101 - PDFsam - Robbins & Cotran Pathologic Basis of Disease, 9e

82 C H A P T E R 3
Inflammation and Repair
In all these situations, the mechanisms by which leu- offending agents are removed simply because the media
kocytes damage normal tissues are the same as the mech- tors of inflammation are produced in rapid bursts, only as
anisms involved in antimicrobial defense, because once long as the stimulus persists, have short half-lives, and are
the leukocytes are activated, their effector mechanisms do degraded after their release. Neutrophils also have short
not distinguish between offender and host. During activa half-lives in tissues and die by apoptosis within a few
tion and phagocytosis, neutrophils and macrophages hours after leaving the blood. In addition, as inflammation
produce microbicidal substances (ROS, NO, and lysosomal develops, the process itself triggers a variety of stop signals
enzymes) within the phagolysosome; these substances are that actively terminate the reaction. These active termina
also released into the extracellular space. These released tion mechanisms include a switch in the type of arachi
substances are capable of damaging normal cells and vas donic acid metabolite produced, from proinflammatory
cular endothelium, and may thus amplify the effects of the leukotrienes to antiinflammatory lipoxins (described later),
initial injurious agent. If unchecked or inappropriately and the liberation of antiinflammatory cytokines, including
directed against host tissues, the leukocyte infiltrate itself transforming growth factor-β (TGF-β) and IL-10, from
becomes the offender, and indeed leukocyte-dependent macrophages and other cells. Other control mechanisms
tissue injury underlies many acute and chronic human dis that have been demonstrated experimentally include
eases (Table 3-1). This fact becomes evident in the discus neural impulses (cholinergic discharge) that inhibit the
sion of specific disorders throughout the book. production of TNF in macrophages.
The contents of lysosomal granules are secreted by leu
kocytes into the extracellular milieu by several mecha KEY CONCEPTS
nisms. Controlled secretion of granule contents is a normal
response of activated leukocytes. If phagocytes encounter Leukocyte Activation and Removal
materials that cannot be easily ingested, such as immune of Offending Agents
complexes deposited on immovable flat surfaces (e.g., glo ■ Leukocytes can eliminate microbes and dead cells
merular basement membrane), the inability of the leuko by phagocytosis, followed by their destruction in
cytes to surround and ingest these substances (frustrated phagolysosomes.
phagocytosis) triggers strong activation, and the release of ■ Destruction is caused by free radicals (ROS, NO) gener-
large amounts of lysosomal enzymes into the extracellular ated in activated leukocytes and lysosomal enzymes.
environment. Some phagocytosed substances, such as
■ Neutrophils can extrude their nuclear contents to form
urate crystals, may damage the membrane of the pha
extracellular nets that trap and destroy microbes.
golysosome and also lead to the release of lysosomal
■ Enzymes and ROS may be released into the extracellular
granule contents.
environment.
Other Functional Responses of Activated Leukocytes ■ The mechanisms that function to eliminate microbes and
In addition to eliminating microbes and dead cells, acti dead cells (the physiologic role of inflammation) are also
vated leukocytes play several other roles in host defense. capable of damaging normal tissues (the pathologic con-
Importantly, these cells, especially macrophages, produce sequences of inflammation).
cytokines that can either amplify or limit inflammatory ■ Antiinflammatory mediators terminate the acute inflamma-
reactions, growth factors that stimulate the proliferation tory reaction when it is no longer needed.
of endothelial cells and fibroblasts and the synthesis of
collagen, and enzymes that remodel connective tissues. Mediators of Inflammation
Because of these activities, macrophages are also critical
cells of chronic inflammation and tissue repair, after the The mediators of inflammation are the substances that
inflammation has subsided. These functions of macro initiate and regulate inflammatory reactions. Many medi
phages are discussed later in the chapter. ators have been identified and targeted therapeutically to
In this discussion of acute inflammation, we emphasize limit inflammation. In this discussion, we review their
the importance of neutrophils and macrophages. However, shared properties and the general principles of their pro
it has recently become clear that some T lymphocytes, duction and actions.
which are cells of adaptive immunity, also contribute to
acute inflammation. The most important of these cells are • The most important mediators of acute inflammation
those that produce the cytokine IL-17 (so-called TH17 cells), are vasoactive amines, lipid products (prostaglandins
which are discussed in more detail in Chapter 6. IL-17 and leukotrienes), cytokines (including chemokines),
induces the secretion of chemokines that recruit other leu and products of complement activation (Table 3-4).
kocytes. In the absence of effective TH17 responses, indi These mediators induce various components of the
viduals are susceptible to fungal and bacterial infections, inflammatory response typically by distinct mecha
and the skin abscesses that develop are “cold abscesses,” nisms, which is why inhibiting each has been therapeu
lacking the classic features of acute inflammation, such as tically beneficial. However, there is also some overlap
warmth and redness. (redundancy) in the actions of the mediators.
• Mediators are either secreted by cells or generated
Termination of the Acute Inflammatory Response from plasma proteins. Cell-derived mediators are nor
mally sequestered in intracellular granules and can be
Such a powerful system of host defense, with its inherent rapidly secreted by granule exocytosis (e.g., histamine
capacity to cause tissue injury, needs tight controls to mini in mast cell granules) or are synthesized de novo (e.g.,
mize damage. In part, inflammation declines after the prostaglandins and leukotrienes, cytokines) in response
Acute inflammation 83
Table 3-4 Principal Mediators of Inflammation

