gray matter in, 210
Colony-forming unit-megakaryocyte (CFU- loose (areolar), 126, 126b of hair shaft, 341, 341f
Meg), 246 macrophages in, 122–123, 122f, 123f of lymph nodes, 291, 291f, 292f
Colony-stimulating factors (CSFs), 241, mast cells in, 112f, 117–121, 119f, 122b of lymphoid nodule, 291
242t, 274 mesenchymal, 125–126 of suprarenal glands, 312t, 318–320,
effect on bone, 154 mucous, 126 319f, 321–322, 321f
Colostrum, 487, 488 myofibroblasts in, 114–115 ovarian, 463–471, 465f, 466f
Columnar epithelium origins of cells of, 111, 112f renal, 437, 438f–439f, 440f
pseudostratified, 86t, 87f, 89–90, 90f pericytes in, 113f, 115 thymic, 288–289, 288f, 289f
simple, 86t, 87, 87f, 88f plasma cells in, 124, 124f, 125f Corti, organ of, 532f, 533–534, 533f, 535
stratified, 86t, 87f, 88 proper, 111, 126–128, 126t Cortical arch, 437
Columns of Bertin, 437 reticular, 127, 128f Cortical arteries, 318
Coma, hepatic, 432b specialized, 111, 125, 126t Cortical collecting tubules, 446f, 451
Common bile duct, 382f, 419, 434 structure of, 111, 113f Cortical columns (of Bertin), 437
Common hepatic duct, 434 transient cells of, 124–125 Cortical labyrinth, 437
Communicating junctions. See Gap Connective tissue investments, of Cortical lattice, of hair cells, 534
junctions. peripheral nerves, 205–206, 205f Cortical nephrons, 438f–439f, 439, 448t
Compact bone, 143, 144f, 147 Connexins, 101 Cortical plates, of dental alveolus, 375
haversian canal systems of, 144f, gene mutations of, 102b Cortical reaction, 481
145–146, 145f, 152 Connexons, 97f, 101, 101f Cortical sinuses, of lymph nodes, 291
lamellar systems of, 143–145, 144f Constant regions, of T-cell receptors, 280 Corticosteroids, 312t, 318
Complement proteins Constant (Fc) regions, of antibodies, 32 effect on thymus, 290
in inflammatory response, 121 Constitutive secretory pathway Corticosterone, 312t, 318, 321
in innate immune system, 273, 277, 277b of glands, 104 Corticotrophs, 308–309, 322
in phagocytosis, 32 of Golgi apparatus, 30 Corticotropic hormone, and uterine
in plasma, 221t transport along, 31 contractions, 477
Index ■ ■ ■ 545
Corticotropin-releasing hormone (CRH), Cytokines Decidua, 483–484, 483f

306, 307t, 309, 322 antigen-presenting cell release of, 284, Decidua basalis, 483, 483f
Cortisol, 312t, 318, 321 284t Decidua capsularis, 483, 483f
effect on cartilage, 135t as signaling molecules, 104, 276 Decidua parietalis, 483
Cortisone, effect on cartilage, 135t in class (isotope) switching, 279t, 280 Decidual cells, 484
Cotranslation, 25 mast cell release of, 117 Deciduous teeth, 368, 373
Cough reflex, 351b T cell release of, 232, 280 Decorins, 72
Countercurrent exchange system, 458, types of, 274 Deep dorsal artery and vein, of penis, 507f,
460f, 460t Cytokinesis, 62, 65–66, 65f, 68 508
in testes, 490 modified, 495 Default pathway, to Golgi apparatus, 27, 30
Countercurrent multiplier system, Cytomorphosis, of keratinocytes, 328 Defensins, 274, 401
455–457, 456f Cytoplasm, 11–48, 14f, 15f Degranulation
Coupled transport, 18f, 19, 20 annulate lamella in, 41 of eosinophils, 229
Coupling, in bone resorption, 152 cell membrane around, 11–22 of mast cells, 120, 120f
Cowper’s glands, 489, 490f, 507 centrioles in, 14f, 43f, 48 Dehydration, in tissue preparation, 2
Cranial nerves, 207, 210 cytoskeleton in, 11, 42–48 Dehydroepiandrosterone, 312t, 321, 322
Craniosacral outflow, 208 defined, 11 Demarcation channels, 247
CRE-binding protein (CREB), 22 endocytosis, endosomes, and lysosomes Demyelination, 199b
Creatine phosphate, in muscle contraction, in, 32–36 Dendrites, 186, 188f, 189f, 190, 190f
168 endoplasmic reticulum in, 23–24, 23f Dendritic cells
Cretinism, 316b Golgi apparatus in, 27–32, 28f–30f epidermal, 332
Cristae, mitochondrial, 39, 39f inclusions in, 11, 41–42, 41b, 41t, 42f follicular, 292, 293
Cristae ampullares, 528f, 530, 531f mitochondria in, 37–40, 39f in renal interstitium, 452
Crossing over, of chromosomes, 495 of neuron, 187 interdigitating, 296
Crown, of tooth, 368, 368f, 369f organelles in, 11–41, 14f, 15f Dendrodendritic synapse, 200
Crypts peroxisomes in, 37, 38f Dense bars, 170
of Lieberkühn polyribosomes in, 24 Dense bodies, in smooth muscle, 180, 182,
of colon, 407, 408f–410f proteasomes in, 37 182f
of rectum and anal canal, 409, 410 protein synthetic and packaging Dense connective tissue, 126–129, 127f, 128f
of small intestine, 398, 399f, 400–401, machinery in, 22–32 Dense tubular system, of platelets, 233,
400f, 404f ribosomes in, 22 233f, 234f, 236t
of palatine tonsils, 299 Cytoplasmic bridge, 494f, 495 Dental lamina, 371, 372f
Crystal(s) Cytoplasmic ring, 50, 54f Dental papilla, 372, 373
in cytoplasm, 42, 42f Cytoskeleton, 42–48 Dental sac, 373
of Charcot-Böttcher, 42, 492 defined, 11, 42 Denticles, 371
of Reinke, 42, 498 intermediate filaments of, 43f, 44–45, Dentin, 368f, 369–370, 369f, 370b, 370f
Crystallins, of lens, 518 45b, 46t Dentinal tubules, 370b
Crystallization, nidi of, 151 microtubule-associated proteins of, Dentinoenamel junction (DEJ), 370f, 374
Cuboidal cells, in hepatic ducts, 427 47–48, 47f Deoxycorticosterone, 312t, 320
Cuboidal epithelium microtubules of, 14f, 45–46, 46b, 47f Deoxyribonucleic acid (DNA)
simple, 86–87, 86t, 87f of erythrocyte, 223–224, 224b, 224f circular (cDNA), 40
stratified, 86t, 87f, 88, 89f of neuron, 189–190 in chromosomes, 52
Cumulus oophorus, 465f, 469t thin filaments of, 14f, 42–44, 43f–45f, 44t in nucleus, 49
Cupula, of semicircular ducts, 530 Cytosol in protein synthesis, 24
CURL endosomes, 33–34, 33f, 35f defined, 11 intronic RNA segments in, 58–59
Cushing’s disease, 322b protein synthesis in, 24–25, 26f linker, 52
Cuticle Cytotoxic T lymphocytes (CTLs), 232, 275, mitochondrial, 40
enamel, 369 282, 285–286, 286f structure of, 57
of hair, 340, 341, 341f Cytotoxicity, antibody-dependent cell- transcription of, 57–59, 58f
of nail, 343, 343f mediated, 275, 279t Depolarization, 171, 199
Cyclic adenosine monophosphate (cAMP) Cytotrophoblasts, 481 wave of, 200
and fat release, 117 Dermal ridges (papillae), 327, 330f, 334,
as second messenger, 22, 304 D 335, 340
in mast cells, 120 Dermatan sulfate, 70, 71t, 334
in signaling, 18, 20 D-Amino acid oxidase, 36 Dermatoglyphs, 327, 335
Cyclic adenosine monophosphate (cAMP) δ cells, 420, 421, 421t Dermis, 334–335
phosphodiesterases, 22 δ-granules, of platelets, 233, 233f, 236t epidermal interface with, 330f, 335
Cyclic adenosine monophosphate (cAMP) δ-tubulin, 48 papillary layer of, 329t, 330f, 334
response elements (CREs), 22 Dark cells reticular layer of, 328f, 329t, 334–335
Cyclic guanosine monophosphate (cGMP), of eccrine sweat gland, 337, 337f structure of, 327, 328f, 329t, 334
18, 20, 304 of saccule and utricle, 529 Descemet’s membrane, 515f, 516
Cyclin(s), 62 of taste buds, 378 Desmin
Cyclin-dependent kinases (CDKs), 62 Dark zone, of lymphoid nodule, 292 in capillaries, 259
Cystic duct, 433, 434 Daughter cells, 61, 62, 65 in cytoskeleton, 45, 46t
Cytochrome b-c1 complex, 40 Deafness in skeletal muscle, 161
Cytochrome oxidase complex, 40 conductive, 537b in smooth muscle, 181
Cytocrine secretion, 333 nerve, 536b Desmocollin, 99
Cytokeratin, 330 nonsyndromic, 102b Desmogleins, 97f, 99
546 䡲䡲䡲 Index
Desmoplakins, 99 Discontinuous (sinusoidal) capillaries, 259, Ductus utriculosaccularis, 528f, 529

Desmosine cross-links, 78 262f, 263 Duodenal glands, 401–402, 401f, 403
Desmosine residues, 114 Discrimination, tactile, 513 Duodenal papilla (of Vater), 403, 419
Desmosomes, 97f, 99, 100f, 101b Disk(s) Duodenum, 394t, 401, 403. See also Small
of cardiac muscle, 178f intercalated, 175, 176f, 177, 178f–179f intestine.
of skin, 329 intervertebral Dura mater, 143, 211, 212f, 213
Desquamation, 331 fibrocartilage organization in, 135 Dust cells, 123, 359f, 361, 361b, 362f, 363
Detoxification of drugs, in liver, 433 ruptured, 136, 136b Dyad(s)
Detumescence, of penis, 510 Merkel’s, 512, 512f in cardiac muscle, 177
Diabetes insipidus, 311b optic, 520 in retina, 525
congenital nephrogenic, 458b Z Dynamin, 32
Diabetes mellitus, 422b, 423t in cardiac muscle, 178f Dynein
Diacylglycerol, in signaling, 20, 22 in skeletal muscle, 160, 161, 161f, 162, and minus end of MTOC, 29
Diakinesis, 67 162f, 164, 164f as microtubule motor protein, 47–48
in spermatogenesis, 495 Disse, perisinusoidal space of, 426, 427f, in axonal transport, 192
Diapedesis, 225, 264, 292 428f of cilia, 92, 92b
Diaphragma sellae, 304 Distal ring, of nuclear basket, 51, 54f Dystroglycans, 79, 83
Diaphysis, 143, 148, 148t Distal tubule, 448–451, 449f Dystrophin, 83, 161
Diarrhea, 408b convoluted, 439f, 446f, 448, 449, 449f,
Diarthroses, 156, 156f 459t E
Diastole, 258 Distributing arterioles, of liver, 425
Diffuse lymphoid system, 273 Distributing veins, of liver, 425 E-face
Diffuse neuroendocrine system (DNES) Diuresis, 456f of cell membrane, 14, 16f, 17f
cells Diversity, of adaptive immune system, of microvillar membrane, 94, 99f
of colon, 407, 409f 276 Ear(s), 526–536, 527f
of respiratory epithelium, 352, 353 DNA. See Deoxyribonucleic acid (DNA). bony labyrinth of, 528–536, 528f
of small intestine, 392t, 400, 404 Docking protein, 24, 26 cochlea of, 527f, 528, 528f, 532f
of stomach, 386f, 390–391, 392t, 393f Dome-shaped cells, of urinary bladder, 461 cochlear duct of, 530, 532–534, 532f,
paracrine and endocrine hormone Dopamine 533f
production by, 109, 109f DOPA as precursor of, 189 cochlear function of, 535–536, 535f
Diffusion functions of, 203, 204t external, 526–527, 527f
carrier-mediated, 18f in Parkinson’s disease, 204b inner, 528–536, 528f
facilitated, 17 Dorsal artery and vein, of penis, 507f, 508 membranous labyrinth of, 528–534, 528f
ion channel-mediated, 18f Dorsal horns, 211 middle, 527–528, 527f
passive, 17, 18f, 19 Dorsal root ganglia, 186, 187f, 211 organ of Corti of, 532f, 533–534, 533f
simple, 17 Doublets, of microtubules, 91, 348 saccule and utricle of, 528f, 529, 530f,
DiGeorge’s syndrome, 290b Down syndrome, 56b, 68b 531f
Digestive system Drug(s) semicircular ducts of, 528f, 529–530,
alimentary canal in. See Alimentary detoxification of, in liver, 433 531f
canal. tolerance to, 433b vestibular function of, 534
esophagus in, 383–385, 384f, 385b, 394t Duct(s) Early (CURL) endosomes, 33–34, 33f, 35f
gallbladder in, 433–436 alveolar, 346t, 357, 357f–359f Eccrine sweat glands, 328f, 336–338, 336f,
gingiva (gums) in, 368, 368f, 369f, 376 bile 337f
large intestine in, 395t, 407–411 common, 382f, 419, 434 Ectoderm, 85, 327
lips in, 367–368 interlobular, 424f, 427 Ectomesenchyme, in odontogenesis, 371
liver in, 422–433, 424f cochlear, 528f, 530, 532–534, 532f, 533f Edema, 126b, 264
oral cavity in, 367–379 cystic, 433, 434 Effector cells, 232, 277, 281–283
oral mucosa in, 367 ejaculatory, 490f, 502t, 504 Effector memory T cells (TEMs), 281
palate in, 376 endolymphatic, 529 Effector organ, 208
pancreas in, 417–422 extrahepatic, 434, 434t Effector T cells, 277, 281–283
salivary glands in, 413–417, 414f genital, 489, 501–502, 502t Efferent components
small intestine in, 394t–395t, 398–406 hepatic, 427–430, 434 of autonomic nervous system, 207
stomach in, 385–397 lactiferous, 486, 486f of peripheral nervous system, 185, 206
teeth in, 368, 368f, 369f, 376 lymphatic, 270, 271 of somatic nervous system, 207
tongue in, 376–379, 377f nasolacrimal, 526 Efferent fibers, 206
Digital imaging technique, 3 of Bellini, 437, 439, 451 Efferent lymphatic vessels, 270, 290, 291,
Dihydrotestosterone, 501, 506 of eccrine sweat glands, 336, 337f, 338 291f
Dihydroxyphenylalanine (DOPA), 189 of salivary glands, 414–415, 414f Efferent neurons. See Motor neurons.
Diiodinated tyrosine (DIT), 314–315 pancreatic, 418, 418f, 419 Ehlers-Danlos syndrome, 78b, 257b
Dilator pupillae muscle, 515f, 518 semicircular, 528f, 529–530, 531f Ejaculate, 507, 508–509, 509b
Dimers, 279t thoracic, 271 Ejaculation, 508–509
Dipalmitoyl phosphatidylcholine, 360 Duct cells, 108f Ejaculatory ducts, 490f, 502t, 504
Dipeptidases, 405 Ductal carcinoma, 488b Elastic arteries, 253–254, 254t, 255f
Diploë, 143, 147 Ductules, terminal, of mammary gland, Elastic cartilage, 131, 133t, 134–135, 135f
Diploid cells, 56, 66 485 Elastic fibers, 78–79, 79b, 79f–81f
Diplotene, 67 Ductuli efferentes, 489, 490f, 502, 502t in connective tissue, 113–114, 126
Direct immunocytochemistry, 5, 5f, 6f Ductus deferens, 489, 490f, 502t, 504 in dermis, 334
Disaccharidases, 405 Ductus reuniens, 528f, 529 of trachea, 353
Index ■ ■ ■ 547
Elastic lamina Endoplasmic reticulum (ER), 14f, 23–24 Ependymal cells, 196, 211
of arterioles, 256 and Golgi apparatus, 27–32, 28f–30f Epicardium, 269
of blood vessels, 252, 252f hormone synthesis in, 319–320 Epidermal growth factor (EGF), 336, 402
of elastic arteries, 253, 254 of neuron, 187 in odontogenesis, 373
of muscular arteries, 255, 255f, 256 rough (RER), 23–24 Epidermal melanin unit, 333
of trachea, 353 collagen synthesis on, 75–76, 77f Epidermal ridges, 327, 330f
Elastin in chondrogenic cells, 133 Epidermis, 327–333, 329t
in blood vessels, 252 of neurons, 187 dermal interface with, 330f, 335
in connective tissue, 114 outer nuclear membrane as, 49 keratinocytes in, 328–331
in extracellular matrix, 78, 80f protein synthesis on, 25–26, 27f Langerhans cells in, 328f, 331–332
Electrical potential difference, 19 proteoglycan synthesis on, 71 melanocytes in, 332–333, 334f
Electrical synapse, 200 structure of, 14f, 15f, 23–24 Merkel cells in, 323f, 332
Electrochemical gradient, 40 vesicles associated with, 28–29 nonkeratinocytes in, 331–333
Electron microscopy, 4f, 7–10 smooth (SER) stratum basale (stratum germinativum)
Electron transport chain, 40 hormone synthesis in, 319–320 of, 328, 328f, 329–330, 329t, 330f,
Eleidin, 331 of hepatocytes, 429 335b
Elliptocytic red blood cells, 224 of neuron, 187 stratum corneum of, 328, 328f, 329t, 331
Embedding, 2 of prostate, 506, 506f stratum granulosum of, 328, 328f, 329t,
Embolus, saddle, 237b structure of, 14f, 23, 23f 330–331
Embryoblasts, 482 transitional, 27, 30f stratum lucidum of, 328, 328f, 329t, 331
Embryonic connective tissue, 125–126, transport vesicles associated with, 28–29 stratum spinosum of, 328, 328f, 329t,
126t Endoplasmic reticulum/Golgi intermediate 330, 330f, 331f
Emphysema, 361b compartment (ERGIC), 27, 28f, 30f thick skin in, 328–329, 328f, 329t, 330f
Emulsification, of lipids, 405, 407f Endorphins, 203, 204t thin skin in, 328f, 329
En passant type of synapse, 182, 201 Endosomal carrier vesicles, 34–35 Epididymis, 489, 490f, 502t, 503–504, 504f
Enamel, 368–369, 368f, 369f, 374 Endosomal compartment, 34, 230 Epidural space, 213
Enamel cuticle, primary, 369 Endosomes, 33–35, 35f Epiglottis, 377f
Enamel epithelium, 372, 372f early (CURL), 33–34, 33f, 35f Epilepsy, 186b
Enamel knot, 372 late, 30f, 33–34 Epimysium, 158, 159f
Enamel organ, 372, 372f recycling, 34 Epinephrine
Enamel rods, 369 Endosteum, 136 as neurotransmitter, 203
Enamelins, 369 Endothelial cells, 112f functions of, 312t
End bulbs, 187, 188f of arteries, 254 in fat release, 117
Krause, 334, 512f, 514 of capillaries, 260, 261f production of, 318, 322, 324
End piece, of spermatozoon, 497f, 498 Endothelin Epineurium, 205, 205f
Endocardium, 267–268 in clot formation, 233 Epiphyseal plates, 132, 143, 148t, 149,
Endochondral bone formation, 131, secretion of, by capillaries, 265 149f, 150–151
147–150, 147f–150f, 148t Endothelium Epiphysis(es), 143, 148t
Endocrine cells, 303 of cornea, 515f, 516 Episclera, 516
Endocrine gland(s), 107–109, 304–325 of endocardium, 267 Epithelial reticular cells, 288–289, 290
defined, 104, 303 of eye, 515f Epithelial tissue, 85
pancreas as, 418f, 420–422, 420f, 421t, Enkephalins, 203, 204t, 323 Epithelioid cells, 123
422b, 422f, 423t Entactin, 73, 79 Epithelioid precursor cells, 129
parathyroid, 312t, 313f, 316–317 Enteric nervous system, 381–382 Epithelium, 85–103
pineal, 312t, 324–325, 324f Enteritis, 408b adenocarcinoma of, 103b
pituitary, 304–311 Enteroendocrine cells apical domain of, 90–92, 91f–96f
suprarenal (adrenal), 312t, 318–324, 319f of small intestine, 392t, 400, 404 basal surface specializations of, 102, 103f
thyroid, 311, 312t, 313–316 of stomach, 386f, 390–391, 392t, 393f basolateral domain of, 92, 94–102
Endocrine signaling, 20, 104 Enteroglucagon, 392t carcinoma of, 103b
Endocrine substances, of DNES cells, 391 Enterohepatic recirculation, of bile salts, cell renewal in, 102–103
Endocrine system, 303–325 430 cell-surface specializations of, 90–102
defined, 303 Enzyme-linked receptors, 21 cilia of, 91–92, 95f, 96f. See also Ciliated
hormones in, 303–304 Eosin stain, 2, 3t cells.
Endocytosis, 32–33, 33f Eosinophil(s), 228–230 classification of, 85–90, 86t, 87f
clathrin-mediated, 201 features of, 226t defined, 85
receptor-mediated, 32–33, 34f formation of, 239t, 240f, 243 desmosomes in, 97f, 99, 100f, 101b
Endocytotic vesicles, 33f, 35f functions of, 125, 229–230 enamel, 372, 372f
Endoderm, 85 granules of, 226t, 229, 229f flagella in, 90
Endogenous proteins, 283 increase or decrease in, 230b gap junctions in, 97f, 101–102, 101f,
Endolymph, 529, 531f, 532, 534 origins of, 112f 102b
Endolymphatic duct, 529 structure of, 220f, 222f, 229, 229f germinal, 463, 491, 491f, 492f
Endolymphatic sac, 528f, 529 Eosinophil chemotactic factor (ECF), 117, hemidesmosomes in, 102, 103f
Endometriosis, 478b 120f, 121, 121t junctional complexes in, 94–99, 97f
Endometrium, 464f, 476, 477f Eosinophil-derived neurotoxin, 229 lateral membrane specializations of, 92,
in menstrual cycle, 478–480, 479f, 480f Eosinophilic cationic protein, 229 94–102
Endomitosis, 247 Eosinophilic metamyelocyte, 239t, 240f mesothelial, 463, 464f, 466
Endomysium, 158, 159f Eosinophilic myelocyte, 239t, 240f metaplasia of, 103b
Endoneurium, 205f, 206 Eosinophilic stab cell, 239t, 240f microvilli in, 90–91, 91f–94f
548 䡲䡲䡲 Index
Epithelium (Continued) Erectile bodies, 485 Extracellular matrix (Continued)

of alimentary canal, 381, 394t–395t Erectile dysfunction, 509b, 510b lamina reticularis of, 80, 81f–83f
of anus, 410 Erectile tissue, 507, 507f, 508 of cartilage, 131
of bladder, 461, 461f Erection, 508, 509b, 509f of connective tissue, 111, 113–114
of bulbourethral glands, 507 εRI receptors, on basophils, 230 proteoglycans in, 70–72, 70f, 72f
of cervix, 478 Erythroblast(s), 238, 239t, 240f, 244f, 245f, Extrafusal fibers, 172, 174f
of ciliary body, 517 246t Extrahepatic ducts, 434, 434t
of cornea, 516, 525 Erythroblastosis fetalis, 225b Extrapulmonary bronchi, 346t, 354
of ductuli efferentes, 502, 502t Erythrocyte(s), 112f, 220–225 Extrapulmonary conducting division, 346t
of ductus deferens, 502t, 504 cell membrane of, 223–224, 224f, 224t Extratesticular genital ducts, 490f,
of ejaculatory duct, 502t, 504 defects in, 223b–225b 502–504, 502t
of endometrium, 476, 477f elliptocytic, 224 Extrinsic muscles
of epididymis, 502t, 503–504 formation of, 238, 239t, 240f, 241, of eye, 515, 515f
of esophagus, 383, 394t 243f–245f, 246t of larynx, 351
of gallbladder, 434, 434f hemoglobin in, 221–223 of tongue, 376
of gingiva, 369f, 376 phagocytosis of, in spleen, 297 Eye(s), 514–526, 515f
of Henle’s loop, 448, 448t structure of, 220–221, 220f, 222f, 223f accessory structures of, 515f, 525–526
of large intestine, 395t Erythrokeratodermia variabilis, 102b bulb of, 515
of larynx, 351 Erythropoiesis, 240f, 241, 243f–245f, 246t choroid of, 515f, 517
of oral mucosa, 367 Erythropoietin, 241, 242t, 453 ciliary body of, 515f, 517
of oviducts, 475, 476f Esophageal cardiac glands, 384, 394t conjunctiva of, 515f, 525
of paranasal sinuses, 350 Esophageal varices, 267b cornea of, 515f, 516
of prostate, 506, 506f Esophagus, 383–385, 384f, 385b, 394t disorders of, 517b, 519b, 521b, 525b
of renal calyces, 459 Estradiol embryonic development of, 514–515
of rete testis, 501–502, 502t effect on cartilage, 135t extrinsic muscles of, 515, 515f
of seminal vesicles, 505, 505f in follicular development, 468 floaters in, 519b
of small intestine, 394t–395t, 398–400 Estrogens iris of, 515f, 517–518
of stomach, 386–387, 387f, 388f, 394t in follicular development, 470 lacrimal apparatus of, 515, 526
of trachea, 352–353, 352f, 353f in lactation, 486 lens of, 515f, 518, 518f, 519f
of tubuli recti, 501, 502t in mammary gland development, 485 retina (neural tunic) of, 515f, 520–525,
of tympanic cavity, 527 in menstrual cycle, 478, 479f 520f–524f
of ureter, 460 in ovarian regulation, 472, 473t sclera of, 515–516, 515f
of urethra, 462 in placental development, 484 tunica fibrosa of, 515–516, 515f
of vagina, 485 osteoporosis and, 155b tunica vasculosa of, 515f, 516–518
olfactory, 347, 348f Euchromatin, 51f, 52, 52f vitreous body of, 515f, 519
oral, in odontogenesis, 371, 372f Eustachian tube, 527, 527f Eyelashes, 525
pathology of, 103b Excitatory neurotransmitters, 18 Eyelids, 525
pigmented Excitatory postsynaptic potential, 200
of ciliary body, 517 Excitatory responses, 202 F
of retina, 520, 520f, 521 Excretory passages, of urinary system,
plasma membrane enfoldings in, 102 458–462 F-actin, 42, 45f, 164f, 166–167
polarity of, 90 Exhalation, 364 F cells, 421t
pseudostratified, 86t, 87f, 89–90, 90f Exocrine glands, 103, 104–107, 104f, 105f Fab fragment, 278
respiratory, 347, 352–353, 352f, 353f classification of, 104 Facial expression, muscles of, 335
seminiferous, 489, 491, 491f, 492f multicellular, 106–107, 107f–109f Facial nerve, 527f
cycle of, 498, 499f pancreas as, 418–419, 418f, 419f Facilitated diffusion, 17
wave of, 498 unicellular, 105–106, 105f, 106f Factor VII deficiency, 237b
simple, 85, 86t, 87f Exocytosis, 30 Factor VIII deficiency, 237b
columnar, 86t, 87, 87f, 88f Exogenous proteins, 283 Factor IX deficiency, 237b
cuboidal, 86–87, 86t, 87f Exons, 58 Factor X deficiency, 237b
squamous, 86, 86t, 87f Exophthalmos, 316b Falciform ligament, 424f
stratified, 85–86, 86t, 87f Exportins, 52 Fallopian tubes, 464f, 470, 474–475, 476f
columnar, 86t, 87f, 88 Externum, of eosinophil, 229 Fascia adherens
cuboidal, 86t, 87f, 88, 89f Exteroceptors, 511 of cardiac muscle, 178f
squamous Extracellular fluid, 220, 270 of epithelium, 99
keratinized, 86t, 87f, 88, 89f Extracellular matrix, 69–83 Fasciae occludentes, of capillaries, 260, 262
nonkeratinized, 86t, 87–88, 87f, 89f basal lamina of, 79–80, 81f–83f Fascicles
subcapsular, 518, 518f basement membrane of, 79–80, 81f muscle, 158, 159f
tracheal, 352–353, 352f, 353f defined, 69 peripheral nerve, 204–205, 205f
transitional, 86t, 87f, 88, 89f dystroglycans in, 83 Fasciculus longitudinalis, 434, 434t
zonulae adherentes in, 94, 97f, 98f, 99 fibers of, 73–79 Fat(s)
zonulae occludentes in, 94, 97f–99f collagen, 73–78, 74f, 75f, 76t absorption and processing of, 405–406,
Epitope(s), 37, 231, 276, 278 elastic, 78–79, 79f–81f 407f
on major histocompatibility complex fluid flow in, 69, 70f formation of
molecules, 280–281, 283–284 glycoproteins in, 72–73 primary, 129
Epitope-MHC complex, 286, 286f, 287f glycosaminoglycans in, 69–70, 70f, 71t secondary, 129
Eponychium (cuticle), 343, 343f ground substance of, 69–73, 70f Fat cells. See Adipose cells (adipocytes).
Equatorial division (meiosis II), 66, 67f, 68 integrins in, 81, 83 Fat-storing cells, in liver, 426, 427f
Index ■ ■ ■ 549
Fatty acids Fibrous sheath, of spermatozoon, 496, 498 Fracture face, 9, 10f
absorption and processing of, 406, 407f Fibrous subunit, of intermediate filaments, Freckles, 335b
in adipocytes, 116, 117, 119f 43f Freeze-fracture technique, 9, 10f
in hormones, 303 Fibrous tunic, of eye, 515–516, 515f Fructose-rich seminal fluid, 505, 508
Fatty acyl tails, in cell membrane, 13, 16f Filaggrin, 45, 336 Functionalis layer, of endometrium, 476,
Fatty stool, 430b Filamin, 44t 477f
Fc fragment, 278 Filiform papillae, 377, 377f necrosis of, 479
Fc receptors Filopodia, 359f Fundic glands, 385, 386f, 387–393, 388t,
of antibodies, 278 Filtrate 394t
on basophils, 230 glomerular, 442, 447, 455 Fundic stomach, 386–393, 386f, 394t
on macrophages and neutrophils, 32 monitoring of, in juxtaglomerular Fundus, of uterus, 475–477
on mast cells, 118, 120f apparatus, 457, 457t Fungiform papilla, 377, 377f, 378f
Fc (constant) regions, of antibodies, 32, 280 Filtration, glomerular, 442, 445, 455 Fusiform precursor cells, 129
Feces, 409 Filtration barrier, 441, 455 Fusiform smooth muscle fibers, 179
Feedback mechanism Filtration force, 455
for hormones, 304 Filtration slits, 442, 443f, 445f G
negative, for glucocorticoids, 322 Fimbria, 464f, 474
Female pronucleus, 481 Fimbrin, 43, 44t, 94f, 529 G-actin, 42, 164, 165t, 166
Female reproductive system, 463–486, 464f Fingerprints, 327, 335 γ-actin, 43
cervix in, 478 First polar body, 469 γ-aminobutyric acid (GABA)
external genitalia in, 485 Fixation, 1–2 functions of, 203, 204t
fertilization in, 480–481, 481f, 482f Fixatives, for transmission electron in Huntington’s chorea, 204b
hormones in, 471–474, 473t, 474t microscopy, 9 G bands, 57
implantation in, 481f, 482 Fixed cells, of connective tissue, 114–123 G cells, 420, 421t, 422
mammary glands in, 485–488 Flagella, 90 γ-globulin, 221t
menstrual cycle in, 478–480, 479f Flagellar axoneme, 495, 497f, 498 γ-motor neuron, 173, 174f, 175b
ovaries in, 463–475 Flatus, 409 G protein(s)
oviducts (fallopian tubes) in, 474–475, Flavin adenine dinucleotide (FADH2), 40 Go, cell signaling via, 22
476f Floaters, in eye, 519b Gs and Gi, cell signaling via, 21–22, 21f
placental development in, 482–484, 483f, Fluid flow, in extracellular matrix, 69, 70f hormone-receptor complexes and, 304
484f Fluid mosaic model, of membrane signaling via, 21–22, 21f
uterus in, 475–477 structure, 14, 16f types of, 21
vagina in, 484–485 Fluorescence-labeled antibodies, 5, 6f G-protein-gated channels, 18–19
Fenestra cochleae, 527, 528, 528f Fluoride, 369b G-protein-linked receptors, 21–22, 21f
Fenestra vestibuli, 527, 528, 528f, 535 5-Fluorouracil, 66b γ-tubulin ring complex, 45, 48
Fenestrated capillaries, 259, 262, 262f Focal contacts, 44 G0 (outside, stable) phase, of cell cycle, 61
glomerular, 441, 442f, 443f Foliate papillae, 377–378 G1 (gap) phase, of cell cycle, 61–62, 61f
Fenestrated membranes, 254, 255f Follicle(s) G2 phase, of cell cycle, 61f, 62
Fertilization, 480–481, 481f, 482f of hair, 328f, 329, 334, 340–342, Gallbladder, 433–436
Fetal hemoglobin, 223 340f–342f histophysiology of, 435–436
Fibrillin, 78 of thyroid, 313, 313f structure of, 434, 434f, 435f
Fibrin, 234 ovarian. See Ovarian follicles. Gallstones, 436b
Fibrinogen, 234 Follicle-stimulating hormone (FSH), 307t, GALT (gut-associated lymphoid tissue),
Fibroblast(s) 309, 310 298–299, 300f
active, 114, 115f in follicular development and ovulation, Ganglion(ia)
differentiation of, 114b 465, 468, 470, 471–474, 472f, 473t autonomic, 208, 210, 211f
fibronectin produced by, 72 in male reproductive system, 499, 500, parasympathetic, 208
in fixed connective tissue, 114, 115f 501f sensory, 186, 187f, 210
in loose connective tissue, 126 Follicular cells spiral, 528, 532f, 533f
in muscle regeneration, 183 dendritic, 292, 293 Ganglion cell(s), of suprarenal gland, 322
in periodontal ligament, 375 of endocrine glands, 109 Ganglion cell layer, of retina, 520f, 525
in renal interstitium, 452 of ovary, 465f, 466, 467t Gangliosidoses, 37t
inactive, 114 of thyroid, 313, 313f, 314–316, 314f Gap junctions
origin of, 112f Follicular phase, of menstrual cycle, of bone, 138, 140, 143
Fibroblast growth factor-4 (FGF-4), in 479–480 of capillaries, 261
odontogenesis, 373 Follicular type glands, 109 of cardiac muscle, 177, 178f
Fibrocartilage, 131, 132f, 133t, 135–136, Folliculostellate cells, 310 of cytoplasm, 20
136f Folliostatin (folliculostatin), 468, 472 of epithelium, 97f, 101–102, 101f, 102b
Fibrocytes, 114 Fontanelles, 147 of salivary glands, 416
Fibroma, 192b Foramen cecum, of tongue, 377, 377f Gap phase, of cell cycle, 61–62, 61f
Fibronectin Foreign-body giant cells, 123, 231 Gap regions
cell-surface, 73 Foreign cells, 232 in tropocollagen, 74f, 76, 77
in connective tissue, 113 Formalin, 1 of collagen, 113
in cytoskeleton, 44, 45f Formed element(s), of blood. See Blood. Gas(es)
in extracellular matrix, 72–73, 79 Fovea centralis, 515f, 520 as neuromodulators, 203
in glomerulus, 442 Foveolae, 385, 386f in colon, 409
release of, by capillaries, 264 Fracture, bone repair after, 152–153, 153b, Gas exchange, 358f, 363–364
Fibrous astrocytes, 194, 194f 153f Gas transport, 345
550 䡲䡲䡲 Index
Gastric. See also Stomach. Gland(s) (Continued) Glicentin, 392t

Gastric carcinoma, 398b endocrine. See Endocrine gland(s). Glisson’s capsule, 423
Gastric contents, emptying of, 396 esophageal cardiac, 384, 394t Globulins, in blood, 221t
Gastric glands, 385, 386f, 387–393, 388t, exocrine, 103, 104–107, 104f, 105f Glomerular arterioles, 440, 441f, 453, 457
394t multicellular, 106–107, 107f–109f Glomerular capillaries, 441, 442f, 443f,
Gastric inhibitory peptide (GIP), 392t, 397 unicellular, 105–106, 105f, 106f 453, 453f, 454f
Gastric intrinsic factor, 389, 389b, 396f follicular type, 109 Glomerular filtrate, 442, 447, 455
Gastric lipase, 385, 396 gallbladder as, 433–436, 434f, 434t, Glomerular filtration rate (GFR), 455
Gastric phase, of HCI secretion, 396–397 435f Glomerular ultrafiltrate, 442, 447, 455
Gastric pits, 385, 386f gastric (fundic), 385, 386f, 387–393, Glomerulonephritis, 445b
Gastrin, 392t, 396, 397, 421t, 422 388t, 394t Glomerulus(i)
Gastroenteric reflex, 405 holocrine, 105, 105f of cerebellar cortex, 216
Gastroesophageal sphincters, 385 interstitial, 468–469, 471 of nephron, 262, 439f, 441–442, 442f,
Gastrointestinal peptides, 203 lacrimal, 515, 526 443f
Gastrointestinal tract. See Alimentary liver as, 422–433, 424f of olfactory bulb, 350
canal; Digestive system. mammary, 485–488, 486f, 487f Glomus(era), 263
Gate(s), 17 mechanisms of secretion by, 104–105, Glomus cells, 258
Gated channels, 17–19. See also Voltage- 105f Glucagon, 392t, 421, 421t
gated channels. meibomian, 525 Glucocorticoid(s), 312t, 319, 321–322
Gated ion-channel receptors, 200 merocrine, 104–105, 105f and mammary gland development, 485
Gaucher’s disease, 37t mammary, 488 receptors for, on adipose cells, 128
Gel-like networks, 43–44, 45f mixed, 104, 104f, 109 Gluconeogenesis, 421, 432
Gelatinase, 142 mucous, 104 Glucose, in secondary active transport, 20
Gelsolin, 44, 44t of bladder, 461 Glucose-6-phosphatase deficiency, 41t
Genes, 57 of Bartholin, 485 Glucose permease, 421
Genioglossus muscle, 377f of large intestine, 395t Glucose transport units, 421
Geniohyoid muscle, 377f of Littre, 462 Glucuronide, bilirubin, 430, 432f
Genital ducts, 489, 490f, 501–502, 502t of Möll, 338, 525 Glucuronyltransferase, 430
Genital glands, accessory, 490f, 504–507 of skin, 327, 336–339 Glutamate, as neurotransmitter, 203, 204t
Genome, 55, 57 of small intestine, 394t–395t, 404 Glutaraldehyde, as fixative, 9
Germinal centers, of lymphoid nodules, of von Ebner, 378 Glutathione peroxidase, 228
292, 292f, 296 of Zeis, 525 Gluten, 406b
Germinal epithelium, 463, 491, 491f, 492f pancreas as, 417–422, 418f–420f, 421t, Gluten enteropathy, 406b
Germinal vesicle, 466 422b, 422f Glycerol
Ghrelin, 385 parathyroid, 312t, 313f, 316–317 absorption and processing of, 406, 407f
Giant cells, foreign-body, 123, 231 parotid, 416, 417b in adipose tissue, 116, 119f
Giemsa stain, 3t pineal, 312t, 324–325, 324f in cell membrane, 13
Gigantism, pituitary, 154 pituitary, 304–311 Glycerophosphocholine, 504
Gingiva, 368, 368f, 369f, 376 prostate as, 490f, 505–506, 505f, 506f Glycine
scurvy effects on, 78b, 78f salivary, 108f, 367, 413–417 as neurotransmitter, 203, 204t
Gingival epithelium, 369f, 376 sebaceous, 328f, 329, 334, 337f, in collagen, 113
Gingival sulcus, 369f 338–339, 339b, 339f in elastin, 114
Gland(s), 103–109 serous, 104, 104f, 377f, 378, 378f Glycocalyx
accessory genital, 490f, 504–507 simple, 106, 107f in cell membrane, 16
acinar (alveolar), 107, 107f simple coiled tubular, 336 in small intestine, 399
alveolar, 107, 107f sublingual, 104, 414f, 415f, 416–417 of microvilli, 91
anal, 410 submandibular, 104, 104f, 417, 417b, Glycogen
apocrine, 105, 105f 417f in clear cells, 337
mammary, 105 suprarenal (adrenal), 312t, 318–324, in cytoplasm, 41
sweat, 338 319f in hepatocytes, 430, 431f
areolar (of Montgomery), 488 sweat, 328f, 336–338, 336f, 337f in vagina, 485
Bowman’s (olfactory), 347, 347f, 348f, thyroid, 312t, 313–316, 313f, 315b–316b Glycogen-lactic acid system, 168
349 tubular, 107, 107f Glycogen storage disorders, 41b, 41t
Brunner’s (duodenal), 401–402, 401f, of endometrium, 476, 477f, 480 Glycogenolysis, 432, 432f
403 tubuloacinar (tubuloalveolar), 107, Glycogenosis, 37t
bulbourethral (Cowper’s), 489, 490f, 107f Glycolipids, in cell membrane, 13, 16f
507 compound, of mammary gland, 486 Glycolysis, 168
ceruminous (wax), 338, 526 prostate, 506 Glycophorin A, 223
cervical, 478 salivary, 413 Glycophorin C, 224, 224f
circumanal, 410 uterine, 476, 477f, 480 Glycoprotein(s)
classification of, 103–104 vestibular, 485 as cell-surface receptors, 21
compound, 106, 107f Glans clitoridis, 485 associated with nuclear pore complex, 50
tubuloalveolar, 486 Glans penis, 490f, 507f, 508 cell adhesive, 72–73, 111
cord type, 107, 109 Glassy membrane, 340, 341f in bone, 137
diffuse neuroendocrine system as, 109, Glaucoma, 517b in cell membrane, 16f
109f Glial fibrillary acidic protein (GFAP), 45, in connective tissue, 111, 113
ductless, 104, 107, 303 46t, 193 in extracellular matrix, 72–73
duodenal, 401–402, 401f, 403 Glial scar, 218 Glycoproteinosis, 37t
Index ■ ■ ■ 551
Glycosaminoglycans (GAGs), in Graves’ disease, 277b, 316b Heavy meromyosin, 164f, 165, 181
extracellular matrix, 69–70, 70f, 71t Gray matter, 191, 210, 211 Helical arteries
of bone, 137 Great alveolar cells, 360–361, 361f, 362f of endometrium, 476, 477f
of cartilage, 131 Grooves of erectile tissue, 508
of connective tissue, 111, 113 in dermal ridges, 335–336 Helicobacter pylori, 396, 398b
Glycosylation, terminal, 30f of nails, 344 Helicotrema, 535, 535f
Goblet cells, 13f Ground-substance, 69–73, 70f Hematocrit, 219
of colon, 407, 408f, 409f of connective tissue, 111, 113, 126 Hematopoiesis. See Hemopoiesis.
of glands, 105–106, 105f, 106f Growth factor(s) Hematopoietic stem cell, 112f
of respiratory epithelium, 352, 352f epidermal, 336, 402 Hematoxylin and eosin (H & E) stain, 2, 3t
of small intestine, 399–401, 399f, 401f in odontogenesis, 373 Heme, 221, 223b, 363
Goiter, 316b fibroblast, in odontogenesis, 373 Hemidesmosomes, 81f, 83f
Golgi apparatus, 27–32, 28f–30f hemopoietic, 241, 242t in epithelium, 102, 103f
alternative concept of, 31–32 insulin-like, 307t, 308 of skin, 329
collagen synthesis in, 75, 77f on keratinocytes, 336 Hemoglobin, 42, 221–223, 223b, 363–364
of prostate, 506, 506f platelet-derived, 259b Hemolytic jaundice, 432b
proteoglycan synthesis on, 71 transforming, 336 Hemophilia, 237b
structure of, 14f, 15f transforming-β, 138, 154 Hemopoiesis, 236–249
transport vesicles associated with, 28–29 Growth hormone. See Somatotropin. cells of, 238–241, 239t, 240f, 242t
Golgi complex, 187 Guanosine diphosphate (GDP), 21 defined, 236
Golgi intermediate compartment, 27 Guanosine monophosphate, cyclic (cGMP), hemopoietic growth factors (colony-
Golgi network 18, 20, 304 stimulating factors) in, 241, 242t
cis, 27, 28, 29f Guanosine triphosphate (GTP), 21 of granulocytes, 240f, 243, 247f, 248t
trans, 27–28, 28f Guillain-Barré syndrome, 199b, 364b of lymphocytes, 239t, 247, 249
collagen synthesis in, 75, 77f Gums (gingiva), 368, 368f, 369f, 376 of monocytes, 246
in spermiogenesis, 495 Gut-associated lymphoid tissue (GALT), of platelets, 237f, 246–247, 249f
sorting in, 29–31, 30f 298–299, 300f of red blood cells, 240f, 241, 243f–245f,
transport vesicles in, 29, 264f Gyri, 215 246t
Golgi phase, of spermiogenesis, 495, 497f postnatal, 238–249, 238f, 239t
Golgi stack, 27 H prenatal, 237–238
Golgi tendon organs, 171–172, 175, 175b, spleen in, 297
512f, 514 H band, in skeletal muscle, 160, 161f, 162 stem cells, progenitor cells, and
Gonadotrophs, 309 Hair(s), 328f, 339–343 precursor cells in, 238–239, 239t,
Gonadotropic hormones, 463 arrector pili muscles of, 328f, 329, 335, 240b
Gonadotropin-releasing hormone (GnRH), 341–342 Hemopoietic cells, 238–241, 239t, 240f, 242t
465, 472, 473t, 474t club, 342 islands of, 236
Graafian follicles, 465f, 467t, 469, 474 growth phases of, 342 Hemopoietic compartment, 236
Granular layer histophysiology of, 342–343, 343f Hemopoietic cords (islands), 237
of cerebellar cortex, 216 matrix of, 340 Hemopoietic growth factors, 241, 242t
of cerebral cortex, 215 types of, 339 Hemopoietic stem cells, 238, 239t, 240b
Granulation tissue, in bone repair, 152 Hair bulb, 340 Hemorrhage, of dental pulp, 371b
Granule(s). See also Secretory granules. Hair cells Hemorrhagic discharge (menses), 479
Birbeck (vermiform), 332 of organ of Corti, 532f, 534 Hemorrhoid(s), 267b, 410b
in mast cell cytoplasm, 117, 119f of saccule and utricle, 529, 530f, 531f Hemorrhoidal plexus, 410
keratohyalin, 331 of semicircular ducts, 530, 531f Henle’s layer, 340, 341f
membrane-coating (lamellar), 330, 336 Hair follicles, 328f, 329, 334, 340–342, Henle’s loop, 439f, 448
of eosinophils, 226t, 229, 229f 340f–342f and countercurrent multiplier system,
of juxtaglomerular cells, 450, 450f Hair root, 328f, 340, 340f 455–457, 456f
of neutrophils, 225, 226t, 227f sheaths of, 340, 341, 341f thick limb of
of platelets, 233, 233f, 236t Hair shaft, 328f, 341, 342f ascending, 446f, 448, 449, 456, 457,
trichohyalin, 341 Haploid cells, 56, 66, 68 459t
Granule cells, of cerebral cortex, 215 in spermatogenesis, 493 descending, 445, 457
Granulocyte(s), 225–230, 226t, 227f–229f Hard palate, 376 thin limbs of, 446f, 447–448, 448t, 459t
basophils as, 220f, 222f, 226t, 230 Hartmann’s pouch, 426, 433 ascending, 446f, 457, 459t
eosinophils as, 220f, 222f, 226t, 228–230, Hassall’s corpuscles, 289, 289f descending, 448, 456, 457, 459t
230b Haustra coli, 409 Hensen’s cells, 534
formation of, 240f, 243, 247f, 248t Haversian canal systems (osteons), 144f, Heparan sulfate
neutrophils as, 220f, 222f, 225, 226t, 145–146, 145f, 152 characteristics of, 70, 71t
227–228 Hay fever, 122b in basal lamina, 79, 80
Granulocyte colony-stimulating factor (G- Head, of spermatozoon, 496–497, 497f in glomerulus, 442
CSF), 241, 242t Hearing loss, 535b, 536b Heparin
Granulocyte-macrophage colony-stimulating Heart, 251, 267–269, 267f–269f. See also in extracellular matrix, 70, 71t
factor (GM-CSF), 241, 242t Cardiac; Cardio- entries. mast cell release of, 117, 120f, 121t
Granulocytopoiesis, 240f, 243, 247f, 248t Heart failure cells, 361b Heparin-like molecule, and clot formation,
Granulomere, 233, 236t Heart wall, layers of, 267–269, 267f–269f 233
Granulosa cells, 465f, 466, 467t, 468, 469t Heavy chains Hepatic. See also Liver.
Granulosa-lutein cells, 465f, 470, 471f of immunoglobulin, 278, 278f Hepatic acinus, 425f, 426
Granzymes, 286, 286f of myosin, 165 Hepatic arteries, 423, 424f
552 䡲䡲䡲 Index
Hepatic coma, 432b Hormone(s) (Continued) Humorally mediated immune response,