Mediator Source Action
Histamine Mast cells, basophils, platelets Vasodilation, increased vascular permeability, endothelial activation
Prostaglandins Mast cells, leukocytes Vasodilation, pain, fever
Leukotrienes Mast cells, leukocytes Increased vascular permeability, chemotaxis, leukocyte adhesion, and activation
Cytokines (TNF, IL-1, IL-6) Macrophages, endothelial cells, Local: endothelial activation (expression of adhesion molecules). Systemic: fever, metabolic
mast cells abnormalities, hypotension (shock)
Chemokines Leukocytes, activated macrophages Chemotaxis, leukocyte activation
Platelet-activating factor Leukocytes, mast cells Vasodilation, increased vascular permeability, leukocyte adhesion, chemotaxis, degranulation,
oxidative burst
Complement Plasma (produced in liver) Leukocyte chemotaxis and activation, direct target killing (membrane attack complex),
vasodilation (mast cell stimulation)
Kinins Plasma (produced in liver) Increased vascular permeability, smooth muscle contraction, vasodilation, pain
to a stimulus. The major cell types that produce media- and serotonin. They are stored as preformed molecules in
tors of acute inflammation are the sentinels that detect cells and are therefore among the first mediators to be
invaders and damage in tissues, that is, macrophages, released during inflammation. The richest sources of hista
dendritic cells, and mast cells, but platelets, neutro mine are the mast cells that are normally present in the
phils, endothelial cells, and most epithelia can also be connective tissue adjacent to blood vessels. It is also found
induced to elaborate some of the mediators. Plasma- in blood basophils and platelets. Histamine is stored in
derived mediators (e.g., complement proteins) are pro mast cell granules and is released by mast cell degranula
duced mainly in the liver and are present in the tion in response to a variety of stimuli, including (1) physi
circulation as inactive precursors that must be activated, cal injury, such as trauma, cold, or heat, by unknown
usually by a series of proteolytic cleavages, to acquire mechanisms; (2) binding of antibodies to mast cells, which
their biologic properties. underlies immediate hypersensitivity (allergic) reactions
• Active mediators are produced only in response to
(Chapter 6); and (3) products of complement called ana-
various stimuli. These stimuli include microbial prod phylatoxins (C3a and C5a), described later. Antibodies and
ucts and substances released from necrotic cells. Some complement products bind to specific receptors on mast
of the stimuli trigger well-defined receptors and signal cells and trigger signaling pathways that induce rapid
ing pathways, described earlier, but we still do not degranulation. In addition, leukocytes are thought to
know how other stimuli induce the secretion of media secrete some histamine-releasing proteins but these have
tors (e.g., from mast cells in response to cell injury or not been characterized. Neuropeptides (e.g., substance P)
mechanical irritation). The usual requirement for and cytokines (IL-1, IL-8) may also trigger release of
microbes or dead tissues as the initiating stimulus histamine.
ensures that inflammation is normally triggered only Histamine causes dilation of arterioles and increases
when and where it is needed. the permeability of venules. Histamine is considered to
• Most of the mediators are short-lived. They quickly
be the principal mediator of the immediate transient phase
decay, or are inactivated by enzymes, or they are other of increased vascular permeability, producing interendo
wise scavenged or inhibited. There is thus a system of thelial gaps in venules, as discussed earlier. Its vasoactive
checks and balances that regulates mediator actions. effects are mediated mainly via binding to receptors, called
These built-in control mechanisms are discussed with H1 receptors, on microvascular endothelial cells. The anti
each class of mediator. histamine drugs that are commonly used to treat some
inflammatory reactions, such as allergies, are H1 receptor
• One mediator can stimulate the release of other media- antagonists that bind to and block the receptor. Histamine
tors. For instance, products of complement activation
stimulate the release of histamine, and the cytokine TNF also causes contraction of some smooth muscles.
acts on endothelial cells to stimulate the production of Serotonin (5-hydroxytryptamine) is a preformed vaso
another cytokine, IL-1, and many chemokines. The sec active mediator present in platelets and certain neuroen
ondary mediators may have the same actions as the docrine cells, such as in the gastrointestinal tract, and in
initial mediators but may also have different and even mast cells in rodents but not humans. Its primary function
opposing activities. Such cascades provide mechanisms is as a neurotransmitter in the gastrointestinal tract. It is
for amplifying—or, in certain instances, counteracting— also a vasoconstrictor, but the importance of this action in
the initial action of a mediator. inflammation is unclear.
We next discuss the more important mediators of acute Arachidonic Acid Metabolites
inflammation, focusing on their mechanisms of action and The lipid mediators prostaglandins and leukotrienes are
roles in acute inflammation. produced from arachidonic acid (AA) present in mem-
brane phospholipids, and stimulate vascular and cellular
Vasoactive Amines: Histamine and Serotonin reactions in acute inflammation. AA is a 20-carbon poly
The two major vasoactive amines, so named because they unsaturated fatty acid (5,8,11,14-eicosatetraenoic acid) that
have important actions on blood vessels, are histamine is derived from dietary sources or by conversion from the
84 C H A P T E R 3 Inflammation and Repair
Cell membrane phospholipids
Steroids inhibit
Phospholipases
COOH
CH3
Other
COX-1 and COX-2 ARACHIDONIC ACID HPETEs HETEs
lipoxygenases
inhibitors, aspirin,
indomethacin
inhibit
Cyclooxygenase 5-Lipoxygenase
Prostaglandin G2 (PGG2) 5-HPETE 5-HETE
Prostaglandin H2 (PGH2)
Chemotaxis
Prostacyclin Leukotriene
PGI2 Leukotriene A4 (LTA4) Leukotriene B4 receptor
antagonists
Causes inhibit
vasodilation,
inhibits platelet
Leukotriene C4 (LTC4)
aggregation
Bronchospasm
Leukotriene D4 (LTD4) Increased
Thromboxane A2 vascular
TXA2 permeability
Leukotriene E4 (LTE4)
Causes
vasoconstriction,
promotes platelet
aggregation 12-Lipoxygenase
PGD2
PGE2 Lipoxin A4 (LXA4)
Lipoxin B4 (LXB4)
Causes
vasodilation, Inhibition of
increased inflammation
vascular
permeability
Figure 3-10 Production of arachidonic acid metabolites and their roles in inflammation. Note the enzymatic activities whose inhibition through pharmacologic
intervention blocks major pathways (denoted with a red X). COX-1, COX-2, Cyclooxygenase 1 and 2; HETE, hydroxyeicosatetraenoic acid; HPETE, hydroper-
oxyeicosatetraenoic acid.
essential fatty acid linoleic acid. It does not occur free Prostaglandins
in the cell but is normally esterified in membrane phos Prostaglandins (PGs) are produced by mast cells, macro-
pholipids. Mechanical, chemical, and physical stimuli or phages, endothelial cells, and many other cell types, and
other mediators (e.g., C5a) release AA from membrane are involved in the vascular and systemic reactions of
phospholipids through the action of cellular phospholi inflammation. They are generated by the actions of two
pases, mainly phospholipase A2. The biochemical signals
involved in the activation of phospholipase A2 include an
Table 3-5 Principal Actions of Arachidonic Acid Metabolites
increase in cytoplasmic Ca2+ and activation of various in Inflammation
kinases in response to external stimuli. AA-derived media
tors, also called eicosanoids (because they are derived from Action Eicosanoid
20-carbon fatty acids; Greek eicosa = 20), are synthesized by Vasodilation Prostaglandins PGI2 (prostacyclin), PGE1,
two major classes of enzymes: cyclooxygenases (which PGE2, PGD2
generate prostaglandins) and lipoxygenases (which Vasoconstriction Thromboxane A2, leukotrienes C4, D4, E4
produce leukotrienes and lipoxins) (Fig. 3-10). Eicosanoids Increased vascular permeability Leukotrienes C4, D4, E4
bind to G protein-coupled receptors on many cell types
Chemotaxis, leukocyte adhesion Leukotrienes B4, HETE
and can mediate virtually every step of inflammation
HETE, Hydroxyeicosatetraenoic acid.
(Table 3-5).
cyclooxgenases, called COX-1 and COX-2. COX-1 is pro Lipoxins