Hepatic ducts, 427–430, 434 cartilage effects of, 134, 135t 232, 276, 280
Hepatic phase, of prenatal hemopoiesis, corticotropic, and uterine contractions, T helper cells in, 285, 285f
238 477 Hunter’s syndrome, 37t
Hepatic veins, 423, 424f corticotropin-releasing, 306, 307t, 309, Huntington’s chorea, 204b
Hepatocyte(s), 427–430 322 Hurler’s syndrome, 37t
function of, 422–423 defined, 303 Huxley’s layer, 340, 341f
inclusions in, 41, 430, 431f degradation of, in liver, 433 Huxley’s sliding filament theory, 162, 167
lateral domains of, 424f, 428, 428f follicle-stimulating, 307t, 309, 310 Hyaline cartilage. See Cartilage, hyaline.
organelles of, 429–430, 429f–431f in follicular development and Hyalocytes, 519
protein synthesis in, 429f, 430, 430f ovulation, 465, 468, 470, 471–474, Hyaloid canal, 515f, 519
sinusoidal domains of, 427f, 428, 428f 472f, 473t Hyalomere, 233, 236t
structure of, 423, 427–430 in male reproductive system, 499, 500, Hyaluronic acid
Hepatocyte (limiting) plates, 424, 424f, 501f in extracellular matrix, 70, 71t
426, 426f gonadotropic, 463 in synovial fluid, 156
Hereditary spherocytosis, 224b hypothalamic neurosecretory, 305–306 Hyaluronidase, 71b
Hernia, hiatal, 385b hypothalamic-releasing, 203 Hydration shell, of bone matrix, 137
Herring bodies, 311, 311f in female reproductive system, 471–474, Hydrocephalus, 215b
Hertwig epithelial root sheath (HERS), 473t, 474t Hydrochloric acid (HCl), 396–397, 397f
374 in male reproductive system, 500f, 501f, Hydrocortisone (cortisol), 312t, 318, 321
Heterochromatin, 52, 53f 498–501 effect on cartilage, 135t
Heterogeneous nuclear ribonucleoprotein in ovarian regulation, 471–474, 472f, Hydrogen, in HCl production, 397
particles (hnRNPs), 58, 60 473t, 474t Hydrogen peroxide (H2O2), 36, 228, 228f,
Heterogeneous nucleation, 151 in signaling, 20, 21 229
Heterografts, 153b in smooth endoplasmic reticulum, Hydrogen sulfide, 409
Hiatal hernia, 385b 319–320 Hydrophilic head, of phospholipid
High endothelial venules (HEVs), 266, 292 inhibiting, 306 molecule, 13
Hilum interstitial cell-stimulating, 307t, 309 Hydrophilic ligands, 20
of kidney, 437 lipotrophic, 309 Hydrophobic ligands, 20
of lung, 364 luteinizing, 307t, 309, 310 Hydrophobic tail, of phospholipid
of lymph node, 290 in male reproductive system, 499, 500, molecule, 13
of spleen, 294 501f Hydroxyapatite crystals
Hilus cells, of ovary, 471 in ovulation, 465, 469, 471–474, 472f, in bone, 137, 151
Hinge region, of antibody, 278, 278f 473t in cementum, 370
Hirschsprung disease, 186b luteinizing hormone (LH) receptors, in dentin, 370
Histamine 468, 473 in enamel, 368–369
and capillary permeability, 264 luteinizing hormone-releasing, 306, 307t, Hydroxylysine, in collagen, 113
gastric production of, 392t, 396 309, 465, 472, 473t, 474t Hydroxyproline, in collagen, 113
in hay fever, 122b neurohormones as, 203 Hymen, 485
in HCl secretion, 396 of alimentary canal, 390–391, 392t Hyoid bone, 377f
in inflammatory response, 121 parathyroid, 142, 154, 312t, 316, 317 Hyperadrenocorticism, 322b
inactivation of, by eosinophils, 229, 230b pituitary, 306, 307t Hyperallergic person, 122b
mast cell release of, 117, 120f, 121t prolactin-releasing, 306, 307t Hypercellular obesity, 129b
Histochemistry, 3, 5 somatotropin. See Somatotropin. Hyperparathyroidism, 318b
Histocompatibility molecules. See Major somatotropin-releasing, 306, 307t, 308 Hyperplasia
histocompatibility complex (MHC) steroid, 20, 21, 301, 303, 312t, 318, of myometrium, 477
molecules. 320–322 of skeletal muscle, 183
Histodifferentiation, in odontogenesis, 373 suprarenal, 312t, 318, 320–322 Hypersensitivity reaction, immediate, 118,
Histology thyroid, 309, 311, 312t, 314–315, 315, 120, 120f
defined, 1 315f Hypertension, chronic essential, 457b
introduction to, 1–10 thyroid-stimulating, 307t, 309, 311, 312t, Hyperthyroidism, 316b
Histones, in nucleosomes, 52, 55 315 Hypertrophic obesity, 129b
Holocrine glands, 105, 105f thyroid-stimulating hormone-releasing, Hypertrophy
Homeobox genes, 238 306, 307t, 309 cardiac, 179b
Homografts, 153b thyrotropin-releasing, 203 of myometrium, 477
Horizontal cells Hormone-receptor complex (HRC), 303, of skeletal muscle, 183
in cerebral cortex, 215 304 zone of, 151
in retina, 520f, 524 Hormone-sensitive lipase, 117, 119f Hypervitaminosis A
Hormone(s), 303–304 Horny cells, 331 bone effects of, 155t
α-melanocyte-stimulating, 310 Horseradish peroxidase, 192 cartilage effects of, 135t
adrenocorticotropic, 307t, 309, 312t, 318, Howship lacunae, 138f, 141 Hypochlorous acid, 228, 228f
320, 322b Human chorionic gonadotropin (hCG), Hypodermis, 327, 328f, 334
antidiuretic, 203, 307t, 310, 311 470, 473t, 474, 484 Hypolemmal cisternae, 187
in blood pressure regulation, 258 Human Genome Project, 57 Hyponychium, 344
in urine formation, 456f, 458 Human immunodeficiency virus (HIV) Hypoparathyroidism, 318b
antimüllerian, 493 infection, 196b, 287b Hypophyseal arteries, 305, 306f
bone effects of, 154 Human leukocyte antigen (HLA), 231 Hypophyseal stalk, 305f
in resorption, 142 Human placental lactogen, 473t Hypophyseal veins, 305, 306f
Index ■ ■ ■ 553
Hypophysis. See Pituitary gland. Immune system (Continued) Inhibitory output, of Purkinje cells, 216
Hypothalamic neurosecretory hormones, T lymphocytes in. See T lymphocytes (T Inhibitory postsynaptic potential, 200
305–306 cells). Inhibitory responses, 203
Hypothalamic-releasing hormones, 203 thymus in, 288f, 289–290, 290b Initiator tRNA, 24
Hypothalamohypophyseal tract, 306f, 310 toll-like receptors in, 275–276, 275t, Inlet arterioles, of liver, 425
Hypothalamus, 305f, 311b 276b Inlet venules, of liver, 425
Hypothyroidism, 316b tonsils in, 299, 301, 301f Innate immune system, 273–276
Hypovitaminosis A Immunocompetent B lymphocytes, 247, Inner leaflet, of cell membrane, 12, 13, 14,
bone effects of, 155, 155t 278, 280 15f, 16f
cartilage effects of, 135t Immunocytochemistry, 5, 5f, 6f Inner limiting membrane, of retina, 520f,
Hypovitaminosis C Immunogen(s), 276 525
bone effects of, 155, 155b, 155t Immunogenicity, 276b Inner membrane, mitochondrial, 39–40,
cartilage effects of, 135t Immunoglobulin(s) (Ig), 276, 277–278, 39f
Hypovitaminosis D 278f, 279t Inner nuclear layer, of retina, 520f,
bone effects of, 155, 155b, 155t surface, 277, 279t 524–525
cartilage effects of, 135t Immunoglobulin A (IgA), 278f, 279t Inner nuclear membrane, 49, 51f, 52f,
hepatocytes and, 433 54f
I in small intestine, 404, 405f Inner plexiform layer, of retina, 525
secretory, 367, 404, 416 Inner table, of calvaria, 143, 147
I bands Immunoglobulin D (IgD), 278f, 279t Inner tunnel, of organ of Corti, 533
in cardiac muscle, 178f Immunoglobulin E (IgE), 278f, 279t Innervation. See Nerve supply.
in skeletal muscle, 160, 161f Immunoglobulin E (IgE)-receptor Inositol triphosphate (IP3), 22
Ibuprofen, and ulcers, 398b complex, 118, 120f as second messenger, 20
Ileocecal valve, 407 Immunoglobulin E (IgE) receptor (FcεRI), Insulin, 420–421, 421t, 422b, 423t
Ileum, 395t, 403. See also Small intestine. on basophils, 230 Insulin-like growth factors, 307t, 308
Immediate hypersensitivity reaction, 118, Immunoglobulin G (IgG), 278, 278f, Insulin receptors, 128
120, 120f 279t Integral proteins
Immotile spermatozoa, 496 Immunoglobulin M (IgM), 278f, 279t in cell membrane, 13–14, 16f
Immune response Immunological memory, 276, 277 in rough endoplasmic reticulum, 23–24
cell-mediated, 232, 276 Immunological tolerance, 277 Integrins
humorally mediated, 232, 276, 280 Implantation, 481f, 482 in capillaries, 265
Langerhans cells in, 332 Importins, 52 in cytoplasm, 44, 45f
primary, 277 Impotence, 509b in epithelium, 97f, 102
secondary, 277 Impulse(s) in extracellular matrix, 72, 79, 81, 83,
Immune system, 273–301 generation and conduction of, 198–204, 83b
adaptive, 273, 276 199f, 200f in fibronectin, 72–73
antigen-presenting cells in, 276, 284, 284t transmission of, at neuromuscular in hemidesmosomes, 102
antigens in. See Antigen(s). junctions, 169–172, 169f–172f in neutrophils, 227
B lymphocytes in. See B lymphocytes (B Inactivation gate, 199 Integument, 327–344
cells). Inactive position, of voltage-gated channels, hair in, 328f, 339–343
bronchus-associated lymphoid tissue in, 17 nails in, 343–344, 343f, 344f
299 Incisures of Schmidt-Lanterman, 196–197 sebaceous glands in, 328f, 329, 334,
cells of, 278, 280–283 Inclusions 337f, 338–339, 339b, 339f
interactions among, 284–287, cytoplasmic, 11, 41–42, 41t, 42f skin in. See Skin.
285f–287f in hepatocytes, 41, 430, 431f sweat glands in, 328f, 336–338, 336f,
clonal selection and expansion in, in neurons, 187, 189 337f
276–277 Incontinence, urinary, 462b Interalveolar septum, 357, 358f, 359f, 360,
cytokines in. See Cytokines. Incus, 527, 527f, 535 363
diffuse, 273 Indole, 409 Intercalated cells
gut-associated lymphoid tissue in, Inducible T reg cells, 283 of cortical collecting tubules, 451
298–299, 300f Induction, in drug tolerance, 433b of neurons, 211
hepatocytes in, 433 Infection(s), lymph nodes and, 293b of salivary gland, 414, 414f
immunogens in, 276 Infertility, male, 490b Intercalated disks, 175, 176f, 177,
immunoglobulins in, 277–278, 278f, 279t. Infiltration, 2 178f–179f
See also specific immunoglobulin. Inflammatory response Intercalated ducts
immunological tolerance in, 277 basophils in, 230 pancreatic, 418f, 419
innate, 273–276 edema related to, 126b salivary, 414, 414f
lymph nodes in, 290–293, 291f–293f sequence of events in, 121 Intercellular adhesion molecule type I
lymphoid organs in, 287–299 Infundibulum, of oviduct, 464f, 470, 474 (ICAM-I), 227
major histocompatibility molecules in, Inhalation, 364 Intercellular bridges, 330
275, 275b, 280–281, 283–284, 289 Inhibin Interchromatin granules (IGs), 60
mucosa-associated lymphoid tissue in, in female reproductive system, 468, 472, Intercristal space, 38, 39f
298–301, 300f 473t, 474 Interdental cells, 533
natural killer cells in, 273, 275, 275b in male reproductive system, 493, 500, Interdigitating dendritic cells, 296
overview of, 273, 274t 501f Interfascicular oligodendrocytes, 195
small intestine in, 394t, 403–404, 405f, Inhibiting hormones (inhibiting factors), Interferon(s), 274
406f 306 Interferon-α (IFN-α), 284t
spleen in, 293–298, 294f–299f Inhibitory neurotransmitters, 18 Interferon-β (IFN-β), 284t
554 䡲䡲䡲 Index
Interferon-γ (IFN-γ) Interstitial cell-stimulating hormone Isthmus

antigen-presenting cells and, 284t (ICSH), 307t, 309 of oviducts, 464f, 474
as hemopoietic growth factor, 242t Interstitial cells of thyroid, 313
effect on bone, 154 of Cajal, 382 Ito cells, 426, 433
in T helper cell-mediated killing, of Leydig, 489, 498, 500f
285–286, 286f, 287, 287f of ovary, 463, 471
of pineal gland, 324, 325
J
secretion of, by T helper cells, 282
Interleukin(s) (IL) of renal interstitium, 452 J protein, 279t
cytokines as, 274 Interstitial glands, 468–469, 471 Jaundice, 432b
mast cell release of, 117 Interstitial growth, of hyaline cartilage, 132 Jaw-jerk reflex, 375b
secretion of, by T helper cells, 282 Interstitial lamellae, 146 Jejunum, 395t, 403. See also Small
Interleukin-1 (IL-1) Interterritorial matrix, of hyaline cartilage, intestine.
bone effects of, 154 132f, 134 Joint(s), 156, 156f
in hemopoiesis, 242t, 243 Intervertebral disks, 135, 136, 136b Joint capsule, 156
keratinocytes and, 336 Intestinal phase, of HCl secretion, 397 Junctional complexes, 94–99, 97f
neutrophils and, 227 Intestines. See Large intestine; Small Junctional epithelium, of gingiva, 376
origins and functions of, 284t intestine. Junctional feet, 160
Interleukin-2 (IL-2) Intracellular receptor family, 21 Junctional folds, 170, 171f
functions of, 284t Intraepithelial capillaries, in cochlear duct, Juxtaglomerular apparatus, 441f, 449–451,
in hemopoiesis, 241, 242t 532 450f
T helper cells and, 286, 286f, 287f Intrafusal fibers, 172, 174f monitoring of filtrate in, 457, 457t
Interleukin-3 (IL-3), 241, 242t Intralobar ducts Juxtaglomerular (JG) cells, 441f, 450, 450f,
Interleukin-4 (IL-4), 242t, 284t, 285f pancreatic, 418f, 419 459t
Interleukin-5 (IL-5) salivary, 415 Juxtamedullary nephrons, 438f–439f,
and eosinophils, 229, 230b Intralobular ducts 439–440, 456
functions of, 284t, 285f pancreatic, 419
in hemopoiesis, 241, 242t, 243 salivary, 414
Intramembranous bone formation, 131,
K
Interleukin-6 (IL-6)
bone effects of, 154 146–147, 146f, 147f Kallikrein, 416
functions of, 284t, 285f Intramural region, of oviducts, 464f, 474 Kartagener’s syndrome, 92
in hemopoiesis, 241, 242t Intraperiod gaps, of Schwann cells, 197 Karyokinesis, 62, 495
Interleukin-7 (IL-7), 241, 242t Intraperiod line, of Schwann cells, 197 Karyoplasm, 11
Interleukin-8 (IL-8), 242t Intrapulmonary bronchi, 346t, 354 Karyotyping, 56, 56f
Interleukin-9 (IL-9), 242t Intrapulmonary conducting division, 346t Keloid, 75b
Interleukin-10 (IL-10), 241, 242t, 284t, Intratesticular genital ducts, 490f, 501, Keratan sulfate
285, 285f 502t characteristics of, 70, 71t
Interleukin-12 (IL-12), 241, 242t, 284t Intrinsic muscles in bone, 137
Interlobar arteries, of kidney, 438f, 453 of larynx, 351 Keratin(s), 45, 46t, 336
Interlobar ducts, salivary, 415 of tongue, 376, 377f of hair, 342–343
Interlobar veins, of kidney, 454 Introns, 58, 59 Keratin filaments, 328, 341
Interlobular arteries, of kidney, 438f, 453 Investments Keratin tonofilaments, 102
Interlobular ducts connective tissue, of peripheral nerves, Keratinocytes, 328–331
bile, 427 205–206, 205f Keratohyaline granules, 331
pancreatic, 419 of skeletal muscle, 158, 159f Kerckring, valves of, 398
salivary, 415 Involucrin, 331, 336 Ketone bodies, 431
Interlobular veins, of kidney, 453–454 Involuntary muscle, 179 Ketosis, 432b
Intermediate cells Involuntary (autonomic, visceral) nervous Kidney(s), 437–458. See also Renal entries.
of cochlear duct, 532 system, 185, 207–210, 209f Bowman’s capsule of, 439f, 440, 442,
of parathyroid, 317 Involution, of thymus, 288 443f, 444f, 445
of taste buds, 378 Iodide, and thyroid hormones, 314, 315f Bowman’s space of, 440, 441f, 445, 445f,
Intermediate compartment, of Golgi Iodopsin, 523 450f
apparatus, 27, 28f, 30f Iodotyrosine dehalogenase, 315 calyces of, 437, 438f, 459–460
Intermediate filaments Ion channel(s), 17–19 capsule of, 437, 438f
in cytoplasm, 43f, 44–45, 45b, 46t Ion channel-linked receptors, 18 circulation of, 438f–439f, 452–454, 453f,
in epithelium, 94f, 99 Ion channel-mediated diffusion, 18f 454f
in skin, 329 IP3 (inositol triphosphate), 20, 22 collecting tubules of, 451–452, 459t
Intermediate muscle fiber, 157, 183 Iris, 515f, 517–518 cortical, 446f, 451
Intermembrane space, mitochondrial, Iron-containing pigments, 189 loss of water and urea from filtrate in,
38–39, 39f Iron deficiency anemia, 243b 458, 459t
Interneurons, 193, 211 Iron hematoxylin stain, 3t medullary, 446f, 451
Internodal segments, of Schwann cells, 196 Ischemic heart disease, 269b papillary, 437, 439, 451
Internum, of eosinophil, 229, 229f Islands, blood, 238 structure of, 438f–439f, 446f, 451f,
Internuncial neurons, 211 Islets of Langerhans, 418, 418f, 420, 421t, 452f, 459t
Interoceptors, 511 422f, 423t cortex of, 437, 438f–439f, 440f
Interpapillary peg, 336 Isogenous groups, of chondrocytes, 132, disorders of, 438b, 442b, 458b
Interphase, of cell cycle, 61–62, 61f, 64f 132f distal tubule of, 448–451, 449f
Interplaque regions, of urinary bladder, 461 Isotope switching, 280 convoluted, 439f, 446f, 448, 449, 449f,
Interplexiform cells, in retina, 525 Isotypes, of immunoglobulins, 278 459t
Index ■ ■ ■ 555
Kidney(s) (Continued) L Laminin

functions of, 454–458 hemidesmosomes and, 102
glomerulus of, 439f, 441–442, 442f, 443f λ-granules, of platelets, 233, 233f, 236t in connective tissue, 113
Henle’s loop of, 439f, 448 Labia majora, 485 in cytoskeleton, 45f
and countercurrent multiplier system, Labia minora, 485 in extracellular matrix, 73, 79
455–457, 456f Labyrinth, bony, 528–534, 528f in glomerulus, 442
thick limb of Lacrimal apparatus, 526 release of, by capillaries, 264
ascending, 446f, 448, 449, 456, 457, Lacrimal canaliculi, 526 Langerhans, islets of, 418, 418f, 420, 421t,
459t Lacrimal fluid, 515, 526 422f, 423t
descending, 445, 457 Lacrimal gland, 515, 526 Langerhans cells
thin limbs of, 446f, 447–448, 448t, 459t Lacrimal puncta, 526 macrophage function of, 123
ascending, 446f, 457, 459t Lacrimal sac, 526 of epidermis, 328f, 331–332
descending, 448, 456, 457, 459t Lactation, 486–488, 486f, 487f of esophagus, 384
hilum of, 437 Lacteals, 398, 402 of vagina, 485
innervation of, 454 Lactic acid, in vagina, 485 Lanugo, 339
interstitium of, 452 Lactiferous ducts, 486, 486f Large intestine, 407–411
juxtaglomerular apparatus of, 449–451, Lactiferous sinus, 486, 486f appendix of, 395t, 410–411
450f Lactoferrin, 367, 416 colon of, 395t, 407, 408b, 408f, 409,
monitoring of filtrate in, 457, 457t Lacunae 409f, 410f
juxtaglomerular cells of, 441f, 450, 450f, in implantation, 481 DNES cells and hormones in, 392t
459t in placental development, 484 histology of, 395t
lobated, 438b of bone, 136, 137f, 138, 139f, 140, rectum and anal canal of, 395t, 409–410
lobes and lobules of, 437 151 Laryngeal aditus, 351
lymphatic supply of, 454 of cartilage, 131, 132, 133f Laryngitis, 351b
macula densa of, 440f, 441f, 448, Lamellae, of bone, 143–145, 144f Larynx, 346t, 350–351
449–450, 450f, 457, 459t interstitial, 146 Late endosomes, 30f, 33–34
medulla of, 437, 438f–439f, 440 Lamellar bodies, of pneumocytes, 360 Lateral domains, of hepatocyte, 424f, 428,
medullary rays of, 438f–439f, 439–440 Lamellar granules, 330 428f
mesangial cells of, 441, 442f, 443f Lamin A, 46t, 49 Lateral membrane specializations, of
nephrons of, 438, 438f–439f, 439–451 Lamin B, 46t, 49 epithelium, 92, 94–102
pedicels of, 442, 443f, 445f Lamin C, 46t, 49 Leaflets, of cell membrane, 12, 13, 14, 15f,
pelvis of, 437, 438f, 460 Lamina(e) 16, 16f
podocytes of, 440, 441f–444f, 450f basal. See Basal lamina. Lens
proximal tubule of, 440f, 441f, 445–447, dental, 371, 372f of eye, 515f, 518, 518f, 519f
446f, 447f elastic. See Elastic lamina. suspensory ligaments of, 515f, 517
convoluted, 439f, 445–446, 446f external, 79, 158, 170, 178, 180, of microscope
resorption in, 455 183f condenser, 2, 4f
pyramids of, 437, 438f myocardial, 175 objective, 3, 4f
renal corpuscles of, 437, 440–441, nuclear, 49 ocular, 3, 4f
440f–441f, 459t osseous spiral, 528 projection, 4f
filtration in, 455 succedaneous, 373 Lens capsule, 518
sinus of, 437, 438f Lamina densa, 79, 82f Lens fibers, 518, 519f
structure of, 437, 438f–439f glomerular, 441, 442 Leptin, mutation of, 129b
urinary pole of, 440, 441f, 445 Lamina lucida, 79, 81f–82f Leptotene, 67, 495
urine formation by, 455–458, 456f, 457t, Lamina propria Leukemia
458 defined, 126 acute myeloblastic, 246b
uriniferous tubules of, 438–452, immunological activity of, 394t, 403–404, acute myelogenous, 66b
438f–439f, 446f, 456f, 459t, 460t 405f, 406f Leukocyte(s), 225–232, 226t. See also
vasa recta of, 453 of alimentary canal, 381, 394t–395t specific types of leukocytes.
and countercurrent exchange system, of anal canal, 410 in connective tissue, 124–125
458, 460f, 460t of bladder, 461 Leukocyte adhesion deficiency, 83b
vascular pole of, 440, 441f of bronchioles, 356, 356f Leukotrienes
Kiesselbach’s area, 347b of colon, 410 basophils and, 230
Killer-activating receptors, 275 of endometrium, 476 eosinophils and, 229
Killer cells, 232 of esophagus, 384, 394t in asthma, 355b
Killer-inhibitory receptors, 275 of gallbladder, 434 in inflammatory response, 121
Kinesin of large intestine, 395t mast cell release of, 117, 120, 120f, 121t
and vesicles, 29, 31 of nasal cavity, 347, 349 neutrophil release of, 226, 228
as microtubule motor proteins, 47–48 of oviducts, 475 Leydig cells, 489, 498, 500f
in axonal transport, 192 of small intestine, 394t–395t, 400, 400f, Ligand, 18, 20
Kinetochore, 64 401f, 403f in receptor-mediated endocytosis, 32, 33f
Kinocilium, 529, 530f, 531f of stomach, 387–393, 394t Ligand-gated channels, 18
Klinefelter syndrome, 56b, 495b of trachea, 353 Light cells
Kohn pores, alveolar, 359f, 360 of ureter, 460 of saccule and utricle, 529
Krause end bulb, 334, 512f, 514 of urethra, 462 of taste buds, 378
Krebs cycle, 40 of vagina, 485 Light chains
Kupffer cells, 123, 123f, 426, 426f, 427f, Lamina rara, of glomerulus, 441–442 of immunoglobulin, 278, 278f
433 Lamina reticularis, 79, 80, 81f–83f of myosin, 165, 182
556 䡲䡲䡲 Index
Light meromyosin, 164f, 165 Liver (Continued) Lymph, 251, 270

Light microscopy, 1–7 hormone degradation by, 433 Lymph node(s), 290–293, 291f
advanced visualization procedures in, 3, immune function of, 433 cortex of, 291, 291f, 292f
5–6, 5f–8f Kupffer cells of, 123, 123f, 426, 426f, enlargement of, 291b
digital imaging techniques in, 3 427f, 433 histophysiology of, 293
interpretation of microscopic sections in, lipid metabolism in, 431 infection spread via, 293b
3, 4f lobes of, 422, 424f location of, 270, 290
microscope for, 2–3, 4f lobules of, 425–426, 425f medulla of, 291f, 292–293, 293f
tissue preparation for, 1–2, 3t classical, 423, 425, 425f metastasis to, 271b, 293b
Light zones, of lymphoid nodule, 292 perisinusoidal space (of Disse) of, 426, paracortex of, 292
Limbus 427f, 428f structure of, 290, 291f
of eye, 516 portal areas (triads) of, 423–425, 424f vascularization of, 293
of spiral lamina, 533 protein synthesis in, 429f, 430, 430f, Lymph vessels, 270–271, 270f, 290, 291,
Limiting membrane 431–433, 432f 291f
external regeneration of, 433 Lymphatic anchoring filaments, 270, 270f
of ependymal cells, 196 sinusoids of, 424f, 425, 426, 426f, 427f Lymphatic capillaries, 288, 289
of retina, 520f, 524 structure of, 423–430, 424f Lymphatic dissemination theory, of
inner, of retina, 520f, 525 vascular supply to, 423–425, 424f, 425f endometriosis, 478b
internal, of ependymal cells, 196 vitamin storage in, 432–433 Lymphatic ducts, 270, 271
Limiting plates, of liver, 424, 424f, 426, 426f Lobar arteries, of kidney, 453 Lymphatic vascular system, 251, 270–271,
Linear movements, 534 Lobar bronchi, 354 270f, 290–293, 291f
Lines of Owen, 370 Lobated kidney, 438b of kidney, 454
Lingual papillae, 377–379, 377f, 378f Lobe(s) of lungs, 365
Lingual tonsils, 301, 377f of glands, 107 of small intestine, 402–403
Lining mucosa, 367, 376 of kidney, 437 Lymphoblast, 239t
Link proteins, 71 of thymus, 287 Lymphocyte(s), 231–232, 232f
Linker DNA, 52 of thyroid gland, 313 B. See B lymphocytes (B cells).
Lipid(s) Lobular carcinoma, 488b cloning of, 276–277
emulsification of, 405, 407f Lobule(s) features of, 226t
in cytoplasm, 41 hepatic, 425–426, 425f formation of, 239t, 247, 249
in hepatocytes, 430, 431f classical, 423, 425, 425f functions of, 231–232
in mammary glands, 487, 487f of bronchopulmonary segment, 364 in connective tissue, 125
in neurons, 189 of glands, 107 structure of, 220f, 222f, 231–232, 232f
liver metabolism of, 431 of kidney, 437 T. See T lymphocytes (T cells).
transport of, 116, 119f of mammary glands, 485 types of, 231
Lipid antigens, 283 of thymus, 288, 288f Lymphoid cell(s), 278, 280–284
Lipid bilayer, of cell membrane, 13 Lobuli testis, 489, 490f antigen-presenting cells as, 284, 284t
Lipofuscin Longitudinal muscle B lymphocytes as, 278, 280
in cytoplasm, 42 of myometrium, 477 interaction among, 284–287
in neurons, 189, 190f of ureter, 460 major histocompatibility molecules as,
Lipoid nephrosis, 445b Longitudinal section, 4f 283–284
Lipolysis, 321 Loop of Henle. See Henle’s loop. natural killer cells as, 283
Lipomas, 129b Loose connective tissue, 126, 126b T lymphocytes as, 280–283, 281t
Lipoprotein(s) Low-density lipoprotein (LDL), 221t, 319 Lymphoid cell lines, 238
low-density, 221t, 319 Lubricin, in synovial fluid, 156 Lymphoid nodules, 291–292, 291f, 292f, 293
plasma, 221t Luminal spoke (middle) ring, 50, 54f of alimentary tract, 382f
very-low-density, 116, 221t, 430, 431 Luminal surface, of small intestine, 398, of pharyngeal tonsil, 299, 301f
Lipoprotein lipase, 116, 119f 398f–401f of small intestine, 399f
Liposarcomas, 129b Lung(s). See also Pulmonary entries; of spleen, 294f, 296
Lipotropic hormone (LPH), 309 Respiratory system. Lymphoid organ(s), 287–299
Lips, 367–368 gas exchange in, 358f, 363–364 bronchus-associated lymphoid tissue as,
Liquor folliculi, 467t, 468 gross structure of, 364–365 299
Littre glands, 462 Lunula, 344 gut-associated lymphoid tissue as,
Liver, 422–433, 424f. See also Hepatic; Luteal phase, of menstrual cycle, 480, 480f 298–299, 300f
Hepato- entries. Luteinizing hormone (LH) lymph nodes as, 290–293, 291f
acinus of, 425f, 426 in male reproductive system, 499, 500, mucosa-associated lymphoid tissue as,
bile manufacture by, 430–431, 432f 501f 298–301
capsule of, 423 in ovulation, 465, 469, 471–474, 472f, primary (central), 276, 287
carbohydrate metabolism in, 431–433, 473t secondary (peripheral), 276, 287
432f interstitial cell-stimulating hormone as, spleen as, 293–298, 294f, 295f
detoxification of drugs and toxins by, 310 thymus as, 287–290, 288f, 290b
433, 433b physiologic effects of, 307t, 309 tonsils as, 299, 301, 301f
disorders of, 429b, 430b, 432b Luteinizing hormone (LH) receptors, 468, Lymphoid system. See Immune system.
ducts of, 427–430, 434 473 Lymphoid tissue
hepatocyte (limiting) plates of, 424, 424f, Luteinizing hormone-releasing hormone bronchus-associated, 299
426, 426f (LHRH), 306, 307t, 309, 465, 472, gut-associated, 298–299, 300f
hepatocytes of. See Hepatocyte(s). 473t, 474t mucosa-associated, 298–301, 300f, 301f
histophysiology of, 430–433, 432f Luteolysis, 471 Lymphokines, 232
Index ■ ■ ■ 557
Lymphopoiesis, 239t, 247, 249 Major histocompatibility complex (MHC) Masticatory mucosa, 367, 376
Lysosomal acid maltase deficiency, 41t molecules (Continued) Matrix granules, 40
Lysosomal hydrolases, 142 loading of epitopes on, 283–284 Matrix space, mitochondrial, 39f, 40
Lysosomal proteins, transport of, 30–31, 31f synthesis of, by Langerhans cells, 384 Maturation, of lens fibers, 518
Lysosomal storage disorders, 36b, 37t Malabsorption, 406b Maturation phase, of spermiogenesis, 496,
Lysosomes, 14f, 30f, 35–36, 36f Male infertility, 490b 497f
formation of, 35 Male pronucleus, 481 Maturation zone, 151
in leukocytes, 225 Male reproductive system, 489–510, 490f Mature (graafian) follicles, 465f, 467t, 469,
in neurons, 190f accessory genital glands in, 490f, 504–507 474
in platelets, 233, 233f, 236t bulbourethral glands in, 489, 490f, 507 McArdle’s syndrome, 41t
transport of substances into, 35–36 ductuli efferentes in, 489, 490f, 502, 502t Mechanically gated channels, 18
Lysozyme(s) ductus (vas) deferens in, 489, 490f, 502t, Mechanoreceptors, 511–514
in esophagus, 384 504 encapsulated, 335, 512f, 513–514, 513f
in lacrimal fluid, 526 ejaculatory duct in, 490f, 502t, 504 Merkel cell-neurite complexes as, 332
in oral cavity, 367 epididymis in, 489, 490f, 502t, 503–504, nonencapsulated, 512, 512f
in saliva, 416 504f Mechanotransduction, 140
in small intestine, 401 genital ducts in, 501–502, 502t Meckel’s diverticulum, 403b
in stomach, 393 interstitial cells of Leydig in, 489, 498, Median eminence, 305f, 306f
Lysyl hydroxylase deficiency, 78b 500f Mediastinum testis, 489
penis in, 489, 490f, 507–510, 507f Medulla
M prostate gland in, 490f, 505–506, 505f, of hair shaft, 341, 341f
506f of lymph nodes, 291f, 292–293, 293f
M (microfold) cells, 299, 400, 404, 405f, rete testis in, 489, 490f, 501–502, 502t, of suprarenal glands, 312t, 318, 322–324,
406f 503f 322f
M line, in skeletal muscle, 160, 162 seminal vesicles in, 489, 490f, 505, 505f ovarian, 471
M phase, 62, 62f–64f seminiferous tubules in, 489, 490–498, renal, 437, 438f–439f, 440
Macrophage(s), 122–123 490f–492f thymic, 288f, 289, 289f
activated, 123 Sertoli cells in, 491–493, 492f Medullary collecting tubules, 446f, 451
alveolar, 359f, 361, 361b, 362f, 363 spermatogenic cells in, 492f, 493–498, Medullary rays, 437, 438f, 440f
crystalloid inclusions in, 42, 42f 494f, 496f Medullary sinuses, of lymph node, 291, 291f
development and distribution of, 123, testes in, 489–498, 490f Medullipin, 452
123f, 246 tubuli recti in, 489, 501, 502t Megacolon, congenital, 186b
elicited, 123 Malignant melanoma, 335b Megakaryoblast, 239t, 246–247
fixed, 123 Malleus, 527, 527f, 535 Megakaryocyte, 237f, 239t, 247, 249f
free, 123 Malpighian layer, 328f, 330 Meibomian glands, 525
function of, 123, 231 MALT (mucosa-associated lymphoid Meiosis, 66–68
in bone marrow, 237 tissue), 298–301, 300f, 301f chromosome abnormalities due to, 68b
in fixed connective tissue, 122–123, 122f Mammary glands, 485–488 equatorial division (meiosis II), 66, 67f,
in innate immune system, 273–274 lactating (active), 486–488, 486f, 487f 68
in loose connective tissue, 126 resting (nonsecreting), 486 of oocytes, 464, 466, 469
in lymph nodes, 291 Mammotrophs, 308, 309f of spermatocytes, 492f, 493–495, 494f
in phagocytosis, 32, 231 Manchette, 496 reductional division (meiosis I), 66–67,
in renal interstitium, 452 Mannitol, 214b 66f
in spleen, 296, 297, 299f Mannose, phosphorylation and removal of, Meiosis-inducing substance, 464, 469
origin of, 112f, 231 27, 30–31, 30f, 35 Meiosis-preventing substance, 464
resident, 123 Mannose-6-phosphate receptors, 31, 35 Meissner corpuscles, 328f, 334, 512f, 513,
structure of, 122, 122f, 231 Mantle, of lymphoid nodule, 292 513f
TH1 cell activation of, 286–287, 287f Marfan syndrome, 79b, 257b Meissner’s plexus
TH1 cell interaction with, 286–287, 287f Marginal cells, in cochlear duct, 532 of digestive tract, 381, 383, 401
tingible body, 289 Marginal fold, of capillary, 260 of parasympathetic nervous system, 210
Macrophage colony-stimulating factor (M- Marginal sinuses, of spleen, 294f, 295f, 296 Melanin
CSF), 140, 242t Marginal zone, of spleen, 291f, 294f, 295f, epidermal, 332, 332b
Macula 296, 297f in cytoplasm, 42
of saccule, 528f, 529, 531f Margination, of neutrophils, 243 in neurons, 187, 189
of utricle, 528f, 529, 530f, 531f Marrow. See Bone marrow. α-Melanocyte-stimulating hormone (α-
Macula densa, 440f, 441f, 448, 449–450, Marrow cavity, 136 MSH), 310
450f, 457, 459t Martinotti cells, 215 Melanocytes
Macula lutea, 515f, 520 Masson’s trichrome stain, 3t in epidermis, 332–333, 334f, 341
Maculae adherentes, 97f, 99, 100f, 101b Mast cells, 117–121 in iris, 518
Major basic protein, of eosinophil, 229 activation and degranulation of, 118, Melanoma, malignant, 335b
Major dense line, 197 120–121, 120f Melanosomes, 332, 334f, 341
Major histocompatibiity complex (MHC) development and distribution of, Melatonin, 312t, 325, 325b
antigens, 231 117–118 Membrana granulosa, 465f, 469, 469t
Major histocompatibility complex (MHC) in inflammatory response, 121 Membrane, cell. See Cell membrane.
molecules, 283–284 in loose connective tissue, 126 Membrane attack complex, 273, 277b
and natural killer cells, 275, 275b mediators released by, 117, 120–121, 121t Membrane-bound antibodies, 277, 279t
and T lymphocytes, 280–281, 289 mucosal, 118 Membrane-coating (lamellar) granules,
classes of, 281–282, 283 structure of, 112f, 117, 119f 330, 336
558 䡲䡲䡲 Index
Membrane depolarization, 198 Metaplastic theory, of endometriosis, 478b Minus end

Membrane trafficking, 32, 33f Metarterioles, 254t, 256–257, 263, 264f of microtubules, 29, 45, 47
Membrane transport proteins, 16–19, 18f Metastasis of thin filaments, 42, 166
Membranous labyrinth, 528–534, 528f of breast cancer, 488b Mitochondria, 37–40
Membranous urethra, 462 to lymph nodes, 271b, 293b in cardiac muscle, 175, 178f
Memory, immunological, 276, 277 Methotrexate, 66b in plasma membrane enfoldings, 102
Memory cells Methyldopa, 189 inner membrane of, 39–40, 39f
functions of, 277 MHC molecules. See Major intermembrane space of, 38–39, 39f
of B lymphocytes, 232, 280, 285, 292 histocompatibility complex (MHC) matrix of, 40
of T lymphocytes, 232, 281 molecules. of hepatocytes, 429, 430f
Menarche, 463 Micelles, 405, 407f of neurons, 187
Meniere’s disease, 535b Microbodies, 36 origin and replication of, 40–41
Meningeal dura mater, 211 Microfibrils, of elastic fiber, 78–79, 79b, outer membrane of, 38–39, 39f
Meninges, 211, 212f, 213b 80f, 81f oxidative phosphorylation in, 40
Meningioma(s), 213b Microfilaments structure of, 14f, 15f, 35f, 39f
Meningitis, 213b of cardiac muscle, 177 Mitosis, 62, 62f–64f, 180t
Menopause, 463 of cytoskeleton, 14f, 42–44, 43f–45f, 44t Mitotic figures, in skin, 329–330
Menses (hemorrhagic discharge), 479 of neuron, 189–190 Mitotic spindle apparatus, 64
Menstrual cycle, 478–480, 479f, 480f of skeletal muscle, 160, 161–167, 161f, Mitotic spindle microtubules, 63f, 64
Menstruation, 478 162f, 164f, 165t, 166f Mitral valve, 267, 268b
corpus luteum of, 470, 474 of smooth muscle, 181 Mixed glands, 104, 104f, 109
Mercaptans, 409 Microfold (M) cells, 299, 400, 404, 405f, Mixed peripheral nerves, 206
Merkel cell(s), 328f, 332, 333f, 512 406f Mixing contractions, of small intestine, 405
Merkel cell-neurite complexes, 332 Microglial cells (microglia), 123, 196, 218 Modiolus, 528
Merkel’s disks, 512, 512f Microphages. See Neutrophil(s). Molars (accessional teeth), 368, 373
Merocrine glands, 104–105, 105f, 488 Microscope Molecular layer
Meromyosin compound, 2, 4f of cerebellar cortex, 215
heavy, 164f, 165, 181 light, 2–3, 4f of cerebral cortex, 215
light, 164f, 165 scanning electron, 4f Möll
Mesangial cells, 441, 442f, 443f transmission electron, 4f glands of, 338, 525
extraglomerular, 441, 450 Microscopic sections, interpretation of, 3, space of, 424
intraglomerular, 441, 442f, 443f, 445, 450 4f Monocyte(s), 230–231
Mesaxons, 192f, 197, 198f Microscopy features of, 226t
Mesenchymal cells confocal, 7, 8f, 9f formation of, 239t, 246
in cartilage, 132, 133 electron, 7–10 functions of, 123, 231
in embryonic connective tissue, 125–126 light, 1–7 in phagocytosis, 32, 231
in intramembranous bone formation, Microsomal mixed-function oxidases, 433 origin of, 112f
146, 146f Microspikes, 43 structure of, 220f, 222f, 231
origins of, 112f Microtubule(s) Monocyte colony-stimulating factor (M-
Mesenchymal connective tissue, 125 in axons, 191, 192 CSF), 241, 242t
Mesenchyme, 111 in cilia, 91–92, 95f, 96f Monocytopoiesis, 239t, 246
Mesenteric ganglia, 209f singlets and doublets of, 91, 348 Monoglycerides, absorption and processing
Mesentery, 382f subunits of, 91–92 of, 407f
Mesoblastic phase, of prenatal in cytoplasm, 45–46, 46b, 47f Monoiodinated tyrosine (MIT), 314–315
hemopoiesis, 238 in neurons, 189, 190, 190f Monomer, 279t
Mesoderm, 111, 327 mitotic spindle, 63f, 64 Mononuclear phagocyte system, 123, 140,
Mesodermal germ layer, 85 polar, 64 196, 231
Mesonephros, 466 Microtubule-associated proteins (MAPs), Monosomy, 56b, 68b
Mesothelial cell, 112f 47–48, 47f Morgagni, rectal columns of, 410
Mesothelial epithelium, 463, 464f, 466 in neurons, 190 Morphodifferentiation, in odontogenesis,
Mesothelium, 269 Microtubule organizing center (MTOC), 373
Mesovarium, 463, 464f 29, 45, 63–64 Morula, 481f, 482
Messenger ribonucleic acid (mRNA), 21, Microvilli Motilin, 392t
24, 57–59, 58f of cytoplasm, 14f, 35f, 43 Motor component
Messenger ribonucleoprotein (mRNP), 58 of epithelium, 90–91, 91f–94f of autonomic nervous system, 207
Metachromasia, 2 of hepatocyte, 426 of peripheral nervous system, 185, 206
Metachromatic stain, 2 of parietal cells, 389, 390f of somatic nervous system, 207, 207f
Metalloproteinases, 142 of renal corpuscle, 441f Motor end plates, 169
Metamyelocytes, 239t, 240f, 248t of small intestine, 398, 399 Motor endings, 511
Metaphase Midbody, 65, 65f Motor neurons, 13f, 169, 189f, 193
meiotic, 66f, 67 Middle piece, of spermatozoon, 496, 497f, α-efferent, 169, 173, 174f
in oocytes, 469 498 γ-efferent, 173, 174f, 175b
in spermatocytes, 495 Middle ring, of nuclear pore complex, 50 Motor unit, 169
mitotic, 64, 64f Milk ejection reflex, 488 Mounting, 2
Metaphase II, 67f, 68 Milk production, 486, 488 Mucin, 104, 352, 352f, 400
Metaphase plate, 64 Milk teeth, 368, 373 Mucinogens, 104, 106, 400
Metaphysis, 143 Mineralized components, of teeth, 368–370 Mucoid cells, of eccrine sweat gland, 337,
Metaplasia, 102b, 354b Mineralocorticoids, 312t, 319, 320, 321 337f
Index ■ ■ ■ 559
Mucopolysaccharidosis (MPS), 37t Muscle(s) (Continued) Muscle contraction (Continued)