duced in response to inflammatory stimuli and is also con Lipoxins are also generated from AA by the lipoxygenase
stitutively expressed in most tissues, where it may serve a pathway, but unlike prostaglandins and leukotrienes,
homeostatic function (e.g., fluid and electrolyte balance in the lipoxins suppress inflammation by inhibiting the
the kidneys, cytoprotection in the gastrointestinal tract). In recruitment of leukocytes. They inhibit neutrophil chemo
contrast, COX-2 is induced by inflammatory stimuli and taxis and adhesion to endothelium. They are also unusual
thus generates the prostaglandins that are involved in in that two cell populations are required for the trans
inflammatory reactions, but it is low or absent in most cellular biosynthesis of these mediators. Leukocytes, par
normal tissues. ticularly neutrophils, produce intermediates in lipoxin
Prostaglandins are divided into series based on struc synthesis, and these are converted to lipoxins by platelets
tural features as coded by a letter (PGD, PGE, PGF, PGG, interacting with the leukocytes.
and PGH) and a subscript numeral (e.g., 1, 2), which indi
cates the number of double bonds in the compound. The Pharmacologic Inhibitors of Prostaglandins
most important ones in inflammation are PGE2, PGD2, and Leukotrienes
PGF2a, PGI2 (prostacyclin), and TxA2 (thromboxane A2), The importance of eicosanoids in inflammation has driven
each of which is derived by the action of a specific enzyme attempts to develop drugs that inhibit their production or
on an intermediate in the pathway. Some of these enzymes actions and thus suppress inflammation. These anti-
have restricted tissue distribution. For example, platelets inflammatory drugs include the following.
contain the enzyme thromboxane synthase, and hence
TxA2 is the major product in these cells. TxA2, a potent • Cyclooxygenase inhibitors include aspirin and other
platelet-aggregating agent and vasoconstrictor, is itself nonsteroidal anti-inflammatory drugs (NSAIDs), such
unstable and rapidly converted to its inactive form TxB2. as ibuprofen. They inhibit both COX-1 and COX-2 and
Vascular endothelium lacks thromboxane synthase but thus inhibit prostaglandin synthesis (hence their effi
possesses prostacyclin synthase, which is responsible for cacy in treating pain and fever); aspirin does this by
the formation of prostacyclin (PGI2) and its stable end irreversibly acetylating and inactivating cyclooxygen
product PGF1a. Prostacyclin is a vasodilator and a potent ases. Selective COX-2 inhibitors are a newer class of
inhibitor of platelet aggregation, and also markedly poten these drugs; they are 200-300 fold more potent in block
tiates the permeability-increasing and chemotactic effects ing COX-2 than COX-1. There has been great interest in
of other mediators. A thromboxane-prostacyclin imbal COX-2 as a therapeutic target because of the possibility
ance has been implicated as an early event in thrombus that COX-1 is responsible for the production of prosta
formation in coronary and cerebral blood vessels. PGD2 is glandins that are involved in both inflammation and
the major prostaglandin made by mast cells; along with homeostatic functions (e.g., fluid and electrolyte balance
PGE2 (which is more widely distributed), it causes vasodi in the kidneys, cytoprotection in the gastrointestinal
lation and increases the permeability of postcapillary tract), whereas COX-2 generates prostaglandins that are
venules, thus potentiating edema formation. PGF2a stimu involved only in inflammatory reactions. If this idea is
lates the contraction of uterine and bronchial smooth correct, the selective COX-2 inhibitors should be anti-
muscle and small arterioles, and PGD2 is a chemoattrac inflammatory without having the toxicities of the non
tant for neutrophils. selective inhibitors, such as gastric ulceration. However,
In addition to their local effects, the prostaglandins are these distinctions are not absolute, as COX-2 also seems
involved in the pathogenesis of pain and fever in inflamma to play a role in normal homeostasis. Furthermore,
tion. PGE2 is hyperalgesic and makes the skin hypersensi selective COX-2 inhibitors may increase the risk of
tive to painful stimuli, such as intradermal injection of cardiovascular and cerebrovascular events, possibly
suboptimal concentrations of histamine and bradykinin. It because they impair endothelial cell production of pros
is involved in cytokine-induced fever during infections tacyclin (PGI2), a vasodilator and inhibitor of platelet
(described later). aggregation, but leave intact the COX-1-mediated pro
duction by platelets of thromboxane A2 (TxA2), an
Leukotrienes important mediator of platelet aggregation and vaso
Leukotrienes are produced by leukocytes and mast constriction. Thus, selective COX-2 inhibition may tilt
cells by the action of lipoxygenase and are involved in the balance towards thromboxane and promote vascu
vascular and smooth muscle reactions and leukocyte lar thrombosis, especially in individuals with other
recruitment. There are three different lipoxygenases, factors that increase the risk of thrombosis. Nevertheless,
5-lipoxygenase being the predominant one in neutrophils. these drugs are still used in individuals who do not have
This enzyme converts AA to 5-hydroxyeicosatetraenoic risk factors for cardiovascular disease when their ben
acid, which is chemotactic for neutrophils, and is the efits outweigh their risks.
precursor of the leukotrienes. LTB4 is a potent chemotac • Lipoxygenase inhibitors. 5-lipoxygenase is not affected
tic agent and activator of neutrophils, causing aggrega by NSAIDs, and many new inhibitors of this enzyme
tion and adhesion of the cells to venular endothelium, pathway have been developed. Pharmacologic agents
generation of ROS, and release of lysosomal enzymes. that inhibit leukotriene production (e.g., Zileuton) are
The cysteinyl-containing leukotrienes LTC4, LTD4, and useful in the treatment of asthma.
LTE4 cause intense vasoconstriction, bronchospasm (impor • Corticosteroids are broad-spectrum antiinflammatory