Mucosa extrinsic smooth, 180t, 181, 182, 184f
anal, 410 of eye, 515, 515f uterine, 477
masticatory, 367, 376 of larynx, 351 Muscle cramps, 318b
of alimentary canal, 381, 382f of tongue, 376 Muscle fibers
of bladder, 461 fine structure of, 160–167 cardiac, 175, 177, 178f–179f
of esophagus, 383–384, 384f Golgi tendon organs of, 171–172, 175, intermediate, 157
of gallbladder, 434, 434f 175b red, 157, 158t
of nasal cavity, 349, 350b innervation of, 157, 158t, 168–169 skeletal, 157, 158t, 160–167
of oviducts, 474–475, 475f intrinsic smooth, 179–180, 181f–183f
of small intestine, 398–402 of larynx, 351 white, 157, 158t
of stomach, 386–393, 386f of tongue, 376, 377f Muscle phosphorylase deficiency, 41t
of trachea, 351–353, 352f investments of, 158, 159f Muscle spindles, 171–173, 174f, 175b,
of ureter, 460 light microscopy of, 158, 160, 160f–162f 512f, 514
of vagina, 485 muscle spindles of, 171–173, 174f, Muscle tetany, 290b, 318b
olfactory, 347f 175b, 512f, 514 Muscular arteries, 254t, 255–256, 255f
oral, 367, 376 myofibrils in, 157, 160, 161–167, 161f, Muscularis
specialized, in taste perception, 367 162f, 164f, 165t, 166f of oviduct, 475
Mucosa-associated lymphoid tissue myotendinous junctions of, 168 of ureter, 460
(MALT), 298–301, 300f, 301f neuromuscular junctions of, impulse of vagina, 485
Mucosal glands, of prostate, 506 transmission at, 169–172, Muscularis externa
Mucosal mast cells, 118 169f–172f of alimentary canal, 381–382, 382f,
Mucous acinus(i), of salivary gland, 104f, proteins associated with, 165t 394t–395t
108f, 414, 414f regeneration of, 180t, 183 of anus, 395t, 410
Mucous aspect, of lip, 368 sarcomeres in, 160, 161f, 162f of colon, 395t, 407, 409
Mucous cells sarcoplasmic reticulum in, 157, 158t, of esophagus, 384, 394t
esophageal, 384 160–161, 163f of large intestine, 395t
of salivary gland, 108f, 414, 414f, 415f T tubules in, 160, 163f of small intestine, 394t–395t, 402
Mucous glands triads in, 160, 162f, 163f of stomach, 393, 394t, 396
function of, 104 types of muscle fibers in, 157, 158t Muscularis mucosae
of bladder, 461 smooth, 179–183 of alimentary canal, 381, 394t–395t
Mucous neck cells, 387–388, 389f arrector pili muscles as, 328f, 329, of anus, 395t, 410
Mucous tissue, 126 335, 341–342 of esophagus, 384, 394t
Mucus characteristics of, 159f, 180t of large intestine, 395t
mucin in, 104 contraction of, 182, 184f of small intestine, 394t–395t, 401, 403f
of colon, 409 fine structure of, 181–182, 183f of stomach, 386f, 391, 393, 394t
of small intestine, 352, 352f, 400 in reticular layer, of dermis, 335 Myasthenia gravis, 173b, 364b
of stomach, 386, 396 innervation of, 182–183 Myelin
soluble, 396 intermediate, 183 oligodendrocytes and, 191f, 195
visible, 386, 387, 387f, 396 light microscopy of, 179–180, tubular, 361
Müller cells, retinal, 520f, 525 181f–183f Myelin sheath, 191, 197f, 206
Multicellular glands, 106–107, 107f–109f multiunit, 179, 182 Myelinated axons, 191, 191f, 192f, 196
Multiform layer, of cerebral cortex, of bronchioles, 356b in neuromuscular junction, 169, 171f
215 of ciliary body, 517 of peripheral nerves, 206, 206t
Multilocular fat cells, 115, 116, 118f, of gallbladder, 434 Myelination, 191f, 197
128–129 of myometrium, 477 Myeloblast(s), 239t, 240f, 243, 247f,
Multipass proteins, 14, 19 of prostate gland, 506 248t
Multiple sclerosis (MS), 199b of pupil, 515f, 518 Myeloblastic leukemia, acute, 246b
Multipolar neurons, 189f, 193 of seminal vesicles, 505 Myelocytes, 239t, 240f, 248t
Multipotential hemopoietic stem cells of spleen, 293 Myelogenous leukemia, acute, 66b
(MHSCs), 238 of ureter, 460 Myeloid cell lines, 238
Multivesicular bodies, 33f, 35 regeneration of, 180t, 183–184 Myeloid phase, of prenatal hemopoiesis,
Mumps, 417b unitary (single-unit, vascular, visceral), 238
Muscle(s), 157–184 179, 183 Myenteric plexus, 405. See also Auerbach
cardiac, 175–179, 176f, 177f sphincteral plexus.
characteristics of, 159f, 180t of anus, 410 Myoblasts, 157
contraction of, 175, 180t of esophagus, 385 Myocardial infarct, 237b
intercalated disks of, 175, 176f, 177, of gastrointestinal system, 383 Myocardium, 175, 267, 267f, 268, 268f,
178f–179f of pupil, 515f, 518 269f
organelles of, 177–179 of urethra, 462, 462b Myoepicardial mantle, 175
regeneration of, 183 of urinary bladder, 462 Myoepithelial cells
involuntary, 179 striated, 157, 158f characteristics of, 107, 109f, 184
regeneration of, 180t, 183–184 of facial expression, 335 of eccrine sweat gland, 337f, 338
skeletal, 157–175 Muscle contraction of salivary gland, 414, 414f
characteristics of, 159f, 180t cardiac, 175, 180t Myofibrils, 157, 180t
contraction and relaxation of, 167–169, of small intestine, 405 structural organization of, 160, 161–167,
168f skeletal, 160–161, 167–169, 168f, 180t 161f, 162f, 164f, 165t, 166f
development of, 157 energy sources for, 167–168 Myofibroblasts, 114–115, 184, 374
560 䡲䡲䡲 Index
Myofilaments Negative feedback mechanism, for Neuroepithelial bodies, pulmonary, 353

of cardiac muscle, 177 glucocorticoids, 322 Neuroepithelial cells
of skeletal muscle Nephrons, 438f, 439–451 of organ of Corti, 532f, 534
thick, 157, 161, 162, 164f, 165–166, cortical, 438f–439f, 439, 448t of saccule and utricle, 529, 530f, 531f
166f distal tubule of, 448–451, 449f of semicircular ducts, 530, 531f
thin, 161–162, 164, 164f, 166–167, 166f convoluted, 439f, 446f, 448, 449, 449f, Neuroepithelium, 185
of smooth muscle, 180, 181 459t Neurofibrils, 189
Myoglobin pigments, 157 juxtamedullary 436, 438f–439f, 439–440, Neurofilaments, 45, 46t, 189
Myoid cells, 491 456 Neuroglial cells, 193–197, 193f, 194f
Myomesin, 162, 165t proximal tubule of, 440f, 441f, 445–447, astrocytes as, 193, 194f, 195
Myometrium, 464f, 477, 478b 446f, 447f, 459t defined, 185
Myosin convoluted, 439f, 445–446, 446f ependymal, 196, 211
in contractile bundles, 43 resorption in, 455 microglial, 123, 196, 218
in cytokinesis, 65–66 renal corpuscles of, 437, 440–441, oligodendrocytes as, 191f, 195–196,
in cytoplasm, 43, 44t 440f–441f, 459t 195f
in eccrine sweat glands, 338 filtration in, 455 Schwann cells as. See Schwann cells.
in epithelial microvilli, 90–91 thin limbs of Henle’s loop of, 446f, Neurohormones, 203
Myosin II 447–448, 448t, 459t Neurohypophysis, 305f, 310–311, 311f
in cytoplasm, 43, 44t Nephrosis, lipoid, 445b Neuromodulators, 203
in smooth muscle, 181, 182 Nerve(s) Neuromuscular junctions, impulse
in thick filaments, 43 functional classification of, 206, 206t transmission at, 169–172, 169f–172f
of skeletal muscle, 161, 165–166, 165t regeneration of, 216–218 Neuron(s), 186–193
in vesicle formation, 31 Nerve bundle, 204, 205f axon of, 190–192, 191f, 192f
molecular structure of, 164f, 165 Nerve deafness, 536b defined, 186, 188f
Myosin light chain kinase, 182 Nerve impulses, generation and conduction hypothalamic, 306
Myosin phosphatase, 182 of, 198–204, 199f, 200f myelinated, 191, 191f, 192f, 196
Myosin V, in cytoplasm, 43, 44t Nerve supply in neuromuscular junction, 169,
Myostatin, 183 to alimentary tract, 382–383 171f
Myotendinous junctions, 168 to blood vessels, 253 of olfactory cell, 348
Myotubes, 157 to hair (neuroepithelial) cells, 528, 531f of parasympathetic nerves, 210
Myxedema, 316b to kidneys, 454 type Ib, 175
to lungs, 365 unmyelinated, 191, 192f, 197
N to skeletal muscle, 168–169, 207, 207f bipolar, 189f, 192–193
to smooth muscle, 182–183 in retina, 520f, 524
+
Na . See Sodium entries. Nervous system, 185–218 cell body (soma, perikaryon) of, 186,
Na+-K+-ATPase, 19, 428 autonomic (involuntary, visceral), 185, 186f, 187–190, 187f, 207, 210
Na+-K+ pump, 19, 198 207–210, 209f classification of, 187, 189f, 192–193
NADH dehydrogenase complex, 40 cells of, 186–198 cytoskeleton of, 189–190
NADPH oxidase, 228 neuroglial, 185, 193–197, 193f, 194f dendrites of, 186, 188f, 190, 190f
hereditary deficiency of, 228b neurons as, 186–193 inclusions in, 187, 189
Nail(s), 343–344, 343f, 344f central. See Central nervous system interneurons, 193, 211
Nail bed, 343, 344f (CNS). motor (efferent), 169, 189f, 193
Nail folds, 343, 344 development of, 185–186, 186b α-motor, 169, 173, 174f
Nail grooves, 344 enteric, 382–383 γ-motor, 173, 174f, 175b
Nail matrix, 343 ganglia of, 186, 187f, 208, 210, 211f multipolar, 189f, 193
Nail plate, 343 generation and conduction of nerve plasticity of, 218
Nail root, 343, 343f impulses in, 198–204, 199f, 200f postganglionic, 208, 209f, 210, 325
Naïve cells, 277, 281 neurotransmitters in, 18, 200, 201, preganglionic, 207–208, 209f, 210
Naris, 345 203–204, 204b, 204t Purkinje, 189f
Nasal cavity, 345, 346t, 347–350 parasympathetic, 208, 209f, 210, 508 pyramidal, 189f
anterior portion (vestibule) of, 345, 347 peripheral, 185, 204–206, 206t receptors for, 185, 200
disorders of, 347b, 350b regeneration of nerves in, 216–218 sensory (afferent), 169, 193
histophysiology of, 349–350 somatic, 185, 206–207, 207f structure and function of, 186–187,
mucosa of, 349, 350b sympathetic, 208, 209f, 509 186f–189f
olfactory region of, 346t, 347–349, 347f synapses in, 200–203, 201f, 202f, 524, 525 unipolar (pseudounipolar), 189f, 193
posterior aspect of, 347 tumors of, 192b Neuropeptides, 203, 204t
Nasal conchae, 345 Neural crest, in odontogenesis, 371 Neurophysin, 310, 311
Nasal vestibule, 345, 346t Neural crest cells, 185–186 Neuropil, 210, 212f
Nasolacrimal duct, 526 Neural groove, 185 Neurosecretory cells, hypothalamic, 305f,
Nasopharynx, 346t, 350 Neural plate, 185 306f
Natural killer (NK) cells, 232, 273, 275, Neural tube, 185 Neurosecretory hormones, hypothalamic,
275b, 283 Neural tunic. See Retina. 305–306
Natural T reg cells, 282 Neuro-reticular complex, 257f Neurotendinous spindles (Golgi tendon
Navicular fossa, 462 Neuroblastoma, 192b organs), 171–172, 175, 175b, 512f,
Nebulin, 164, 164f, 165t Neurocrine substances, of DNES cells, 391 514
Neck, of spermatozoon, 497f, 498 Neuroendocrine system, diffuse. See Neurotensin, 203, 392t
Necrosis, of functionalis layer of Diffuse neuroendocrine system Neurotoxin(s), 173b
endometrium, 479 (DNES) cells. eosinophil-derived, 229
Index ■ ■ ■ 561
Neurotransmitter(s), 203–204, 204t Norepinephrine (Continued) Odontoblastic process, 370, 374

binding to gated ion-channel receptors, release of Odontoblastic zone, 371
200 by blood vessels, 253 Odontoclasts, 370
disorders of, 204b by pinealocytes, 325 Odontogenesis, 371–374, 372f
excitatory and inhibitory, 18 by suprarenal medulla, 324 Odor receptor molecule, 350
groups and functions of, 203, 204t Norepinephrine receptors, on adipose cells, Olfactory bulb, 350
in synapse, 200 128 Olfactory cells, 347–348, 348f, 349f
in synaptic vesicles, 201 Nuclear bag fibers, 172, 174f Olfactory cilia, 347f, 348
Neurotransmitter-gated channels, 18 Nuclear basket, 51, 54f Olfactory epithelium, 347, 348f
Neurotrophins, 218 Nuclear chain fibers, 172, 174f Olfactory mucosa, 347f
Neutral proteases Nuclear envelope, 14f, 49–52, 51f, 52f Olfactory receptor cell, 348f, 350
in inflammatory response, 121 Nuclear export signals (NES), 52 Olfactory region, 346t, 347–349, 347f
in mast cells, 117, 121t Nuclear factor kappa B, receptor for Olfactory vesicle, 348, 348f
Neutrophil(s), 225–228 activation of (RANK), 140, 141 Oligodendrocytes, 191f, 195–196, 195f, 197
features of, 226t Nuclear factor kappa B ligand, receptor for Oligodendrogliomas, 192b
formation of, 239t, 240f, 243, 247f, 248t activation of (RANKL), 138, 140, 141 Oncogenes, 61, 66b
functions of, 125, 225, 227–228, 228f Nuclear lamina, 49 Oocytes
granules of, 225, 226t, 227f Nuclear lamins, 45, 46t primary, 464, 466, 466f, 467t
in innate immune system, 275 Nuclear layer secondary, 469
in phagocytosis, 32, 125, 227–228, 228f inner, of retina, 520f, 524–525 Oogonia, 463–464
margination of, 243 outer, of retina, 520f, 524 Open circulation theory, of spleen, 295, 295f
origin of, 112f Nuclear localization signals (NLS), 52 Opioid peptides, 203, 204t
structure of, 220f, 222f, 225, 227f Nuclear matrix, 60 Opsin, 522
Neutrophil chemotactic factor (NCF) Nuclear membrane, 49, 51f, 52f, 54f Opsonins, 279t
in inflammatory response, 121 Nuclear pore(s), 49–52, 51f–53f Opsonization, 297
mast cell release of, 117, 120f, 121t Nuclear pore complex, 50–52, 54f Optic disk, 520
Neutrophilic band, 248t Nuclear ring, 53–54, 54f Optic nerve, 515f
Neutrophilic metamyelocyte, 239t, 240f, Nuclear thyroid hormone receptor Optic nerve fiber layer, of retina, 520f, 525
248t proteins, 315 Ora serrata, 515f, 519
Neutrophilic myelocyte, 239t, 240f, 248t Nucleocytoplasmic shuttling (NS) signals, Oral cavity, 367–379
Neutrophilic stab cell, 239t, 240f, 248t 52 gingiva (gums) in, 368f, 369f, 376
Newborn, respiratory distress of, 361b Nucleolar matrix, 60 lips in, 367–368
Nexin, 91–92 Nucleolar-organizing regions (NORs), 60, oral mucosa in, 367
Nexus. See Gap junctions. 65 palate in, 376
Nicotinamide adenine dinucleotide Nucleolus, 14f, 15f, 49, 50f, 51f, 52f, teeth in, 368–376, 368f, 369f
(NADH), 40 60–61, 61b tongue in, 376–379, 377f
Nicotinamide adenine dinucleotide Nucleolus-associated chromatin, 60 Oral epithelium, in odontogenesis, 371, 372f
(NADH) dehydrogenase complex, 40 Nucleoplasm, 49, 60 Oral mucosa, 367, 376
Nidi of crystallization, 151 Nucleoplasmic ring, 53–54, 54f Orcein’s elastic stain, 3t
Nidogen, 73 Nucleoporins, 52 Organ(s), 11, 85
Niemann-Pick disease, 37t Nucleosomes, 52 Organ of Corti, 532f, 533, 533f, 535
Nipple, 486, 488 Nucleotide(s), 57–58 neuroepithelial cells of, 532f, 534
Nissl bodies, 13f, 187, 190f Nucleotide-gated channels, 18 supporting cells of, 532f, 533–534
Nitric oxide (NO) Nucleus(i) Organ system(s), 11
as neurotransmitter, 203 of cell, 15f, 49–68 Organelle(s), 11–41, 14f, 15f
in gas exchange, 363–364 chromatin in, 52, 55–61, 55f annulate lamella as, 41
in penile erection, 508, 510b of muscles, 180t cell membrane as, 11–22, 15f, 16f, 17f
in signaling, 20 of neuron, 187, 187f defined, 11
in vasodilation, 258 of smooth muscles, 180, 180t, 182f endoplasmic reticulum as. See
inhibition of platelet aggregation by, 233 of white matter, 210 Endoplasmic reticulum (ER).
Nociceptors, 511, 514 Nucleus pulposus, 135, 136b endosomes as, 30f, 33–35, 35f
Nodes of Ranvier, 188f, 195, 196, 197f, 206 Nuel, space of, 534 Golgi apparatus as, 14f, 15f, 27–32,
Non-snRNP splicing factors, 58 Null cells, 232 28f–30f, 71, 75, 77f
Nondisjunction, 68b Nurse cells, 241 lysosomes as, 14f, 35–36, 36f, 225, 233,
Nonmembranous structures, of nuclear Nutrition, and bone growth, 155, 155b, 236t
pore, 50 155t mitochondria as. See Mitochondria.
Nonpolar fatty acyl tails, in cell membrane, of cardiac muscle, 177–179
13, 16f O peroxisomes as, 36, 38f
Nonsteroidal anti-inflammatory drugs polyribosomes as, 24
(NSAIDs), and ulcers, 398b Obesity, 129b proteasomes as, 37, 283
Nontropical sprue, 406b Objective lens, 3, 4f ribosomes as, 22, 24–25
Norepinephrine Oblique section, 4f Orthochromatophilic erythroblast, 239t,
as neurotransmitter, 203, 204t Obstructive jaundice, 432b 240f, 245f, 246t
in autonomic nervous system, 208 Occluding junctions, 94 Orthogonal arrays of particles (OAPs), 101f
in blood pressure regulation, 312t Occludins, 94 Orthograde degeneration, 218
in fat release, 117 Ocular lens, 4f Orthokeratinization, of gingiva, 376
in smooth muscle synapses, 182 Oddi, sphincter of, 434, 434t Osmium tetroxide, as fixative, 9
production of, 318, 322, 324 Odontoblast(s), 370, 371, 373f, 374, 374f Osseous spiral lamina, 528, 532f
562 䡲䡲䡲 Index
Ossicles, 527, 527f, 535 Ovary(ies), 463–475, 464f Papillomaviruses, 335b

Ossification cortex of, 463–471, 465f, 466f Paracortex, of lymph nodes, 291f, 292, 292f
endochondral, 131, 147–150, 147f–150f, medulla of, 471 Paracrine signaling, 20, 104
148t Overlap regions, in tropocollagen, 74f, 77 Paracrine substances, of DNES cells, 391
intramembranous, 131, 146–147, 146f, Oviducts, 464f, 470, 474–475, 476f Parafollicular cells, of thyroid, 154, 313,
147f Ovoid cells, in hepatic ducts, 427 313f, 316
primary center of, 146, 148–149, 148t, Ovulation, 469–470 Paraformaldehyde, as fixative, 9
149f, 150f Ovum, 481 Parakeratinization, of gingiva, 376
secondary centers of, 147f, 148t, 149–150 Owen, lines of, 370 Parallel bundles, 43–44
zone of, 151 Oxidative phosphorylation, 37, 39f, 40–41 Paranasal sinuses, 350
Osteoblasts, 136, 138, 139f, 140 Oxygen exchange, 363–364 Parasympathetic fibers, postganglionic,
alkaline phosphatase in, 138b Oxyhemoglobin, 222, 363 209f, 210
factors in cell membrane of, 140 Oxyntic (parietal) cells, 386f, 387f, Parasympathetic (terminal) ganglia, 208
in bone calcification, 151 389–390, 390f Parasympathetic innervation
in endochondral bone formation, 148, Oxyphil cells, of parathyroid, 317, 317f of gut, 383
148t Oxytocin of lung, 365
in intramembranous bone formation, and milk ejection reflex, 184, 473t, 488 of salivary glands, 416
146, 146f and uterine contractions, 473t, 477 Parasympathetic nervous system, 208, 209f,
origins of, 112f as neurotransmitter, 203 210
Osteocalcin, 137 functions of, 307t, 311 in penile erection, 508
Osteoclast(s), 140–142 neurosecretion of, 310 Parathyroid glands, 316–317
bone resorption mechanism of, 142, 142f cellular organization of, 313f, 316–317
calcium ion level and, 154 P physiological effects of, 312t, 317
in endochondral bone formation, 148t Parathyroid hormone (PTH)
in phagocyte system, 123 P-face and bone, 142, 317
morphology, of, 112f, 138f, 140–142, of cell membrane, 14, 16f, 17f in blood calcium regulation, 154, 317
141f of microvillar membrane, 94, 99f physiological effect of, 312t, 317
Osteoclast-stimulating factor, 140, 154, 317 P-site, ribosomal, 22 synthesis of, 316
Osteocytes, 112f, 136, 136f, 137f, 138, Pacemaker (sinoatrial node), 267f, 268 Parathyroid hormone (PTH) receptors, on
139f, 140 Pachytene, 67, 495 osteoblasts, 140
Osteogenesis. See Bone(s), formation of. Pacinian corpuscles, 335, 512f, 513f, 514 Paratrabecular sinuses, of lymph node, 291
Osteoid, 138, 146f, 151 Pain fibers Paraventricular nuclei, 305f, 310
Osteomalacia, 155b, 155t of dental pulp, 371 Parenchyma, of gland, 103
Osteon(s), 144f, 145–146, 145f of periodontal ligament, 375 Parietal cells, 386f, 387f, 389–390, 390f, 397
Osteonectin, 73, 113, 138, 151 Pakoglobins, 99 Parietal layer, of Bowman’s capsule, 440,
Osteopontin, 137 Palate, 376 441f
Osteoporosis, 142b, 155b Palatine tonsils, 299, 377f Parietal pleura, 364
Osteoprogenitor cells, 136, 137f, 138, 147, Palatoglossal fold, 377f Parkinson’s disease, 204b
151, 152 Pale-staining fibrillar center, of nucleolus, Parotid gland, 416, 417b
Osteoprotegerin (OPG), 140, 141, 154 60 Pars ciliaris, of retina, 517
Osteoprotegerin ligand (OPGL), 140, 141, Palpebral conjunctiva, 525 Pars convoluta
154 Palpebral fissure, 525 of distal tubule, 439f, 446f, 448, 449,
Otic ganglion, 209f Pampiniform plexus of veins, 490 449f, 459t
Otitis media, 536b Pancreas, 417–422 of proximal tubule, 439f, 445–446, 446f
Otoconia, 529 disorders of, 420b, 422b, 423t Pars distalis, of pituitary gland, 305f,
Otolith(s), 529, 530f, 531f, 534 endocrine, 418f, 420–422, 420f, 421t, 306–310, 307t, 308f
Otolithic membrane, 529, 530f, 534 422b, 422f, 423t Pars fibrosa, of nucleolus, 60
Otosclerosis, 536b exocrine, 418–419, 418f, 419f Pars granulosa, of nucleolus, 60
Ouabain, inhibition of Na+-K+ pump by, 19 Pancreatic cancer, 420b Pars intermedia, of pituitary gland, 310
Outer dense fiber, of spermatozoon, 496, Pancreatic cholera, 422b Pars nervosa, of pituitary gland, 305f, 307t,
498 Pancreatic ducts, 418, 418f, 419 310–311, 311f
Outer leaflet, of cell membrane, 12, 13, Pancreatic lipase, 116 Pars recta
15f, 16, 16f Pancreatic polypeptide, 392t of distal tubule, 446f, 448, 449, 456, 457,
Outer membrane, mitochondrial, 38–39, 39f Pancreatic polypeptide (PP) cells, 420, 459t
Outer nuclear membrane, 49, 51f, 52f, 54f 421t, 422 of proximal tubule, 445, 446f, 447–448,
Outer table, of calvaria, 143, 147 Pancreatitis, acute, 420b 459t
Oval window, 527, 528, 528f, 535, 535f Pancreozymin, 419 Pars tuberalis, of pituitary gland, 310
Ovarian follicles, 463, 465–469, 465f, 467t Paneth cells, 401, 404f Passive transport, 17, 18f, 19
atretic, 471 Panniculus adiposus, 327 Pectinate line, 410
dominant, 474 Papanicolaou (Pap) smear, 478b Pedicels
graafian (mature), 465f, 467t, 469, 474 Papilla(e) of astrocytes, 194
primary, 465f, 466, 466f, 468 dental, 372, 373 of podocytes, 442, 443f, 445f
multilaminar, 465f, 466, 467t dermal, 327, 330f, 334, 336, 340 Peg cells, of oviduct, 475, 476f
unilaminar, 466, 467t duodenal (of Vater), 403, 419 Pelvis, renal, 437, 438f, 460
primordial, 465, 465f, 466, 466f, 467f, 467t lingual, 377–379, 377f, 378f Pemphigus vulgaris, 101b
secondary (antral), 465f, 467t, 468–469, renal, 437 Penicillar arteries, 294f, 295, 297f
468f, 469t Papillary collecting tubules, 437, 439, 451 Penile urethra, 462
Ovarian ligament, 464f Papillary layer, of dermis, 329t, 330f, 334 Penis, 489, 490f, 507–510, 507f
Index ■ ■ ■ 563
Pepsin, 385, 396 Phalangeal cells, of organ of Corti, 532f, Plasma, 219, 220, 221t
Pepsinogen, 384, 390, 396 533, 534 Plasma cells
Peptidyl transferase, 24 Phalangeal process, 534 in immune response, 232, 277, 280, 285
Perforins, 286, 286f Pharyngeal tonsil, 299, 301f, 350 in lymphoid nodules, 292
Periarterial lymphatic sheath (PALS), 294f, Pharyngoesophageal sphincter, 385 structure and function of, 124, 124f, 125f
295, 296 Phosphate group, in cell membrane, 13 Plasma fibronectin, 73
Periaxial space, 172 Phosphatidylglycerol, 360 Plasma lipoproteins, 221t
Peribiliary capillary plexus, 425 Phosphatidylinositol metabolites, 304 Plasma membrane. See Cell membrane.
Pericarditis, 269b Phosphocreatine, in muscle contraction, Plasma membrane enfoldings, in
Pericardium, 269 168 epithelium, 102
Pericellular capsule, of hyaline cartilage Phosphocreatine kinase, 168 Plasmalemma. See Cell membrane.
matrix, 134 Phosphodiesterase (PDE), 510b Plasmin, 236
Perichondrium Phosphogen energy system, 168 Plasminogen activators, 236
in cartilage, 131, 133t Phospholipase A Plasticity, neuronal, 218
in endochondral bone formation, 148, 148t in basophil function, 230 Platelet(s), 233–236
outer and inner layers of, 132 mast cell release of, 120 abnormalities of, 237b
structure of, 131, 132f Phospholipase C, 22 activation of, 233, 236
Perichromatin granules (PCGs), 60 Phospholipid(s), in cell membrane, 12 adhesion of, 233
Pericranium, 143 Phospholipid phosphatidylinositol aggregation of, 233–234, 235f
Pericytes bisphosphate (PIP2), 22 formation of, 237f, 246–247, 249f
in capillaries, 252, 260–261, 261f, 262f Photoreception, 521f, 522–525, 523f, 524f function of, 233–234, 235f, 236
in connective tissue, 113f, 115 Photosensory organs, 514 structure of, 220f, 222f, 233, 234f, 235f
in muscle, 184 Phrenic arteries, inferior, 318 tubules and granules of, 233, 233f, 234f,
in postcapillary venules, 265–266, 266f Pia-arachnoid, 213 236t
Perikaryon, 186, 186f, 187–190, 187f Pia-glial membrane, 194 Platelet-activating factor (PAF)
Perilymph, 528, 535 Pia mater, 212f, 213 in inflammatory response, 121
Perilymphatic space, 528 Pigment(s), in cytoplasm, 42 mast cell release of, 117, 121t
Perimysium, 158, 159f Pigment stones, 436b Platelet-derived growth factor (PDGF),
Perineurium, 205, 205f Pigmented epithelium 259b
Perinuclear cisterna, 49 of ciliary body, 517 Platelet factor 3, 234
Periodic acid-Schiff (PAS) reagent, 3t, 5 of retina, 520, 520f, 521 Pleats, of pharyngeal tonsil, 299
Periodontal ligament (PDL), 375, 375f Pillar cells, 532f, 533 Plectin, 45
dental pulp and, 371, 371f Pineal gland (pineal body), 312t, 324–325, Pleura, 364
scurvy effects on, 78b, 78f 324f Pleural cavities, 364
structure and function of, 368f, 369f, Pinealocytes, 324, 324f, 325 Plexiform layer, outer, of retina, 520f, 524
375, 375f Pinna (auricle), 526–527, 527f Plexus(es). See specific plexus, e.g.,
Periosteal bud, 147f, 149 Pinocytosis, 32, 33f Auerbach plexus.
Periosteal dura mater, 211 Pinocytotic vesicles, 32, 34f Plicae circulares, 398
Periosteocytic space, 140 in capillaries, 259–260, 263, 264f Ploidy, 56, 56f
Periosteum, 136, 143 Pit cells, 426 Pluripotential hemopoietic stem cells
Peripheral nervous system (PNS), 185, Pitch, of sound, 351 (PHSCs), 238, 239, 239t, 240b
204–206, 206t Pituicytes, 311, 311f Plus end
Peripheral proteins, in cell membrane, 13, Pituitary adenomas, 311b of microtubules, 29, 45, 47
14, 16f Pituitary gigantism, 154 of thin filaments, 42, 166
Peripheral receptors, specialized, 511–514 Pituitary gland, 304–311 Pneumocytes
Perisinusoidal space (of Disse), 426, 427f, adenohypophysis of, 304, 306–310 type I, 360, 360f
428f blood supply to, 304–306, 306f type II, 360–361, 361f, 362f
Peristalsis, 381, 383, 396, 405, 504 control of secretion of, 304, 306 Podacalyxin, 442
Peristaltic rush, 405b disorders of, 311b Podocytes, 440, 441f–444f, 450f
Peristaltic waves, 405 neurohypophysis of, 304, 305f, 310–311 Podoendin, 442
Peritricial nerve endings, 512, 512f pars distalis of, 305f, 306–310, 307t, 308f Polar body
Peritubular capillary network, 453 pars intermedia of, 310 first, 469
Perivascular glia limitans, 214 pars nervosa of, 305f, 307t, 310–311, second, 481
Perivitelline space, 480 311f Polar heads, in cell membrane, 13, 16f
Perlacan, 79 pars tuberalis of, 310 Polar microtubules, 64
Pernicious anemia, 389b structure of, 304, 305f, 306f Polar molecules, 20
Peroxisomes, 36, 38f Pituitary hormones, physiological effects of, Polarization, 198
Peyer’s patches, 299, 300f, 403 306, 307t Poliomyelitis, 364b
Phagocyte system, mononuclear, 123, 140, Placenta previa, 484b Polychromatophilic erythroblast, 239t, 240f,
196, 231 Placental barrier, 484 246t
Phagocytes, 32 Placental development, 482–484, 483f, 484f Polycystic kidney disease, 438b
Phagocytosis, 32 Placental septa, 484 Polycythemia, secondary, 241b
by Kupffer cells, 433 Plakins, 45 Polydipsia, 422b
eosinophils in, 228–230 Plaque(s) Polymerization, in microtubules, 46
macrophages in, 32, 231 anchoring, of lamina reticularis, 81f–83f disruption of, 46b
neutrophils in, 227–228, 228f attachment, of hemidesmosomes, 102, Polymorphonuclear leukocytes. See
of old erythrocytes, 297 103f Neutrophil(s).
Phagosomes, 32, 35, 227, 228f of urinary bladder, 461 Polypeptides, in hormones, 303
564 䡲䡲䡲 Index
Polyphagia, 422b Procentriole, 48 Prostate gland, 490f, 505–506, 505f, 506f

Polyphosphoinositide, 43 Procentriole organizers, 92 Prostate-specific antigen (PSA), 507b
Polyribosomes, 24, 25f Procollagen molecule, 75, 77, 77f, 78 Prostatic concretions, 506
Polysomes, 24, 25f Procollagen peptidases, 75, 77f Prostatic hypertrophy, benign, 507b
Polyspermy, 481 Proerythroblast, 240f, 241, 243f–245f, 246t Prostatic secretions, 506
Polyubiquinated protein, 37 Profilin, 42 Prostatic urethra, 462
Polyuria, 422b Progenitor cells, 238, 239t Proteases
Pompe’s disease, 37t, 41t Progesterone in inflammatory response, 121
Pore(s) and cervical glands, 478 in mast cells, 117, 121t
alveolar (of Kohn), 359f, 360 in female reproductive system, 473, 473t, Proteasomes, 37, 283
in capillaries, 262, 263 474, 478 Protein(s)
nuclear, 49–52, 51f–53f in follicular development, 468, 470 actin-binding, 43, 44t
sweat, 328f, 336 in lactation, 486 anchoring, 99
taste, 378, 378f, 379f in mammary gland development, 485 androgen-binding, 493, 499, 501f
Pore protein, 24, 26 in menstrual cycle, 478, 479f associated with skeletal muscle, 165t
Porins, 38 in placental development, 484 band 3, 221, 223, 224, 224f
Porta hepatis, 423 Programmed cell death, 68. See also band 4.1, 224, 224f
Portal areas (triads), 423–425, 424f, 425f Apoptosis. bone morphogenetic, 138, 373
Portal lobule, 425, 425f Proinsulin, 420 bone sialoprotein as, 137, 138, 151
Portal veins, 295, 423, 424f Projection lens, 4f C, 162, 165t
hypophyseal, 305, 306f Prolactin C-reactive, 259b
Postcapillary venules, 265–266, 266f in mammary gland development, 485 Cap Z, 164, 165t
of lymph nodes, 291f, 293 in milk production, 487, 488 capping, 43
Posterior chamber, of eye, 515f in pars distalis, 307t, 308 carrier, 17, 19–20
Postganglionic fibers synthesis of, 484 channel, 17–19
autonomic, 208 Prolactin inhibitory factor (PIF), 306, 307t, class II-associated invariant (CLIP), 283,
parasympathetic, 209f, 210 308, 473t 284
sympathetic, 208, 209f, 210, 325 Prolactin-releasing factor, 308, 310 clotting, 221t
Postsynaptic density, 201f Prolactin-releasing hormone (PRH), 306, cluster of differentiation (CD), 280, 281t
Postsynaptic membrane, 170, 200, 201f, 202 307t complement. See Complement proteins.
Postsynaptic potential, excitatory and Proliferation, zone of, 150 CRE-binding (CREB), 22
inhibitory, 200 Proliferative phase, of menstrual cycle, docking, 24, 26
Potassium (K+), in HCl production, 397 479–480 endogenous, 283
Potassium (K+) channels, voltage-gated, Proline eosinophilic cationic, 229
199 in collagen, 113 exogenous, 283
Potassium (K+) leak channels, 19, 198, 199f in elastin, 114 G
Potassium permanganate, as fixative, 9 tritiated, 5–6, 7f hormone-receptor complexes and, 304
Power stroke, 167, 168f Prometaphase, of cell cycle, 63f, 64, 64f receptors linked to, 21–22, 21f
Preacrosomal granules, 495 Promonocyte, 239t, 246 signaling via, 21–22, 21f
Preadipocytes, 129 Promyelocytes, 239t, 240, 248t types of, 21
Precapillary sphincter, 263, 264f Pronucleus glial fibrillary acidic, 45, 46t, 193
Precursor cells, 239, 239t, 240f female, 481 glycoproteins as. See Glycoprotein(s).
Precursor messenger RNA (pre-mRNA), male, 481 in blood, 220, 221t, 432, 432f
58 Pro-opiomelanocortin (POMC), 310 in cell membrane, 12–14, 16–19, 16f, 18f
Preganglionic fibers, 207–208, 209f, 210 Proparathyroid hormone, 317 in hormones, 303
Pregnancy Propeptides, 75, 77f integral (transmembrane), 13–14, 16f,
corpus luteum of, 470–471, 474 Prophase, of cell cycle 23–24
mammary glands during, 486–487 meiotic, 66f, 67 J, 279t
Rh-negative blood and, 225b in oocytes, 464, 466 link, 71
Preprocollagen, 75, 77f in spermatocytes, 494–495 lipoproteins as. See Lipoprotein(s).
Preproinsulin, 420 mitotic, 63–64, 64f lysosomal, transport of, 30–31, 31f
Preproparathyroid hormone, 317 Prophase II, of cell cycle, 67f, 68 major basic, 229
Prepuce, 508 Proplatelets, 247 mammary gland production of, 488
Presbyopia, 519b Proprioception, 175b membrane transport, 16–19, 18f
Presynaptic dense projection, 201f Proprioceptive fibers, of periodontal microtubule-associated, 47–48, 47f, 190
Presynaptic membrane, 170, 200, 201, 201f ligament, 375, 375b multipass, 14, 19
Presynaptic vesicles, 202f Proprioceptors, 511 nuclear thyroid hormone receptor, 315
Primitive streak, 481f Propulsive contractions, of small intestine, peripheral, 13, 14, 16f
Primordial follicles, 465, 465f, 466, 466f, 405 polyubiquinated, 37
467f, 467t Prostacyclins pore, 24, 26
Principal cells and clot formation, 233 rab3a, 201
of cortical collecting tubules, 451 capillary release of, 265 Ran-binding, 50, 52, 54f
of epididymis, 503 Prostaglandins regulated secretory, transport of, 30f, 31
of thyroid, 313, 313f, 314–316, 314f and uterine contractions, 477 ribosome receptor, 24
Principal piece, of spermatozoon, 496, in inflammatory response, 121 secretory, transport of, 30f, 31
497f, 498 inhibition of HCl release by, 397 signal recognition particle (SRP)
Principal salivary duct, 415 mast cell release of, 117, 120, 120f, 121t receptor, 24, 26
Prisms, in enamel, 369 placental manufacture of, 484 sorting of, 29–31, 30f
Index ■ ■ ■ 565
Protein(s) (Continued) Purkinje cells, 12f, 215, 216, 216f Receptor(s) (Continued)
surfactant, 360–361 Purkinje fibers, 267f, 268, 268f selectin, 227
Tamm-Horsfall, 449 Purkinje neuron, 189f sensory, 511
transmembrane, 14, 16f Pus, 125, 228 sensory nerve action potential (SNARE),
transmembrane linker, 81, 99, 102 Pyloric sphincter, 396 201
vesicle coat, 201 Pyloric valve, 385 signal recognition particle, 24, 26
Protein C3, 277b Pylorus, 385, 393, 393f, 394t specialized peripheral, 511–514
Protein kinase(s) Pyramid(s), renal, 437, 438f steroid hormone, 21
A-kinase, 22 Pyramidal cells, of cerebral cortex, 215 T-cell, 277, 280
C-kinase, 22 Pyramidal layer, of cerebral cortex, 215 thermoreceptors as, 511, 514
calcium-calmodulin-dependent (CaM- Pyramidal lobe, of thyroid, 313 toll-like, 275–276, 275t, 276b
kinase), 22 Pyramidal neurons, 189f transferrin, 214b
cyclin-dependent (CDKs), 63 Pyrimidines, 57 Receptor coupling factors, 120
in cell cycle, 62 Receptor for activation of nuclear factor
myosin light chain, 180 Q kappa B (RANK), 140, 141
phosphocreatine, 166 Receptor for activation of nuclear factor
Protein synthesis, 24–26, 25f–27f Quanta, 170–171 kappa B ligand (RANKL), 138, 140, 141
by smooth muscle, 179 Receptor-mediated endocytosis, 32–33, 34f
cytosolic, 24–25, 26f R Receptor-mediated transport
in liver, 429f, 430, 430f, 431–433, 432f in blood-brain barrier, 214
on rough endoplasmic reticulum, 25–27, rab3a protein, 201 in nuclear pore, 51
27f Radial spokes, of cilia, 91 Rectal columns of Morgagni, 410
Proteoglycans, in extracellular matrix, Radiation therapy, demyelination due to, Rectal examination, 410b
70–72, 70f, 72f 199b Rectum, 395t, 409–410
of bone, 137 Radioautography, 5–6, 7f, 8f Recycling endosome, 34
of cartilage, 131, 134 Ran binding protein(s), 50, 52, 54f Red blood cells (RBCs). See
of connective tissue, 111, 113 Ranvier, nodes of, 188f, 195, 196, 197f, 206 Erythrocyte(s).
Proteolysis, 37, 321 Rappaport, acinus of, 426 Red bone marrow, 236, 237b
Prothrombin, 234, 237b Raschkow plexus, 371 Red muscle fibers, 157, 158t
Proto-oncogenes, 61, 66b Rathke’s cysts, 310 Red pulp, of spleen, 291f, 294f, 295, 296,
Protofilaments, 46 Rathke’s pouch, 304 297f, 298f
Proton motive force, 40 Reaginic antibody, 279t 5α-Reductase, 501
Protoplasm, 11 Receptor(s) Reductional division (miosis I), 66–67, 66f
Protoplasmic astrocytes, 194, 194f B-cell, 277, 278 Reflex(es), somatic vs. visceral, 207f
Proximal tubule, 440f, 441f, 445–447, 446f, cargo, 32–33 Reflex arc, simple, 175b
447f, 459t catalytic, 304 Refractory period, of voltage-gated
convoluted, 439f, 445–446, 446f cell-surface, 20, 21–22, 21f, 303 channels, 17, 199
resorption in, 455 chemoreceptors as, 258 Regeneration
Pseudomembranous colitis, 408b enzyme-linked, 21 of liver, 433
Pseudostratified epithelium, 86t, 87f, εRI, on basophils, 230 of muscles, 180t, 183–184
89–90, 90f Fc of nerves, 216–218
Psoriasis, 335b of antibodies, 278 Regenerative cells
Pterygopalatine ganglion, 209f on basophils, 230 of colon, 407, 408f
Ptyalin, 416 on macrophages and neutrophils, 32 of small intestine, 399f, 401
Puberty, ovarian cortex at onset of, on mast cells, 118, 120f of stomach, 386f, 388
464–465 for acetylcholine, 171 Regulated secretory pathway
Pulmonary artery, 355f, 364–365 pancreatic, 419 of glands, 104
Pulmonary circuit, 251 for hormones, 303, 304 of Golgi apparatus, 30
Pulmonary neuroepithelial bodies, 353 for neurons, 185, 200 Regulated secretory proteins, transport of,
Pulmonary surfactant, 360–361, 361b G-protein-linked, 21–22, 21f 30f, 31
Pulmonary trunk, 253, 267 gated ion-channel, 200 Regulatory chains, of myosin, 182
Pulmonary veins, 267, 355f, 365 glucocorticoid, on adipose cells, 128 Regulatory component, of A-kinase, 22
Pulp growth hormone, on adipose cells, 128 Regulatory T cells, 232, 282–283
of spleen immunoglobulin E, 118, 120f, 230 Regurgitation theory, of endometriosis,
red, 291f, 294f, 295, 296, 297f, 298f insulin, 128 478b
white, 291f, 294f–296f, 295, 296 ion channel-linked, 18 Reinke, crystals of, 42, 498
of tooth, 369f, 371, 371b, 371f killer-activating, 275 Reissner’s membrane, 530, 532f, 533f
Pulp arteriole, 294f, 295 killer-inhibitory, 275 Relaxin, 473t, 474
Pulp chamber, 368 luteinizing hormone, 468, 473 Release factor, in protein synthesis, 25
Pulp cords, 294f, 295f mannose-6-phosphate, 31, 35 Releasing hormones (releasing factors), 306
Pulp core, 371 mechanoreceptors as, 332, 335, 511–514, Remodeling, of bone, 140, 151–152
Pulp stones (denticles), 371 512f, 513f Renal. See also Kidney(s).
Pulp veins, 295, 295f nociceptors as, 511, 514 Renal artery, 318, 438f, 452
Pupil (pupillary aperture), 517, 518 norepinephrine, 128 Renal column, 438f
dilator muscle of, 515f, 518 nuclear thyroid hormone, 315 Renal corpuscles, 437, 440–441, 440f–441f,
sphincter muscle of, 515f, 518 olfactory, 348f, 350 459t
Pupillary zone, 518 parathyroid hormone, 140 filtration in, 455
Purines, 57 ribosome, 24 Renal cortex, 437, 438f–439f, 440f
566 䡲䡲䡲 Index
Renal glomerulus, 262 Reticular fibers, 73, 76t, 82f RNA polymerase II, 57, 58
Renal interstitium, 452 in bone marrow, 236 Rod segments, in enamel, 369, 374
Renal medulla, 437, 438f–439f in connective tissue, 126 Rods, 520f, 521f, 522, 523f
Renal papilla, 437 in smooth muscle, 180 Root
Renal pelvis, 437, 438f, 460 in spleen, 294–295, 295f of lung, 364
Renal pyramids, 437, 438f Reticular layer, of dermis, 328f, 329t, of tongue, 377
Renal sinus, 437, 438f 334–335 of tooth, 368, 368f, 369f, 374
Renal vein, 438f, 454 Reticular tissue, 127, 128f Root canal, 368, 368f, 369f
Renin Reticulocyte, 239t, 240f, 246t Root sheath(s), of hair, 340, 341, 341f
in blood pressure regulation, 258 Reticuloendothelial system, 123 Rosettes, 41
in juxtaglomerular cells, 450 Reticulum Rough endoplasmic reticulum (RER). See
Rennin, 385, 396 of clot, 234 Endoplasmic reticulum (ER), rough
Reparative dentin, 370 stellate, in odontogenesis, 372 (RER).
Reproductive system. See Female Retina, 515f, 520–525 Round ligament, 464f
reproductive system; Male “blind spot” of, 520 Round window, 527, 528, 528f, 535f
reproductive system. detachment of, 521b Ruffini corpuscles (endings), 335, 512f, 514
Reserve cells, 493 external (outer) limiting membrane of, Ruffled border, of osteoclast, 141, 142f
Residual bodies, 35, 42 520f, 524 Rugae, 385
Resolution, of lens, 3 ganglion cell layer of, 520f, 525
Resorption inner limiting membrane of, 520f, 525 S
in proximal tubule, 455 inner nuclear layer of, 520f, 524–525
of bone, 142, 142f inner plexiform layer of, 520f, 525 S phase, of cell cycle, 61f, 62, 67
of periodontal ligament collagen, 375 optic nerve fiber layer of, 520f, 525 Saccule, 528f, 529, 530f, 531f
Respiration, 364 outer nuclear layer of, 520f, 524 Sacral (spinal) outflow, 383
external and internal, 345 outer plexiform layer of, 520f, 524 Saddle embolus, 237b
Respiratory bronchioles, 346t, 357, 358f pars ciliaris of, 517 Saliva, 415–416
Respiratory burst, 227 pigmented epithelium of, 520, 520f, 521 Salivary amylase, 367, 416
Respiratory chains, 40 rods and cones in, 521f, 522–524, 523f, Salivary glands, 413–417, 414f
Respiratory distress of the newborn, 361b 524f anatomy of, 413, 414f
Respiratory epithelium, 347 Retina proper, 520 autonomic innervation of, 416
tracheal, 352–353, 352f, 353f Retinal, in photoreception, 522 disorders of, 417b
Respiratory regulators, 353 Retrograde reaction, to nerve injury, 218 duct portions of, 414–415, 414f
Respiratory system, 345–365 Retrograde transport, 29 histophysiology of, 415–416
alveolar ducts in, 346t, 357, 357f–359f axonal, 191, 192 major, 367, 413–417
alveolar macrophages in, 359f, 361, 362f, Retroperitoneal area, 477 minor, 367, 415
363 Retzius, striae of, 369, 369f mixed, 104, 104f, 108f
alveoli in, 347t, 357, 358f, 359f, 360 RGD sequence, 72 parotid, 416, 417b
blood-gas barrier in, 360f, 363 Rh blood group, 225, 225b secretory portions of, 413–414, 414f
bronchi in, 346t, 354 Rh-negative blood, in pregnancy, 225b sublingual, 414f, 415f, 416–417
bronchial tree in, 346t, 354–357, 355f Rh-positive blood, 224 submandibular, 104, 104f, 417, 417b, 417f
bronchioles in, 346t, 355–357, 355f, 357f Rheumatic fever, 268b vascular supply to, 415
characteristic features of, 345, 346t–347t Rheumatic heart valve disease, 268b Salivon, 413
conducting portion of, 345–357, 346t Rhodopsin, 522 Saltatory conduction, 206
gas exchange in, 358f, 363–364 Rhythmicity, of cardiac muscle, 175 Sarcolemma, 157, 159f
gross structure of lungs in, 364–365 Ribonucleic acid (RNA), 57–60 Sarcoma(s)
innervation of, 365 messenger, 21, 24, 57–59, 58f liposarcoma as, 129b
interalveolar septum in, 357, 358f, 359f, precursor messenger, 58 malignant, 192b
360, 363 ribosomal, 22, 24, 59–60, 59f Sarcomere(s)
larynx in, 346t, 350–351 splicing of, 58 in cardiac muscle, 177, 180t
mechanism of ventilation in, 364 transfer, 22, 24, 59 in skeletal muscle, 160, 161f, 162, 162f,
nasal cavity in, 345, 346t, 347–350 Ribonucleoprotein particles (RNPs), 59 164f, 180t
nasopharynx in, 346t, 350 heterogeneous nuclear (hnRNPs), 58, 60 Sarcoplasm, 157, 159f
paranasal sinuses in, 350 messenger (mRNP), 58 Sarcoplasmic reticulum
pleural cavities in, 364 small nuclear (snRNPs), 58, 60 of cardiac muscle, 177–178, 180t
pneumocytes in, 360–361, 360f–362f Ribosomal RNA (rRNA), 22, 24, 59–60, 59f of skeletal muscle, 23, 157, 158t,
respiratory portion of, 346t, 357, 357f 45S rRNA (pre-rRNA), 59 160–161, 163f, 180t
trachea in, 346t, 351–354, 352f Ribosomal subunits, 22 of smooth muscle, 180t
vascular and lymphatic supply to, 355f, Ribosome(s) terminal cisternae of, 160, 162f, 167
364–365 in neurons, 190f Sarcosomes, 157
Resting potential, 171, 198, 199f protein synthesis on, 24–25 Satellite cells, 158–159, 183, 210, 211f
Rete apparatus structure and function of, 22 Satellite oligodendrocytes, 196
of lips, 368 Ribosome receptor protein, 24 Scaffold, of nuclear pore, 54f
of skin, 327 Ribozymes, 22 Scala media, 528f, 530, 532–534, 532f, 533f
Rete testis, 489, 490f, 501–502, 502t, 503f Rickets, 155, 155b, 155t, 318b Scala tympani, 530, 532f, 533f, 535
Reticular cells Rigor mortis, 167b Scala vestibuli, 530, 532f, 533f, 535
adventitial, of bone marrow, 237, 237b Rima glottidis, 351 Scaling zone, of osteoclast, 141
epithelial, 288–289 RNA. See Ribonucleic acid (RNA). Scanning electron microscopy (SEM), 4f,
stellate, of spleen, 296 RNA polymerase I, 59, 59f 9–10
Index ■ ■ ■ 567
Scar tissue, 75b Semicircular ducts, 528f, 529–530, 531f Sertoli cells, 491–493, 492f
Schlemm’s canal, 515f, 516 Semilunar valves, 268 Serum, 220
Schmidt-Lanterman, clefts of, 196–197 Seminal fluid, 507, 508–509 vs. cerebrospinal fluid, 215t
Schwann cells, 196–197, 197f, 198f fructose-rich, 505, 508 Sex chromatin, 55–56
in anterograde reaction, 217–218 Seminal vesicles, 489, 490f, 505, 505f Sex chromosomes, 55–56, 225
in endoneurium, 205f, 206 Seminiferous epithelium, 489, 491, 491f, Sexual development, phenotypic, 464
in myelinated nerve fiber, 170, 192f, 197, 492f Sharpey’s fibers
197f, 198f cycle of, 498, 499f in bone, 143, 144, 144f
in neuromuscular junction, 170, 171f Seminiferous tubules, 489, 490–498, in cementum, 370
in retrograde reaction, 218 490f–492f in periodontal ligament, 375
in unmyelinated nerve fiber, 192f, 197 differentiation of spermatogonia in, 492f, Sheath cells, 258
oligodendrocytes vs., 196, 197 493, 494f Sheathed arteriole, 294f, 295, 298f
Schwann tubes, 218 epithelium of, 489, 491, 491f, 492f Shock, anaphylactic, 230b
Sclera, 515–516, 515f cycle of, 498, 499f Sialoprotein, bone, 137, 138, 151
Sclerocorneal junction, 516 wave of, 498 Sickle cell anemia, 223b
Scrotum, 490b, 490f interstitial cells of Leydig in, 489, 498, Sieve plates, 426
Scurvy, 78b, 155b, 155t 500f Signal peptidase, 26, 27f
Sebaceous glands, 328f, 329, 334, 337f, meiotic division of spermatocytes in, Signal peptide, 25
338–339, 339b, 339f 492f, 493–495, 494f Signal recognition particle (SRP), 25–26,
Sebum, 339 Sertoli cells of, 491–493, 492f 27f
Second messenger system, 20, 22, 203, 304 spermatogenic cells of, 492f, 493–498, Signal recognition particle (SRP) receptor
Second polar body, 481 494f, 496f protein, 24, 26
Secondary active transport, 20 structure of spermatozoa in, 496–498, Signal transduction, 21, 303
Secondary bronchi, 346t, 354 497f pathways for, 61
Secondary (antral) follicles, 465f, 467t, transformation of spermatids in, Signaling
468–469, 468f, 469t 495–498, 496f, 497f autocrine, 20
Secondary response, 21 Senses, special, 511–536 endocrine, 20
Secretin, 390, 392t, 419 Sensitization, 118 paracrine, 20
Secretomotor function, 208 Sensory component synaptic, 20
Secretory activity, of small intestine, 383, of alimentary canal, 383 via G proteins, 21–22, 21f
404 of peripheral nervous system, 185, 206 Signaling cells
Secretory antibody, 279t Sensory endings, 173, 511 in cytoplasm, 20
Secretory component, of immunoglobulins, Sensory fibers, of dental pulp, 371 in glands, 104
279t, 404 Sensory ganglion, 186, 187f, 210 Signaling molecules, 20–21
Secretory endings, 511 Sensory nerve action potential-25 (SNAP- binding of, to proteoglycans, 72
Secretory granules 25), 201 cytokines as, 104
in cytoplasm, 14f, 15f, 30, 31 Sensory nerve action potential receptor mechanisms of action of, 20–21
in glands, 103 (SNARE), 201 neurotransmitters as, 203
in neurons, 189 Sensory nerve fibers receptors for, 14
in stomach, 387, 388f group Ia, 173, 174f secretion by osteoblasts, 140
pancreatic, 418f, 419, 419f group II, 173, 174f Sildenafil (Viagra), 510b
Secretory immunoglobulin A (IgA), 367, Sensory neurons, 169, 193 Silver stain, 3t
404, 416 Sensory receptors, 511 Simple diffusion, 17
Secretory pathway Septae, of glands, 107 Simple epithelium, 85, 86–87, 86t, 87f, 88f
constitutive Septal cells, 360–361, 361f, 362f Simple multicellular glands, 106, 107f
of glands, 104 Septum membranaceum, 269 Simple reflex arc, 175b
of Golgi apparatus, 30 Serine/threonine phosphoprotein Singlets, of microtubules, 91, 348
regulated phosphatases, 22 Sinoatrial node, 267f, 268
of glands, 104 Serosa Sinus(es)
of Golgi apparatus, 30 of alimentary canal, 382, 382f, 394t–395t anal, 410
Secretory phase, of menstrual cycle, 480, of colon, 395t, 409 carotid, 257
480f of esophagus, 384–385, 394t lactiferous, 486, 486f
Secretory portion of large intestine, 395t marginal, of spleen, 294f, 295f, 296
of pancreas, 418–419, 419f of oviducts, 475 of lymph nodes, 291, 291f, 292f
of salivary glands, 413–414, 414f of small intestine, 394t–395t, 402 paranasal, 350
Secretory proteins, transport of, 30f, 31 of stomach, 394t, 396 renal, 437, 438f
Secretory unit, of eccrine sweat glands, uterine, 477 splenic, 294f, 296, 298f
336f, 337–338 Serotonin, 203, 204t, 392t Sinusoid(s)
Sectioning, in tissue preparation, 2 Serous acinus(i), of salivary gland, 108f, hepatic, 424f, 425, 426, 426f, 427f
Segmental arteries, of kidney, 452 413, 414f of bone marrow, 236
Selectin molecules, 227, 265, 292 Serous cell(s) of organs and glands, 263
Selectin receptors, 227 of esophagus, 384 Sinusoidal (discontinuous) capillaries, 259,
Self-antigens, 289 of respiratory epithelium, 353 262f, 263
Self-epitopes, 290 of salivary gland, 108f, 413, 414f Sinusoidal domains, of hepatocytes, 427f,
Self-MHC molecules, 290 Serous demilunes, 104, 104f 428, 428f
Self/nonself recognition, 276 of salivary gland, 108f, 414f, 416, 417 Sinusoidal lining cells, 426, 427f
Semen, 489, 507, 508 Serous glands, 104, 104f, 377f, 378, 378f Sister chromatids, 63, 63f, 64–65
Semicircular canals, 527f, 528, 528f Serous secretion, of parotid gland, 416 Skeletal muscles. See Muscle(s), skeletal.
568 䡲䡲䡲 Index
Skin, 327–339. See also Integument. Smooth endoplasmic reticulum (SER). See Spermiogenesis, 493, 495–498, 496f, 497f
dermis (corium) of, 327, 334–335 Endoplasmic reticulum (ER), smooth Spherocytosis, hereditary, 224b
epidermis of. See Epidermis. (SER). Sphincter ampullae, 434, 434t
functions of, 327 Smooth muscle. See Muscle(s), smooth. Sphincter choledochus, 434, 434t
glands of, 327, 336–339 Smooth muscle cells, in dermis, 335 Sphincter muscles
histophysiology of, 336 Sneeze reflex, 350b anal, 410
hypodermis of, 327, 328f, 334 Sodium (Na+) channels esophageal, 385
structure of, 327, 328f, 329t fast, 178 of gastrointestinal system, 383
thick, 328–329, 328f, 329t, 330f slow, 178 of pupil, 515f, 518
thin, 328f, 329 voltage-gated, 199, 200f of urethra, 462, 462b
Skull base, 147 Sodium ion, as second messenger, 304 of urinary bladder, 462
Skull cap, 143 Sodium-potassium (Na+-K+) pump, 19, 198 Sphincter of Oddi, 434, 434t
Sliding filament theory of Huxley, 162, Sodium pumps, in proximal tubules, 455 Sphincter pancreaticus, 434, 434t
167 Soft palate, 376 Sphingolipidosis, 37t
Slipped disk, 136b Soluble mucus, 396 Spicules, 138f, 143, 146
Slit diaphragm, 442, 443f, 445f Soma, neuronal, 186, 186f, 187–190, 187f Spike trigger zone, 191, 198
Slow-reacting substance of anaphylaxis Somatic afferent pathways, 511 Spina bifida, 186b
(SRS-A), 230 Somatic nervous system, 185, 206–207, 207f Spinal cord
Small-granule mucous cells, 352f, 353 Somatic reflex, 207f cerebrospinal fluid in, 214–215, 215b, 215t
Small intestine, 398–406 Somatomammotropin, chorionic, 484 demyelination disorders of, 199b
absorption by, 405–406, 407f Somatomedins, 308 development of, 185–186
Auerbach’s myenteric plexus of, 402 Somatostatin gray matter of, 211
Brunner’s glands of, 401–402, 401f, 403 as neurotransmitter, 203 meninges of, 211, 212f, 213b
brush border of, 399 in pars distalis, 307t, 308 regeneration of, 218
crypts of Lieberkühn of, 398, 399f, inhibition of HCl production by, 397 Spinal dura mater, 213
400–401, 400f, 404f production of, 392t, 421, 421t Spinal nerves, 206
digestion by, 405 Somatotrophs, 308, 309f Spindle fibers, 64
disorders of, 403b, 405b Somatotropin Spine(s), of dendrites, 190
DNES (enteroendocrine) cells and and mammary gland development, 485 Spiral cells, 532f
hormones in, 392t, 400, 404 effect on cartilage, 135t Spiral ganglion, 528, 532f, 533f
epithelium of, 394t–395t, 398–400 excess of, acromegaly due to, 154b Spiral lamina
glands of, 394t–395t, 404 in bone growth, 154 limbus of, 533
goblet cells of, 399–401, 399f, 401f in T-cell development, 290 osseous, 528, 532f
histology of, 394t–395t, 398–403 physiologic effects of, 307t Spiral prominence, of cochlear duct,
histophysiology of, 403–406 receptors for, on adipose cells, 128 532–533, 532f
immunological activity of, 394t, 403–404, secretion by acidophils, 308 Spiral sulcus, internal, 533
405f, 406f Somatotropin-releasing hormone (SRH), Splanchnic nerves, preganglionic
lacteals of, 398, 402 306, 307t, 308 sympathetic, 322
lamina propria of, 394t–395t, 400, 400f, Sonic hedgehog, 373 Spleen, 293–298, 294f, 295f
401f, 403f Space of Disse, 426, 427f, 428f histophysiology of, 297–298, 299f
luminal surface of, 398, 398f–401f Space of Möll, 424 marginal zone of, 294f, 295f, 296, 297f
lymphatic and vascular supply of, Space of Nuel, 534 red pulp of, 294f, 295, 296, 298f
402–403 Specific granules rupture of, 298b
lymphoid nodules of, 399f of basophils, 226t, 230 structure of, 294–295, 294f, 295f
microfold (M) cells of, 400, 404, 405f, of eosinophils, 226t, 229 vascular supply of, 294f, 295, 295f
406f of neutrophils, 225, 226t white pulp of, 294f–296f, 295, 296
microvilli of, 398, 399 Specificity Splenic artery, 295
movement of, 405 of adaptive immune system, 276 Splenic cords, 296, 298f
mucosa of, 398–402 of antibodies, 278 Splenic phase, of prenatal hemopoiesis, 238
muscularis externa of, 394t–395t, 402 Spectrin, 44, 44t Splenic sinuses, 294f, 296, 298f
muscularis mucosae of, 394t–395t, 401, Spectrin tetramers, in erythrocyte cell Splenic vein, 295
403f membrane, 224, 224f Spliceosomes, 58
Paneth cells of, 401, 404f Spermatic cord, 490 Spongiocytes, 321
Peyer’s patches in, 403 Spermatids, 493, 494f Spongiosa, of dental alveolus, 375
plicae circulares (valves of Kerckring) of, transformation of, 495–498, 496f, 497f Spongy bone, 143, 144f
398 Spermatocytes, 492f, 493–495, 494f Spongy urethra, 462
regenerative cells of, 399f, 401 Spermatocytogenesis, 493 Sprue, 406b
regional difference in, 403 Spermatogenesis, 493, 494f, 495–498, 496f, Squames, 331
secretory activity of, 404 497f Squamous alveolar cells, 360, 360f
serosa (adventitia) of, 394t–395t, 402 cycle of, 498, 499f Squamous cell carcinoma, 335b
submucosa of, 394t–395t, 401–402, Spermatogenic cells, 492f, 493–498, 494f, Squamous epithelium
401f 496f of thin limbs of Henle’s loop, 448t
surface absorptive cells of, 398–400, Spermatogonia, 492f, 493, 494f simple, 86, 86t, 87f
399f, 401f, 402f Spermatozoa, 493 stratified
villi of, 398, 398f–401f capacitation of, 475, 496, 502 ectodermally-derived, 327
Small-molecule transmitters, 203, 204t defined, 489 keratinized, 86t, 87f, 88, 89f
Small nuclear ribonucleoprotein particles structure of, 496–498, 497f nonkeratinized, 86t, 87–88, 87f, 89f
(snRNPs), 58, 60 Spermiation, 496 of oral cavity, 367
Index ■ ■ ■ 569
Squamous metaplasia, 102b Stone(s) Submucosal lymphatic plexus, 403