tant in asthma), and increased permeability of venules. agents that reduce the transcription of genes encoding
Leukotrienes are more potent than is histamine in increas COX-2, phospholipase A2, proinflammatory cytokines
ing vascular permeability and causing bronchospasm. (e.g., IL-1 and TNF), and iNOS.
• Leukotriene receptor antagonists block leukotriene The actions of TNF and IL-1 contribute to the local and
receptors and prevent the actions of the leukotrienes. systemic reactions of inflammation (Fig. 3-11). The most
These drugs (e.g., Montelukast) are useful in the treat important roles of these cytokines in inflammation are the
ment of asthma. following.
• Another approach to manipulating inflammatory • Endothelial activation. Both TNF and IL-1 act on endo
responses has been to modify the intake and content of thelium to induce a spectrum of changes referred to as
dietary lipids by increasing the consumption of fish oil. endothelial activation. These changes include increased
The proposed explanation for the effectiveness of this expression of endothelial adhesion molecules, mostly
approach is that the polyunsaturated fatty acids in fish E- and P-selectins and ligands for leukocyte integrins;
oil are poor substrates for conversion to active metabo increased production of various mediators, including
lites by the cyclooxygenase and lipoxygenase pathways other cytokines and chemokines, growth factors, and
but are better substrates for the production of antiin eicosanoids; and increased procoagulant activity of the
flammatory lipid products. endothelium.
• Activation of leukocytes and other cells. TNF aug

Cytokines and Chemokines ments responses of neutrophils to other stimuli such as
bacterial endotoxin and stimulates the microbicidal
Cytokines are proteins produced by many cell types
activity of macrophages, in part by inducing production
(principally activated lymphocytes, macrophages, and
of NO. IL-1 activates fibroblasts to synthesize collagen
dendritic cells, but also endothelial, epithelial, and con-
and stimulates proliferation of synovial and other mes
nective tissue cells) that mediate and regulate immune
enchymal cells. IL-1 also stimulates TH17 responses,
and inflammatory reactions. By convention, growth factors
which in turn induce acute inflammation.
that act on epithelial and mesenchymal cells are not
grouped under cytokines. The general properties and func • Systemic acute-phase response. IL-1 and TNF (as well
tions of cytokines are discussed in Chapter 6. Here the as IL-6) induce the systemic acute-phase responses asso
cytokines involved in acute inflammation are reviewed ciated with infection or injury, including fever (described
(Table 3-6). later in the chapter). They are also implicated in the
syndrome of sepsis, resulting from disseminated bacte
Tumor Necrosis Factor (TNF) and Interleukin-1 (IL-1) rial infection. TNF regulates energy balance by promot
TNF and IL-1 serve critical roles in leukocyte recruitment ing lipid and protein mobilization and by suppressing
by promoting adhesion of leukocytes to endothelium appetite. Therefore, sustained production of TNF con
and their migration through vessels. These cytokines are tributes to cachexia, a pathologic state characterized by
produced mainly by activated macrophages and dendritic weight loss and anorexia that accompanies some chronic
cells; TNF is also produced by T lymphocytes and mast infections and neoplastic diseases.
cells, and IL-1 is produced by some epithelial cells as well. TNF antagonists have been remarkably effective in
The secretion of TNF and IL-1 can be stimulated by micro the treatment of chronic inflammatory diseases, particu
bial products, immune complexes, foreign bodies, physical larly rheumatoid arthritis and also psoriasis and some
injury, and a variety of other inflammatory stimuli. The types of inflammatory bowel disease. One of the complica
production of TNF is induced by signals through TLRs and tions of this therapy is that patients become susceptible to
other microbial sensors, and the synthesis of IL-1 is stimu mycobacterial infection, reflecting the reduced ability of
lated by the same signals but the generation of the biologi macrophages to kill intracellular microbes. Although many
cally active form of this cytokine is dependent on the of the actions of TNF and IL-1 seem overlapping, IL-1
inflammasome, described earlier. antagonists are not as effective, for reasons that remain
Table 3-6 Cytokines in Inflammation

Cytokine Principal Sources Principal Actions in Inflammation
In Acute Inflammation
TNF Macrophages, mast cells, T lymphocytes Stimulates expression of endothelial adhesion molecules and secretion of other cytokines; systemic effects
IL-1 Macrophages, endothelial cells, some Similar to TNF; greater role in fever
epithelial cells
IL-6 Macrophages, other cells Systemic effects (acute phase response)
Chemokines Macrophages, endothelial cells, Recruitment of leukocytes to sites of inflammation; migration of cells in normal tissues
T lymphocytes, mast cells, other
cell types
IL-17 T lymphocytes Recruitment of neutrophils and monocytes
In Chronic Inflammation
IL-12 Dendritic cells, macrophages Increased production of IFN-γ
IFN-γ T lymphocytes, NK cells Activation of macrophages (increased ability to kill microbes and tumor cells)
IL-17 T lymphocytes Recruitment of neutrophils and monocytes
IFN-γ, Interferon-γ; IL-1, interleukin-1; NK cells, natural killer cells; TNF, tumor necrosis factor.
The most important cytokines involved in inflammatory reactions are listed. Many other cytokines may play lesser roles in inflammation. There is also considerable overlap between the cytokines involved
in acute and chronic inflammation. Specifically, all the cytokines listed under acute inflammation may also contribute to chronic inflammatory reactions.
LOCAL INFLAMMATION SYSTEMIC PROTECTIVE EFFECTS SYSTEMIC PATHOLOGICAL EFFECTS