Stab cell, 239t, 240f, 248t in gallbladder, 436b Submucosal (Meissner’s) plexus
Stable phase, of cell cycle, 61 pigment, 436b of digestive tract, 381, 383, 401
Staining, 2, 3t pulp (denticles), 371 of parasympathetic nervous system,
Stapedius, 527 Stool, fatty, 430b 210
Stapes, 527, 527f, 535 Stop codons, 25, 57 Submucosal vascular plexus, 403
Start codon, 24, 57, 58 Straight arteries, of endometrium, 476, Subosteoclastic compartment, 141
Steel factor, 241, 242t 477f Subperiosteal bone collar, 147f, 148–149,
Stellate cells Stratified epithelium, 85–86, 86t, 87–88, 148t
of cerebral cortex, 215 87f, 89f Substance P, 203, 392t
of liver, 426, 433 Stratum basale, 328, 328f, 329–330, 329t, Succedaneous lamina, 373
Stellate reticular cells 330f, 335b Succedaneous teeth, 368, 373
of lymph nodes, 291 Stratum corneum, 328, 328f, 329t, 331 Sulci, 215
of spleen, 296 Stratum germinativum, 328, 328f, 329–330, Sulcus terminalis, of tongue, 376
Stellate reticulum, in odontogenesis, 372 329t, 330f Superficial fascia, 327
Stellate veins, of kidney, 453 Stratum granulosum, 328, 328f, 329t, Superoxides, 227–228, 229
Stem, of goblet cell, 352 330–331 Supporting cells
Stem cell(s), 238–239, 239t, 240b Stratum intermedium, in odontogenesis, of saccule and utricle, 529, 531f
null cells as, 232 373 of semicircular ducts, 530, 531f
of colon, 407, 408f Stratum lucidum, 328, 328f, 329t, 331 Supraoptic nuclei, 305f, 310
of small intestine, 399f, 401 Stratum spinosum, 328, 328f, 329t, 330, Suprarenal arteries, 318
of stomach, 386, 386f, 388 330f, 331f Suprarenal (adrenal) glands, 312t, 317–324,
Stem cell factor, 241, 242t Stratum vasculare, of myometrium, 477 319f
Stereocilia Stress fibers, 44 blood supply to, 318, 320f
function of, 91 Stretch reflex, 172 cortex of, 312t, 318–320, 319f, 321–322,
of epididymis, 503 Stria vascularis, 532, 532f 321f
of mechanically gated channels, 19 Striae of Retzius, 369, 369f disorders of, 322b
of neuroepithelial hair cells, 529, 531f, 534 Striated anchoring fibers (SAFs), 103f medulla of, 312t, 318, 322–324, 322f
Sterility, 508b Striated border, 90 structure of, 317–318, 319f
Sterilization, 504b Striated ducts zona fasciculata of, 320–321, 321f
Steroid hormone(s) defined, 102 zona glomerulosa of, 319f, 320, 321f
composition of, 303 of salivary gland, 414, 414f zona reticularis of, 319f, 321–322
in cell signaling, 20, 21 Striated muscle, 157, 158f Surface absorptive cells
production of, by suprarenal glands, Stroma of colon, 407, 408f
312t, 318, 320–322 of cornea, 516 of small intestine, 398–400, 399f, 401f,
Steroid hormone receptors, 21 of gland, 103 402f
Stigma, of oocyte, 469 of kidney, 439 Surface immunoglobulins (SIGs), 277,
Stimulus transmission, at neuromuscular of ovarian cortex, 463 279t
junctions, 170–171, 172f of prostate gland, 506 Surface lining cells, of stomach, 386,
Stomach, 385–397. See also Gastric entries. Stromal cells 386f–388f
body (corpus) of, 385 endometrial, 482 Surface-opening tubules, of platelets, 233,
carcinoma of, 398b ovarian, 463, 468 233f, 234f, 236t
cardiac, 385, 393, 394t Subarachnoid space, 212f, 213 Surface remodeling, 152
chief (zymogenic) cells of, 386f, 387f, Subcapsular epithelium, 518, 518f Surfactant, 360–361, 361b
390, 391f Subcapsular plexus, 318 Surfactant apoproteins, 360–361
diffuse neuroendocrine system cells of, Subcapsular sinus, of lymph nodes, 291, Suspensory ligaments, of lens, 515f, 517
386f, 390–391, 392t, 393f 291f, 292f Sustentacular cells, of nasal cavity, 348,
disorders of, 398b Subdural space, 212f, 213 348f
emptying of contents of, 396 Subendocardial layer, 268 Sweat glands, 336–338
epithelium of, 386–387, 387f, 388f, 394t Subendothelial layer, of blood vessels, 252, apocrine, 338
fundic, 386–393, 386f, 394t 252f eccrine, 328f, 336–338, 336f, 337f
glands of, 385, 386f, 387–393, 388t, 394t Sublingual gland, 104, 414f, 415f, 416–417 Sweat pore, 328f, 336
histology of, 385–396, 386f, 394t Sublobular vein, of liver, 425 Swell bodies, 350b
histophysiology of, 396–397 Submandibular ganglion, 209f Symbiotic relationship, 40
hydrochloric acid production by, Submandibular gland, 104, 104f, 417, 417b, Symmetric synapse, 202–203
396–397, 397f 417f Sympathetic cells, of suprarenal gland,
lamina propria of, 387–393, 394t Submucosa 322
mucosa of, 386–393, 386f of alimentary canal, 381–382, 382f, Sympathetic chain ganglia, 210
mucous neck cells of, 387–388, 389f 394t–395t Sympathetic fibers, postganglionic, 208,
muscularis externa of, 393, 394t, 396 of anal canal, 410 209f, 210
muscularis mucosae of, 391, 393, 394t of colon, 408f Sympathetic innervation
parietal (oxyntic) cells of, 386f, 387f, of esophagus, 384, 394t of dental pulp, 371
389–390, 390f of large intestine, 395t of gut, 383
pyloric, 385, 393, 393f, 394t of small intestine, 394t–395t, 401–402, of lung, 365
regenerative (stem) cells of, 386f, 388 401f of salivary glands, 416
serosa (adventitia) of, 394t, 396 of stomach, 386f, 393, 394t, 396 Sympathetic nervous system, 208, 209f
submucosa of, 393, 394t, 396 of trachea, 351–353, 352f in ejaculation, 509
surface lining cells of, 386, 386f–388f Submucosal glands, of prostate, 506 Sympathetic postganglionic fibers, 325
570 䡲䡲䡲 Index
Symport transport, 18f, 19 T memory cells, 232, 281 Testis(es) (Continued)