TNF, Brain Heart
TNF Increased TNF,
IL-1 permeability TNF
IL-1,
IL-6
Increased Low
expression of Fever output
adhesion molecules
IL-1, Liver Endothelial cells, blood vessels
IL-6
Endothelial cells
TNF
IL-1,
chemokines Acute
phase
proteins Increased
Leukocytes Thrombus
permeability
TNF, Bone marrow
IL-1, IL-6, IL-1, Multiple tissues
chemokines IL-6
TNF, Activation TNF, Skeletal
IL-1 IL-1 muscle
Leukocyte
production
Insulin resistance
Figure 3-11 Major roles of cytokines in acute inflammation. PDGF, Platelet-derived growth factor; PGE, prostaglandin E; PGI, prostaglandin I.
obscure. Also, blocking either cytokine has no effect on the • CX3C chemokines contain three amino acids between the
outcome of sepsis, perhaps because other cytokines con two cysteines. The only known member of this class is
tribute to this serious systemic inflammatory reaction. called fractalkine. This chemokine exists in two forms: a
cell surface-bound protein induced on endothelial cells
Chemokines by inflammatory cytokines that promotes strong adhe
Chemokines are a family of small (8 to 10 kD) proteins sion of monocytes and T cells, and a soluble form, derived
that act primarily as chemoattractants for specific types by proteolysis of the membrane-bound protein, that has
of leukocytes. About 40 different chemokines and 20 dif potent chemoattractant activity for the same cells.
ferent receptors for chemokines have been identified. They
are classified into four major groups, according to the Chemokines mediate their activities by binding to
arrangement of cysteine (C) residues in the proteins: seven-transmembrane G protein–coupled receptors. These
receptors (called CXCR or CCR, for C-X-C or C-C chemo
• C-X-C chemokines have one amino acid residue separat kine receptors) usually exhibit overlapping ligand speci
ing the first two of the four conserved cysteine residues. ficities, and leukocytes generally express more than one
These chemokines act primarily on neutrophils. IL-8 receptor type. As discussed in Chapter 6, certain chemo
is typical of this group. It is secreted by activated mac kine receptors (CXCR-4, CCR-5) act as coreceptors for a
rophages, endothelial cells, and other cell types, and viral envelope glycoprotein of human immunodeficiency
causes activation and chemotaxis of neutrophils, with virus (HIV), the cause of AIDS, and are thus involved in
limited activity on monocytes and eosinophils. Its most binding and entry of the virus into cells.
important inducers are microbial products and other Chemokines may be displayed at high concentrations
cytokines, mainly IL-1 and TNF. attached to proteoglycans on the surface of endothelial
• C-C chemokines have the first two conserved cysteine cells and in the extracellular matrix. They have two main
residues adjacent. The C-C chemokines, which include functions:
monocyte chemoattractant protein (MCP-1), eotaxin,
macrophage inflammatory protein-1α (MIP-1α), and • In acute inflammation. Inflammatory chemokines are the
RANTES (regulated and normal T-cell expressed and ones whose production is induced by microbes and
secreted), generally attract monocytes, eosinophils, other stimuli. These chemokines stimulate leukocyte
basophils and lymphocytes, but are not as potent che attachment to endothelium by acting on leukocytes to
moattractants for neutrophils. Although most of the increase the affinity of integrins, and they stimulate
chemokines in this class have overlapping actions, migration (chemotaxis) of leukocytes in tissues to the
eotaxin selectively recruits eosinophils. site of infection or tissue damage.
• C chemokines lack the first and third of the four con • Maintenance of tissue architecture. Some chemokines

served cysteines. The C chemokines (e.g., lymphotactin) are produced constitutively in tissues and are some
are relatively specific for lymphocytes. times called homeostatic chemokines. These organize
EFFECTOR FUNCTIONS
C5a, C3a: Inflammation
Alternative
Microbe
pathway
Recruitment and Destruction of microbes

activation of leukocytes by leukocytes
C3b C3a C3b: Phagocytosis
Classical
pathway C3b
C3b is deposited
Antibody Recognition of bound C3b Phagocytosis
on microbe
by phagocyte C3b receptor of microbe
MAC: Lysis of
Lectin microbe
pathway Mannose Formation of
binding lectin membrane attack
complex (MAC)
Figure 3-12 The activation and functions of the complement system. Activation of complement by different pathways leads to cleavage of C3. The functions
of the complement system are mediated by breakdown products of C3 and other complement proteins, and by the membrane attack complex (MAC).
various cell types in different anatomic regions of the activation and functions of complement are outlined in
tissues, such as T and B lymphocytes in discrete areas Figure 3-12.
of the spleen and lymph nodes (Chapter 6). Complement proteins are present in inactive forms in
the plasma, and many of them are activated to become
Although the role of chemokines in inflammation is well proteolytic enzymes that degrade other complement pro
established, it has proved difficult to develop antagonists teins, thus forming an enzymatic cascade capable of tre
that block the activities of these proteins. mendous amplification. The critical step in complement
activation is the proteolysis of the third (and most abun
Other Cytokines in Acute Inflammation dant) component, C3. Cleavage of C3 can occur by one of
The list of cytokines implicated in inflammation is huge three pathways:
and constantly growing. In addition to the ones described
earlier, two that have received considerable recent interest
• The classical pathway, which is triggered by fixation of
C1 to antibody (IgM or IgG) that has combined with
are IL-6, made by macrophages and other cells, which is antigen
involved in local and systemic reactions, and IL-17, pro
duced mainly by T lymphocytes, which promotes neutro • The alternative pathway, which can be triggered by
microbial surface molecules (e.g., endotoxin, or LPS),
phil recruitment. Antagonists against both are approved or
complex polysaccharides, cobra venom, and other sub
have shown impressive efficacy in the treatment of inflam
stances, in the absence of antibody
matory diseases. Type I interferons, whose normal func
tion is to inhibit viral replication, contribute to some of the • The lectin pathway, in which plasma mannose-binding

systemic manifestations of inflammation. Cytokines also lectin binds to carbohydrates on microbes and directly
play key roles in chronic inflammation; these are described activates C1.
later in the chapter. All three pathways of complement activation lead to
the formation of an active enzyme called the C3 conver-
Complement System tase, which splits C3 into two functionally distinct frag-
The complement system is a collection of soluble pro- ments, C3a and C3b. C3a is released, and C3b becomes
teins and membrane receptors that function mainly in covalently attached to the cell or molecule where comple
host defense against microbes and in pathologic inflam- ment is being activated. More C3b then binds to the previ
matory reactions. The system consists of more than ously generated fragments to form C5 convertase, which
20 proteins, some of which are numbered C1 through C9. cleaves C5 to release C5a and leave C5b attached to the cell
This system functions in both innate and adaptive immu surface. C5b binds the late components (C6-C9), culminat
nity for defense against microbial pathogens. In the process ing in the formation of the membrane attack complex
of complement activation, several cleavage products of (MAC, composed of multiple C9 molecules).
complement proteins are elaborated that cause increased The complement system has three main functions
vascular permeability, chemotaxis, and opsonization. The (Fig. 3-12):
• Inflammation. C3a, C5a, and, to a lesser extent, C4a are proteins cause a variety of disorders, such as macular
cleavage products of the corresponding complement degeneration and hemolytic uremic syndrome, resulting
components that stimulate histamine release from from excessive complement activation.
mast cells and thereby increase vascular permeability
and cause vasodilation. They are called anaphylatoxins
because they have effects similar to those of mast cell
Other Mediators of Inflammation
mediators that are involved in the reaction called ana- Platelet-Activating Factor (PAF)
phylaxis (Chapter 6). C5a is also a chemotactic agent for PAF is a phospholipid-derived mediator that was discov
neutrophils, monocytes, eosinophils, and basophils. In ered as a factor that caused platelet aggregation, but it is
addition, C5a activates the lipoxygenase pathway of AA now known to have multiple inflammatory effects. A
metabolism in neutrophils and monocytes, causing variety of cell types, including platelets themselves, baso
further release of inflammatory mediators. phils, mast cells, neutrophils, macrophages, and endo
• Opsonization and phagocytosis. C3b and its cleavage thelial cells, can elaborate PAF, in both secreted and
product iC3b (inactive C3b), when fixed to a microbial cell-bound forms. In addition to platelet aggregation, PAF
cell wall, act as opsonins and promote phagocytosis by causes vasoconstriction and bronchoconstriction, and at
neutrophils and macrophages, which bear cell surface low concentrations it induces vasodilation and increased
receptors for the complement fragments. venular permeability. In the 1990s there was great interest
• Cell lysis. The deposition of the MAC on cells makes
in PAF as a mediator of inflammation, but trials of PAF
these cells permeable to water and ions and results in antagonists in various inflammatory diseases have been
death (lysis) of the cells. This role of complement is disappointing.
important mainly for the killing of microbes with thin
cell walls, such as Neisseria bacteria, and deficiency of Products of Coagulation
the terminal components of complement predisposes to Studies done more than 50 years ago suggested that inhib
Neisseria infections. iting coagulation reduced the inflammatory reaction to
some microbes, leading to the idea that coagulation and
The activation of complement is tightly controlled inflammation are linked processes. This concept was sup
by cell-associated and circulating regulatory proteins. ported by the discovery of protease-activated receptors
Different regulatory proteins inhibit the production of (PARs), which are activated by thrombin (the protease that
active complement fragments or remove fragments that cleaves fibrinogen to produce fibrin, which forms the
deposit on cells. These regulators are expressed on normal clot), and are expressed on platelets and leukocytes. It is,
host cells and are thus designed to prevent healthy tissues however, likely that the major role of the PARs is in platelet
from being injured at sites of complement activation. activation during clotting (Chapter 4). In fact, it is difficult
Regulatory proteins can be overwhelmed when large to dissociate clotting and inflammation, since virtually all
amounts of complement are deposited on host cells and in forms of tissue injury that lead to clotting also induce
tissues, as happens in autoimmune diseases, in which indi inflammation, and inflammation causes changes in endo
viduals produce complement-fixing antibodies against thelial cells that increase the likelihood of abnormal clot
their own cell and tissue antigens (Chapter 6). The most ting (thrombosis, described in Chapter 4). However,
important of these regulatory proteins are the following: whether the products of coagulation, per se, have a key role
in stimulating inflammation is still not established.
• C1 inhibitor (C1 INH) blocks the activation of C1, the
first protein of the classical complement pathway. Kinins
Inherited deficiency of this inhibitor is the cause of Kinins are vasoactive peptides derived from plasma pro
hereditary angioedema. teins, called kininogens, by the action of specific proteases
• Decay accelerating factor (DAF) and CD59 are two pro
called kallikreins. The enzyme kallikrein cleaves a plasma
teins that are linked to plasma membranes by a glyco glycoprotein precursor, high-molecular-weight kininogen,
phosphatidyl (GPI) anchor. DAF prevents formation of to produce bradykinin. Bradykinin increases vascular per-
C3 convertases and CD59 inhibits formation of the meability and causes contraction of smooth muscle, dila-
membrane attack complex. An acquired deficiency of tion of blood vessels, and pain when injected into the
the enzyme that creates GPI anchors leads to deficiency skin. These effects are similar to those of histamine. The
of these regulators and excessive complement activation action of bradykinin is short-lived, because it is quickly
and lysis of red cells (which are sensitive to complement- inactivated by an enzyme called kininase. Bradykinin has
mediated cell lysis) in the disease called paroxysmal noc- been implicated as a mediator in some forms of allergic
turnal hemoglobinuria (PNH) (Chapter 14). reaction, such as anaphylaxis (Chapter 6).
• Other complement regulatory proteins proteolytically
cleave active complement components. Neuropeptides
Neuropeptides are secreted by sensory nerves and various
The complement system contributes to disease in sev leukocytes, and may play a role in the initiation and regula
eral ways. The activation of complement by antibodies or tion of inflammatory responses. These small peptides,
antigen-antibody complexes deposited on host cells and such as substance P and neurokinin A, are produced in the
tissues is an important mechanism of cell and tissue injury central and peripheral nervous systems. Nerve fibers con
(Chapter 6). Inherited deficiencies of complement proteins taining substance P are prominent in the lung and gastro
cause increased susceptibility to infections (Chapter 6), intestinal tract. Substance P has many biologic functions,
and, as mentioned earlier, deficiencies of regulatory including the transmission of pain signals, regulation of
Table 3-7 Role of Mediators in Different Reactions of Inflammation superimposed on these general features, depending on the
Reaction of Inflammation Principal Mediators severity of the reaction, its specific cause, and the particular
tissue and site involved. The importance of recognizing the
Vasodilation Histamine
gross and microscopic patterns is that they often provide
Prostaglandins
valuable clues about the underlying cause.
Increased vascular permeability Histamine and serotonin
C3a and C5a (by liberating vasoactive Serous Inflammation
amines from mast cells, other
cells) Serous inflammation is marked by the exudation of cell-
Leukotrienes C4, D4, E4 poor fluid into spaces created by cell injury or into body
cavities lined by the peritoneum, pleura, or pericardium.
Chemotaxis, leukocyte recruitment TNF, IL-1
and activation
Typically, the fluid in serous inflammation is not infected
Chemokines
C3a, C5a
by destructive organisms and does not contain large
Leukotriene B4 numbers of leukocytes (which tend to produce purulent
inflammation, described later). In body cavities the fluid
Fever IL-1, TNF
may be derived from the plasma (as a result of increased
Prostaglandins
vascular permeability) or from the secretions of mesothe
Pain Prostaglandins lial cells (as a result of local irritation); accumulation of
Bradykinin
fluid in these cavities is called an effusion. (Effusions also
Tissue damage Lysosomal enzymes of leukocytes occur in noninflammatory conditions, such as reduced
Reactive oxygen species blood outflow in heart failure, or reduced plasma protein
levels in some kidney and liver diseases.) The skin blister
resulting from a burn or viral infection represents accumu
blood pressure, stimulation of hormone secretion by endo lation of serous fluid within or immediately beneath the
crine cells, and increasing vascular permeability. damaged epidermis of the skin (Fig. 3-13).
When Lewis discovered the role of histamine in inflamma Fibrinous Inflammation