Synamin, 45 T regulatory cells, 232, 282–283 seminiferous tubules of, 489, 490–498,
Synapse(s), 200–203, 201f, 202f T (transverse) tubules 490f–492f
asymmetric, 202 of cardiac muscle, 177–178, 180t Sertoli cells of, 491–493, 492f
axoaxonic, 200 of skeletal muscle, 160, 163f, 180t spermatogenic cells of, 492f, 493–498,
axodendritic, 200, 201f–203f, 212f Tactile discrimination, 513 494f, 496f
retinal, 524, 525 Taeniae coli, 409 structure of spermatozoa in, 496–498,
axosomatic, 200, 201f Tail, of spermatozoon, 497–498, 497f 497f
chemical, 200 Talin, 44, 45f transformation of spermatids in,
dendrodendritic, 200 Tamm-Horsfall protein, 449 495–498, 496f, 497f
electrical, 200 Tanycytes, 196 vascular supply to, 489–490
en passant, 182 Target cells Testosterone
morphology of, 201–203, 203f in cytoplasm, 20 effect on cartilage, 135t
symmetric, 202–203 of glands, 104 in male reproductive system, 489, 498,
Synapsin-I, 201 of hormones, 303 499, 500–501, 501f
Synapsin-II, 201 Tarsal plates, 525 Tetany, 290b, 318b
Synaptic clefts, 200, 201f, 202 Tastants, 378 Tetrads, of spermatocytes, 495
primary, 170 Taste buds, 367, 377, 378–379, 378f, 379f TH0 cells, 282
secondary, 170 Taste hairs, 378 TH1 cells, 282, 285–287, 286f, 287f
Synaptic ribbon(s) Taste pore, 378, 378f, 379f TH2 cells, 282, 285, 285f
in pinealocytes, 325 Tay-Sachs disease, 36, 37t TH3 cells, 283
in retina, 524, 525 Tear(s), 526 Thalassemia, 223b
in saccule and utricle, 529 Tear film, 525 Theca, of goblet cell, 104f, 105, 352
Synaptic signaling, 20 Tectorial membrane, 18, 532f, 533 Theca externa, 465f, 467t, 468
Synaptic vesicles, 170, 182 Teeth. See Tooth (teeth). Theca folliculi, 465f
morphology of, 201, 201f, 203f Telogen phase, of hair growth, 342 Theca interna, 465f, 467t, 468, 470
Synaptobrevin, 201 Telophase, of cell cycle Theca-lutein cells, 465f, 470
Synaptonemal complex, 67 meiotic, 66f, 67 Thermogenins, 40, 129
Synaptophysin, 201 in spermatocytes, 495 Thermoreceptors, 511, 514
Synaptotagmin, 201 mitotic, 64f, 65–66, 65f Thick filaments
Synarthrosis(es), 156 Telophase II, of cell cycle, 67f, 68 of cytoskeleton, 43
Synchondrosis, 156 Tenascin, 73 of skeletal muscle, 157, 161, 162, 164f,
Syncytiotrophoblasts, 482, 484 Tenon, capsule of, 516 165–166, 166f
Syncytium, of spermatids, 495 Tensor tympani, 527 of smooth muscle, 181
Syndecans, 72 Terminal arbor, 190 Thick skin, 328–329, 328f, 329t, 330f
Syndesmosis, 156 Terminal arterial capillaries, of spleen, Thin filaments
Synostosis, 156 294f, 295 of cardiac muscle, 177
Synovial fluid, 156 Terminal arterioles, 263 of cytoskeleton, 14f, 42–44, 43f–45f,
Synovial membrane, 156, 156f Terminal bars, 94 44t
Synthetic phase, 61f, 62, 67 Terminal boutons, 187, 201 of neuron, 189–190
Systemic circuit, 251 Terminal bronchioles, 346t, 356–357 of skeletal muscle, 161–162, 164, 164f,
Systole, 258 Terminal cisternae, of sarcoplasmic 166–167, 166f
reticulum, 160, 162f, 167 of smooth muscle, 181
T Terminal duct, salivary, 414 Thin skin, 328f, 329
Terminal ductules, of mammary gland, 485 Thiocyanate ions, 416
T-cell receptor(s) (TCRs), 277, 280 Terminal ganglia, 208, 210 Thoracic duct, 271
T-cell receptor complex, 280, 281t Terminal glycosylation, 30f Thoracolumbar outflow, 208
T helper cells Terminal hairs, 339 Thoroughfare channel, 263, 264f
functions of, 232, 282 Terminal signal complex, 26f Thrombin, 234
in humoral immune response, 285, 285f Terminal web, 44, 90, 93f Thrombocytopenia, 237b
in killing of virally transformed cells, Territorial matrix, of hyaline cartilage, 132f, Thromboembolism, 237b
285–286, 286f 134 Thrombomodulin, and clot formation, 233
in macrophage killing of bacteria, Tertiary bronchi, 346t, 354 Thromboplastids. See Platelet(s).
286–287, 287f Tertiary granules, of neutrophils, 225 Thromboplastin, in clot formation, 233
types of, 282 Testicular artery, 489 Thrombopoietin, 241, 242t
T killer cells, 232, 283 Testicular lobules, 490f Thrombospondin, 233
T lymphoblast, 239t Testicular transferrin, 493 Thromboxane(s)
T lymphocytes (T cells), 231–232, 280–283, Testis(es), 489–498, 490f in clot formation, 234
281t cycle of seminiferous epithelium in, 498, in inflammatory response, 121
cytotoxic, 232, 275, 282, 285–286, 286f 499f mast cell release of, 117, 120, 120f, 121t
effector, 232, 281–283 differentiation of spermatogonia in, 492f, Thrombus, 234, 235f
features of, 226t 493, 494f Thymic corpuscles, 289, 289f
formation of, 239t, 247, 249, 280 general structure of, 489–490, 490f Thymic humoral factor, 290
functions of, 231–232 histophysiology of, 498–501, 500f, 501f Thymic-independent antigens, 280
in thymus, 288, 288f interstitial cells of Leydig in, 489, 498, Thymocytes, 288
surface markers on, 280, 281t 500f Thymopoietin, 290
types of, 281–283 meiotic division of spermatocytes in, Thymosin, 42, 44t, 290
vs. B cells, 280 492f, 493–495, 494f Thymulin, 290
Index ■ ■ ■ 571
Thymus, 287–290, 288f Tooth (teeth), 368–376, 368f, 369f Transport (Continued)
congenital disorder of, 290b accessional (molars), 368, 373 along constitutive pathway, 31
cortex of, 288–289, 288f, 289f alveolus of, 368, 368f, 369f, 375–376 anterograde, 29, 31
histophysiology of, 290 cementum of, 368f, 369f, 370, 370f, 374 axonal, 191, 192
involution of, 288 cervix of, 368, 369f antiport, 18f, 19
medulla of, 288f, 289, 289f crown of, 368, 368f, 369f coupled, 18f, 19, 20
T lymphocytes in, 232 deciduous (milk), 368, 373 of lysosomal proteins, 30–31, 31f
vascular supply to, 290 dentin of, 368f, 369–370, 369f, 370f of regulated secretory proteins, 30f,
Thyrocalcitonin, 312t, 316 development of, 371–374, 372f 31
Thyroglobulin, 313, 314, 315f disorders of, 369b, 370b, 371b passive, 17, 18f, 19
Thyroid follicle, 313, 313f enamel of, 368–369, 368f, 369f, 374 receptor-mediated, 51, 214
Thyroid gland, 311–316 gingiva (gums) of, 368, 368f, 376 retrograde, 29
cellular organization of, 313–316, 313f mineralized components of, 368–370 axonal, 191, 192
disorders of, 316b periodontal ligament of, 368, 368f, 369f, symport, 18f, 19
hormones of. See Thyroid hormone(s). 371, 371f, 375, 375f uniport, 18f, 19
structure of, 313, 313f pulp of, 369f, 371, 371b, 371f via membrane transport proteins, 16–19,
Thyroid hormone(s) root canal of, 368, 368f, 369f 18f
and thyrotrophs, 309 root of, 368, 368f, 369f, 374 via nuclear pore, 51–52, 54f
functions of, 311, 312t structures associated with, 374–376 Transport vesicles, 26, 28–29
physiological effects of, 315 succedaneous, 368, 373 Transporter, in nuclear pore complex, 50
release of, 315 Tooth germ, 373 Transverse (T) tubules
synthesis of, 314–315, 315f Toxins, detoxification of, in liver, 433 of cardiac muscle, 177–178, 180t
Thyroid hormone receptor proteins, Trabeculae of skeletal muscle, 160, 163f, 180t
nuclear, 315 arachnoid, 213 Triad(s)
Thyroid peroxidase, 314 bony, 143, 146, 146f, 147, 147f in retina, 524
Thyroid-stimulating hormone (TSH), 307t, of lymph node, 291, 291f in skeletal muscle, 160, 162f, 163f
309, 311, 312t, 315 of spleen, 294, 294f, 295, 295f Tricarboxylic acid cycle, 40
Thyroid-stimulating hormone-releasing Trabecular arteries, 294f, 295 Trichohyalin granules, 341
hormone (TRH), 306, 307t, 309 Trabecular meshwork, of scleral sulcus, 516 Tricuspid valve, 267
Thyroidectomy, 316b Trabecular veins, 295f Triglycerides
Thyrotroph(s), 309 Trachea, 346, 351–354, 352f absorption and processing of, 406,
Thyrotropin, 309 adventitia of, 351f, 352f, 354 407f
chorionic, 484 mucosa of, 351–353, 352f digestion of, 116, 117, 119f
Thyrotropin-releasing hormone, 203 submucosa of, 352f, 353 in cytoplasm, 41
Thyroxine (T4) trans Golgi network, 27–28, 28f Trigone, 461
and thyrotrophs, 309 collagen synthesis in, 75, 77f Trigonum fibrosum, 269
effect on cartilage, 135t in spermiogenesis, 495 Triidothyronine (T3)
functions of, 311, 312t sorting in, 29–31, 30f and thyrotrophs, 309
in colloid, 313 transport vesicles in, 29, 264f functions of, 311, 312t
physiological effects of, 315 Transcription, 21, 24, 57–59, 58f in colloid, 313
release of, 315 Transcription factors, 62 physiological effects of, 315
synthesis of, 314–315, 315f Transcytosis, 34, 264–265, 264f, 404 release of, 315
thymulin production and, 290 Transducin, in photoreception, 522 synthesis of, 314–315, 315f
Tight junction(s), 94, 97f–99f Transduction, 21, 61, 303 Trisomy, 68b
of capillaries, 260 Transfer RNA (tRNA), 22, 24, 59 Trisomy 21, 56b, 68b
Tight junction strands, 94, 99f Transfer vesicles, 27, 28f Tritium (3H), in autoradiography, 5–6, 7f
Tingible body macrophages, 289 Transferrin, 297 Trophic influence, 218
Tissue(s) Transferrin receptors, 214b Trophic relationships, axonal, 191
defined, 11, 71 Transforming growth factor (TGF), 336 Trophoblasts, 481f, 482
types of, 11, 69, 85 Transforming growth factor-β (TGFβ), 138, Tropocollagen molecules, 74f, 75–77, 77f,
Tissue fluid flow, 69, 70f 154 78b, 113
Tissue preparation, for light microscopy, Transient cells, of connective tissue, Tropomodulin, in skeletal muscle, 164,
1–2, 3t 124–125, 124f, 125f 164f, 165t
Tissue thromboplastin, in clot formation, Transitional endoplasmic reticulum (TER), Tropomyosin
233 27, 30f in skeletal muscle, 164f, 165t, 167
Titin, 162, 164, 165t Transitional epithelium, 86t, 87f, 88, 89f in smooth muscle, 181
Tolerance Translation, 24–26, 25f–27f Troponin
drug, 433b Transmembrane linker proteins, 81, 99, in skeletal muscle, 164f, 165t, 167
immunological, 277 102 in smooth muscle, 181
Toll-like receptors, 275–276, 275t, 276b Transmembrane proteins, 14, 16f Trypsin inhibitor, 419
Toluidine blue stain, 2 Transmission electron microscopy (TEM), Tubular glands, 107, 107f
Tomes’ process, 374 4f, 7–9 of endometrium, 476, 477f, 480
Tongue, 376–379, 377f Transneuronal degeneration, 218 simple coiled, 336
papillae in, 377–379, 377f, 378f Transport Tubular myelin, 361
taste buds in, 378–379, 378f, 379f active, 17, 18f, 19 Tubule(s). See also Microtubule(s).
Tonofibrils, 330, 331f primary, by Na+-K+ pump, 19 dentinal, 370b
Tonofilaments, 46t, 329, 330 secondary, by coupled carrier proteins, of platelets, 233, 233f, 234f, 236t
Tonsils, 299, 301, 301f, 350, 377f 20 seminiferous, 489, 490–498, 490f–492f
572 䡲䡲䡲 Index
Tubule(s) (Continued) Tunica media (Continued) Valve(s)

T (transverse) of muscular arteries, 254t, 255, 255f, 256f anal, 410
of cardiac muscle, 177–178, 180t of veins, 265t, 266 ileocecal, 407
of skeletal muscle, 160, 163f, 180t thickness of, 258 of heart, 267, 268b
uriniferous, 438–452, 438f–439f, 446f, Tunica propria, 491 of Kerckring, 398
456f, 459t, 460t Tunica vaginalis, 489 of lymphatic vessels, 290
Tubuli recti, 489, 501, 502t Tunica vasculosa of veins, 267
Tubulin dimers, 43f, 192 of eye, 515f, 516–518 pyloric, 385
Tubuloacinar (tubuloalveolar) glands, 107, of testis, 489, 498 Varices, esophageal, 267b
107f Turner’s syndrome, 56b Varicose veins, 267b
compound Tympanic cavity, 527–528, 527f Vas deferens, 489, 490f, 502t, 504
of mammary gland, 486 Tympanic lip, 533 Vasa recta, 453
prostatic, 506 Tympanic membrane, 526, 527, 535 and countercurrent exchange system,
salivary, 413 Tympanum, 527f 458, 460f, 460t
Tubulocisternal network, 390f Tyrosinase, 332, 341 Vasa vasorum, 252–253
Tubulovesicular complexes, 27 Tyrosine Vascular compartment, of bone marrow,
Tubulovesicular system, of parietal cells, diiodinated, 314–315 236
389, 390f monoiodinated, 314–315 Vascular dissemination theory, of
Tuftleins, 369 endometriosis, 478b
Tumor(s). See Cancer. U Vascular feet, of astrocytes, 194
Tumor necrosis factor (TNF) Vascular pole, of kidney, 440, 441f
effect on bone, 154 Ubiquination, 37 Vascular supply
in apoptosis, 68 Ubiquitin-activating enzyme, 37 to bone marrow, 236–237
neutrophils and, 227 Ubiquitin-conjugating enzymes, 37 to kidneys, 438f–439f, 452–454, 453f,
Tumor necrosis factor-α (TNF-α) Ubiquitin ligase, 37 454f
antigen-presenting cells and, 284t Ulcers, 398b to liver, 423–425, 424f, 425f
in small intestine, 401 Ultrafiltrate, 442, 447, 455 to lungs, 355f, 364–365
mast cell release of, 117 Ultraviolet radiation, 332b, 333, 333b to lymph nodes, 293
TH1 cells and, 287, 287f Ungated channels, 19 to penis, 507f, 508
Tumor necrosis factor-β (TNF-β), 282 Unicellular glands, 105–106, 105f, 106f to pituitary gland, 304–306, 306f
Tumor necrosis factor (TNF) receptor Unilocular fat cells, 115–116, 117f, 127–128 to placenta, 483f, 484
family, 140 Unipolar neurons, 189f, 193 to salivary glands, 415
Tunic(s), vessel, 251–253, 252f Uniport transport, 18f, 19 to small intestine, 402–403
Tunica adventitia, 251–252, 252f, 254t, Unipotential progenitor cells, 238, 239t, to spleen, 294, 294f, 295, 295f
265t 241 to suprarenal glands, 318, 320f
in blood pressure regulation, 258 Unit membrane, 12 to testes, 489–490
of alimentary canal, 382, 382f, 394t–395t Unmyelinated axons, 191, 192f, 197 to thymus, 290
of arterioles, 254t, 256 Urate oxidase, 36 Vascular system. See Cardiovascular
of bladder, 462 Urea, 432 system; Lymphatic vascular system.
of blood vessels, 252, 252f Ureters, 437, 438f, 460–461 Vascular tunic, of eye, 515f, 516–518
of elastic arteries, 254, 254t Urethra, 437, 462 Vasectomy, 504b
of esophagus, 385, 394t Urinary bladder, 437, 461–462, 461f Vasoactive intestinal peptide, 203, 392t,
of large intestine, 395t Urinary incontinence, 462b 421–422, 421t
of lymphatic ducts, 271 Urinary pole, of kidney, 440, 441f, 445 Vasoconstriction, 208, 253, 258
of muscular arteries, 254t, 256 Urinary space, 440, 441f, 445, 445f, 450f Vasodilation, 258
of small intestine, 394t–395t, 402 Urinary system, 437–462 Vasomotor center, in brain, 258
of stomach, 394t, 396 excretory passages in, 458–462 Vasomotor nerves, 253, 258
of trachea, 351f, 352f, 354 kidneys in, 437–458 Vasomotor tone, 258
of uterus, 464f, 477 Urine, formation of, 438, 455–458, 456f, Vasopressin
of vagina, 485 457t, 458 in blood pressure regulation, 258
of veins, 265t, 266, 267 Uriniferous tubules, 438–452, 438f–439f, in urine formation, 456f, 458
thickness of, 258 446f, 456f, 459t, 460t physiologic effects of, 307t, 311
Tunica albuginea Urogastrone, 397, 402 synthesis of, 310, 311
of ovary, 463 Uronic acid, 69, 71t Veins, 265–267, 265t. See also specific
of penis, 507, 507f Uterine contractions, 477 vein.
of testis, 489 Uterine glands, 476, 477f, 480 classification of, 265–267
Tunica fibrosa, of eye, 515–516, 515f Uterine tube, 464f defined, 251, 265
Tunica intima, 251, 252, 252f, 254t, 265t Uterus, 464f, 475–477 hepatic, 425
of arterioles, 254t, 256 broad ligament of, 463, 464f large, 265t, 266–267
of elastic arteries, 253, 254t Utricle, 528f, 529, 530f, 531f medium, 265t, 266
of lymphatic ducts, 271 Uvea (tunica vasculosa), 515f, 516–518 pulmonary, 267
of muscular arteries, 254t, 255, 255f Uvula, 376, 377f small, 265–266, 265t, 266f
of veins, 265t, 266 tunics of, 251–253, 252f, 265t
thickness of, 258, 259b V valves of, 267
Tunica media, 251, 252, 252f, 254t, 265t varicose, 267b
of arterioles, 254t, 256, 256f Vagina, 464f, 484–485 Vellus hairs, 339
of elastic arteries, 254, 254t Vagovasal reflex, 383 Velocity-dependent channels, 17
of lymphatic ducts, 271 Vagus nerve, 383 Vena cava, 267, 267f, 424f
Index ■ ■ ■ 573
Venae rectae, 453 Visceral layer Weibel-Palade bodies, 254

and countercurrent exchange system, of Bowman’s capsule, 440, 442, 443f, Weigert’s elastic stain, 3t
458, 460f, 460t 444f, 445 Wharton’s jelly, 126
Venous sinusoids, of spleen, 294f, 295 of pericardium, 269 White adipose tissue, 115–116, 117f,
Ventilation, 345 Visceral motor component, 207 127–128
mechanism of, 364 Visceral nervous system, 185, 207–210, White blood cells (WBCs). See
Ventral horns, 211 209f Leukocyte(s).
Ventricles, of heart, 267, 267f Visceral pleura, 364 White fibers. See Collagen fibers.
Venules, 256f, 263, 265–266, 265t, Visceral reflex, 207f White matter, 191, 210, 211
266f Visceromotor nuclei, 208 White muscle fibers, 157, 158t
hepatic, 425 Visible mucus, of stomach, 386, 387, 387f, White pulp, of spleen, 291f, 294f–296f,
high endothelial, 266, 292 396 295, 296
postcapillary, 265–266, 266f, 291f, Visual purple (rhodopsin), 522 Wilson’s disease, 429b
293 Vitamin(s) Wound healing, 75b
Vermiform appendix, 395t, 410–411 effect on cartilage, 134, 135t Wright stain, 3t
Vermiform granules, 332 storage, in liver, 432–433
Vermilion zone, 368 Vitamin A deficiency X
Verner-Morrison syndrome, 422b bone effects of, 155, 155t
Very-low-density lipoprotein (VLDL), 116, cartilage effects of, 135t X chromosome, 55, 56, 56f
221t, 430, 431 Vitamin A excess XO genotype, 56b
Vesicle coat protein AP-2, 201 bone effects of, 155t XX genotype, 55
Vesicular zone, of osteoclast, 141–142, cartilage effects of, 135t XXY genotype, 56b, 495b
141f Vitamin C deficiency XY genotype, 55
Vessels bone effects of, 155, 155b, 155t
blood. See Blood vessels. cartilage effects of, 135t Y
lymphatic, 270–271, 270f connective tissue effects of, 78b Y chromosome, 55, 56f
Vestibular apparatus, 511, 534 Vitamin D deficiency Yellow bone marrow, 236, 237b
Vestibular folds, of larynx, 351 bone effects of, 155, 155b, 155t Yolk sac, 481f
Vestibular glands, 485 cartilage effects of, 135t
Vestibular lip, 533 Vitamin K deficiency, 237b Z
Vestibular membrane, 530, 532f, 533f Vitreous body, 515f, 519, 519b
Vestibule Vitreous cavity, 519 Z disk (Z line)
nasal, 345, 346t Vitreous opacities, 519b in cardiac muscle, 177, 178f
of ear, 528, 528f, 535f Vocal fold, 351 in skeletal muscle, 160, 161, 161f, 162,
of external genitalia, 485 Vocal ligament, 351 162f, 164, 164f
Vestibulocochlear apparatus. See Ear(s). Volkmann canals, 144f, 145, 145f Zeis glands, 525
Vestibulocochlear nerve, 527f, 528, 529, Voltage-gated channels Zona arcuata, of vestibular membrane, 530
531f, 535, 535f calcium ion, 201 Zona fasciculata, of suprarenal gland,
Viagra (sildenafil), 510b calcium release, 167 320–321, 321f
Vibrissae, of nasal cavity, 345 mechanisms of action of, 17 Zona glomerulosa, of suprarenal gland,
Villin, 43, 90, 94f of terminal cisternae, 160 319f, 320, 321f
Villus(i) potassium (K+), 199 Zona intermedia, of pituitary gland, 310
anchoring, 484 sodium (Na+), 199, 200f Zona pectinata, of vestibular membrane,
chorionic, 483, 483f, 484, 484f Volume transmission, 204 530
free, 484 von Ebner glands, 378 Zona pellucida, 465f, 466, 467t, 468, 480,
microvilli as. See Microvilli. von Gierke’s disease, 41t 482f
of jejunum, 403 von Willebrand disease, 254b Zona reticularis, of suprarenal gland, 319f,
of small intestine, 398, 398f–401f von Willebrand factor, 254 321–322
Vimentin in clot formation, 233 Zone(s)
in capillaries, 259 dark, of lymphoid nodule, 292
in cytoskeleton, 45, 46t W marginal of spleen, 291f, 294f, 295f, 296,
in nuclear membrane, 49 297f
in skeletal muscle, 161 Wallerian degeneration, 218 of epiphyseal plate, 149f, 150–151
in smooth muscle, 181 Warts, 335b Zonulae adherentes, 94, 97f, 98f, 99
Vincristine, 66b Water Zonulae occludentes, 94, 97f–99f
Vinculin, 44, 45f, 99 in cartilage, 134 Zonule fibers, 517
Virally transformed cells, 232 in cytoplasm, 11 Zygote, 481
T-helper cell-mediated killing of, in gastric juices, 396 Zygotene, 67, 495
285–286, 286f Wave of depolarization, 200 Zymogen granules, pancreatic, 418f, 419,
Virgin cells, 277 Wavy collagen fibers, 175 419f
Visceral afferent pathways, 511 Wax glands, 338, 526 Zymogenic cells, 386f, 387f, 390, 391f

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Leslie P.

JAMES L. HIATT, PhD

COLOR TEXTBOOK OF HISTOLOGY ISBN-13: 978-1-4160-2945-8

Library of Congress Control Number: 2006930093

Reg. ISBN-13: 978-1-4160-2945-8

Acquisitions Editor: Inta Ozols

Last digit is the print number: 9 8 7 6 5 4 3 2

2 䡲 䡲 䡲 Chapter 1 䡲 Introduction to Histology and Basic Histological Techniques

Chapter 1 䡲 Introduction to Histology and Basic Histological Techniques ■ ■ ■ 3

objects are separated by a distance. The quality of a lens

Condenser Viewing window

Lamp Mirror Image on Specimen Image on Television

Figure 1–2 Histology requires

Chapter 1 䡲 Introduction to Histology and Basic Histological Techniques ■ ■ ■ 5

6 䡲 䡲 䡲 Chapter 1 䡲 Introduction to Histology and Basic Histological Techniques

Figure 1–4 Example of direct immunocytochemistry. Cultured

scope. The silver grains are positioned over the regions

Chapter 1 䡲 Introduction to Histology and Basic Histological Techniques ■ ■ ■ 7

In confocal microscopy, a laser beam passes through a

The use of electrons as a light source in electron

In light microscopes, optical lenses focus visible light

Figure 1–7 Autoradiography. In this

Scanning Pinhole Photomultiplier

Chapter 1 䡲 Introduction to Histology and Basic Histological Techniques ■ ■ ■ 9

electrons that pass through the hole in the anode have

10 䡲 䡲 䡲 Chapter 1 䡲 Introduction to Histology and Basic Histological Techniques

Figure 1-10 Cytochemistry and freeze-

Figure 2–1 Light micrograph

however, the lipid component outweighs the protein

Figure 2–6 Electron micro-

Figure 2–7 Electron micro-

Figure 2–8 A ﬂuid mosaic model of the cell membrane.

membrane. This coat is usually composed of carbohy-

Figure 2–10 Freeze-fracture rep-

Simple diffusion Ion channel-mediated Carrier-mediated

Figure 2–11 Types of transport.

LIGAND-GATED CHANNELS guanosine monophosphate [cGMP] in rods of the

sine diphosphate (GDP). Trimeric GTPases, or G Activated ATP cAMP

Endoplasmic Reticulum with that of the rough endoplasmic reticulum. Except

Figure 2–13 Electron micrograph of the

Figure 2–14 Electron micrograph of bound

STEP 6 Synthesis of Proteins on the Rough

Figure 2–15 Protein synthesis in the cytosol.

Golgi Apparatus There are two additional compartments of interest,

trans-face Figure 2–17 Rough endoplas-

Figure 2–18 Electron micrograph of the Golgi

COP I Mannose 6-phosphate

mation of clathrin-coated vesicles. The signal for their

linked to its own adaptin, the protein with a binding site

Shortly after their formation, pinocytotic vesicles lose

Figure 2–24 Electron micrographs of trans-

possess proton pumps that actively transport H+ ions

Figure 2–26 Lysosomes of

either with late endosomes or with lysosomes and share Peroxisomes

CLINICAL CORRELATIONS Peroxisomes (microbodies) are small (0.2 to 1.0 µm in

2 䡲䡲䡲 Chapter 1 䡲 Introduction to Histology and Basic Histological Techniques

6 䡲䡲䡲 Chapter 1 䡲 Introduction to Histology and Basic Histological Techniques

10 䡲䡲䡲 Chapter 1 䡲 Introduction to Histology and Basic Histological Techniques

70 䡲䡲䡲 Chapter 4 䡲 Extracellular Matrix