tion, one mediator was thought to be enough. Now, we are With greater increase in vascular permeability, large mol
wallowing in them! Yet, from this large compendium, it is ecules such as fibrinogen pass out of the blood, and fibrin
likely that a few mediators are most important for the reac is formed and deposited in the extracellular space. A
tions of acute inflammation in vivo, and these are sum fibrinous exudate develops when the vascular leaks are
marized in Table 3-7. The redundancy of the mediators and large or there is a local procoagulant stimulus (e.g., cancer
their actions ensures that this protective response remains cells). A fibrinous exudate is characteristic of inflammation
robust and is not readily subverted. in the lining of body cavities, such as the meninges, peri
cardium (Fig. 3-14A), and pleura. Histologically, fibrin
appears as an eosinophilic meshwork of threads or some
KEY CONCEPTS times as an amorphous coagulum (Fig. 3-14B). Fibrinous
Actions of the Principal Mediators of Inflammation exudates may be dissolved by fibrinolysis and cleared by
macrophages. If the fibrin is not removed, over time it may
■ Vasoactive amines, mainly histamine: vasodilation and
stimulate the ingrowth of fibroblasts and blood vessels and
increased vascular permeability
thus lead to scarring. Conversion of the fibrinous exudate
■ Arachidonic acid metabolites (prostaglandins and leukot-
to scar tissue (organization) within the pericardial sac leads
rienes): several forms exist and are involved in vascular
to opaque fibrous thickening of the pericardium and
reactions, leukocyte chemotaxis, and other reactions of
inflammation; antagonized by lipoxins
■ Cytokines: proteins produced by many cell types; usually
act at short range; mediate multiple effects, mainly in leu-

kocyte recruitment and migration; principal ones in acute
inflammation are TNF, IL-1, and chemokines
■ Complement proteins: Activation of the complement
system by microbes or antibodies leads to the generation

of multiple breakdown products, which are responsible for
leukocyte chemotaxis, opsonization, and phagocytosis of
microbes and other particles, and cell killing
■ Kinins: produced by proteolytic cleavage of precursors;
mediate vascular reaction, pain
Morphologic Patterns of Acute Inflammation

The morphologic hallmarks of acute inflammatory reac-
tions are dilation of small blood vessels and accu Figure 3-13 Serous inflammation. Low-power view of a cross-section of a
mulation of leukocytes and fluid in the extravascular skin blister showing the epidermis separated from the dermis by a focal col-
tissue. However, special morphologic patterns are often lection of serous effusion.
F
P
A B
Figure 3-14 Fibrinous pericarditis. A, Deposits of fibrin on the pericardium. B, A pink meshwork of fibrin exudate (F) overlies the pericardial surface (P).
epicardium in the area of exudation and, if the fibrosis is become walled off and ultimately replaced by connective
extensive, obliteration of the pericardial space. tissue.
Purulent (Suppurative) Inflammation, Abscess Ulcers

Purulent inflammation is characterized by the production An ulcer is a local defect, or excavation, of the surface of
of pus, an exudate consisting of neutrophils, the liquefied an organ or tissue that is produced by the sloughing
debris of necrotic cells, and edema fluid. The most fre (shedding) of inflamed necrotic tissue (Fig. 3-16).
quent cause of purulent (also called suppurative) inflamma Ulceration can occur only when tissue necrosis and resul
tion is infection with bacteria that cause liquefactive tissue tant inflammation exist on or near a surface. It is most
necrosis, such as staphylococci; these pathogens are commonly encountered in (1) the mucosa of the mouth,
referred to as pyogenic (pus-producing) bacteria. A common stomach, intestines, or genitourinary tract, and (2) the skin
example of an acute suppurative inflammation is acute and subcutaneous tissue of the lower extremities in older
appendicitis. Abscesses are localized collections of puru- persons who have circulatory disturbances that predispose
lent inflammatory tissue caused by suppuration buried in to extensive ischemic necrosis.
a tissue, an organ, or a confined space. They are produced Ulcerations are best exemplified by peptic ulcer of the
by seeding of pyogenic bacteria into a tissue (Fig. 3-15). stomach or duodenum, in which acute and chronic inflam
Abscesses have a central region that appears as a mass of mation coexist. During the acute stage there is intense
necrotic leukocytes and tissue cells. There is usually a zone polymorphonuclear infiltration and vascular dilation in
of preserved neutrophils around this necrotic focus, and the margins of the defect. With chronicity, the margins
outside this region there may be vascular dilation and and base of the ulcer develop fibroblastic proliferation,
parenchymal and fibroblastic proliferation, indicating scarring, and the accumulation of lymphocytes, macro
chronic inflammation and repair. In time the abscess may phages, and plasma cells.
A B
Figure 3-15 Purulent inflammation. A, Multiple bacterial abscesses (arrows) in the lung in a case of bronchopneumonia. B, The abscess contains neutrophils
and cellular debris, and is surrounded by congested blood vessels.
A B
Figure 3-16 The morphology of an ulcer. A, A chronic duodenal ulcer. B, Low-power cross-section view of a duodenal ulcer crater with an acute inflammatory
exudate in the base.
Outcomes of Acute Inflammation resolution and is the usual outcome when the injury is
limited or short-lived or when there has been little tissue
Although, as might be expected, many variables may destruction and the damaged parenchymal cells can
modify the basic process of inflammation, including the regenerate. Resolution involves removal of cellular
nature and intensity of the injury, the site and tissue debris and microbes by macrophages, and resorption of
affected, and the responsiveness of the host, all acute edema fluid by lymphatics.
inflammatory reactions typically have one of three out-
comes (Fig. 3-17):
• Healing by connective tissue replacement (scarring, or

fibrosis). This occurs after substantial tissue destruction,
• Complete resolution. In a perfect world, all inflamma when the inflammatory injury involves tissues that are
tory reactions, once they have succeeded in eliminating incapable of regeneration, or when there is abundant
the offending agent, should end with restoration of the fibrin exudation in tissue or in serous cavities (pleura,
site of acute inflammation to normal. This is called peritoneum) that cannot be adequately cleared. In all
ACUTE INFLAMMATION RESOLUTION

• Vascular changes • Clearance of injurious stimuli
• Neutrophil recruitment • Clearance of mediators and acute
• Mediators inflammatory cells
• Replacement of injured cells
• Normal function
INJURY
• Infarction
• Bacterial infections
• Toxins
• Trauma Pus formation (abscess)
Progression Healing
Healing
INJURY
Healing
• Viral infections
• Chronic infections
• Persistent injury FIBROSIS
• Autoimmune diseases • Loss of function
CHRONIC INFLAMMATION
• Angiogenesis
• Mononuclear cell infiltrate
• Fibrosis (scar)
Figure 3-17 Outcomes of acute inflammation: resolution, healing by fibrosis, or chronic inflammation. The components of the various reactions and their
functional outcomes are listed.
Chronic inflammation 93
these situations, connective tissue grows into the area of Causes of Chronic Inflammation
damage or exudate, converting it into a mass of fibrous
tissue, a process also called organization. Chronic inflammation arises in the following settings:
• Progression of the response to chronic inflammation
• Persistent infections by microorganisms that are diffi
(discussed later). Acute to chronic transition occurs cult to eradicate, such as mycobacteria and certain
when the acute inflammatory response cannot be viruses, fungi, and parasites. These organisms often
resolved, as a result of either the persistence of the inju evoke an immune reaction called delayed-type hypersen-
rious agent or some interference with the normal process sitivity (Chapter 6). The inflammatory response some
of healing. times takes a specific pattern called a granulomatous
reaction (discussed later). In other cases, an unresolved
acute inflammation may evolve into chronic inflamma
Summary of Acute Inflammation tion, as may occur in acute bacterial infection of the lung
that progresses to a chronic lung abscess.
Now that we have described the components, mediators,
and pathologic manifestations of acute inflammatory • Hypersensitivity diseases. Chronic inflammation plays
an important role in a group of diseases that are caused
responses, it is useful to summarize the main features of a by excessive and inappropriate activation of the immune
typical response of this type. When a host encounters an system. Under certain conditions immune reactions
injurious agent, such as an infectious microbe or dead cells, develop against the individual’s own tissues, leading to
phagocytes that reside in all tissues try to eliminate these autoimmune diseases (Chapter 6). In these diseases, auto
agents. At the same time, phagocytes and other host cells antigens evoke a self-perpetuating immune reaction
react to the presence of the foreign or abnormal substance that results in chronic tissue damage and inflammation;
by liberating cytokines, lipid messengers, and other media examples of such diseases are rheumatoid arthritis and
tors of inflammation. Some of these mediators act on small multiple sclerosis. In other cases, chronic inflammation
blood vessels in the vicinity and promote the efflux of is the result of unregulated immune responses against
plasma and the recruitment of circulating leukocytes to the microbes, as in inflammatory bowel disease. Immune
site where the offending agent is located. The recruited responses against common environmental substances
leukocytes are activated by the injurious agent and by are the cause of allergic diseases, such as bronchial asthma
locally produced mediators, and the activated leukocytes (Chapter 6). Because these autoimmune and allergic
try to remove the offending agent by phagocytosis. As the reactions are inappropriately triggered against antigens
injurious agent is eliminated and anti-inflammatory mech that are normally harmless, the reactions serve no useful
anisms become active, the process subsides and the host purpose and only cause disease. Such diseases may
returns to a normal state of health. If the injurious agent show morphologic patterns of mixed acute and chronic
cannot be quickly eliminated, the result may be chronic inflammation because they are characterized by repeated
inflammation. bouts of inflammation. Fibrosis may dominate the late
The vascular and cellular reactions account for the stages.
signs and symptoms of the inflammatory response. The
increased blood flow to the injured area and increased • Prolonged exposure to potentially toxic agents, either

exogenous or endogenous. An example of an exoge
vascular permeability lead to the accumulation of extravas
nous agent is particulate silica, a nondegradable inani
cular fluid rich in plasma proteins, known as edema. The
mate material that, when inhaled for prolonged periods,
redness (rubor), warmth (calor), and swelling (tumor) of
results in an inflammatory lung disease called silicosis
acute inflammation are caused by the increased blood flow
(Chapter 15). Atherosclerosis (Chapter 11) is thought to
and edema. Circulating leukocytes, initially predominantly
be a chronic inflammatory process of the arterial wall
neutrophils, adhere to the endothelium via adhesion mol
induced, at least in part, by excessive production and
ecules, traverse the endothelium, and migrate to the site of
tissue deposition of endogenous cholesterol and other
injury under the influence of chemotactic agents. Leukocytes
lipids.
that are activated by the offending agent and by endoge
nous mediators may release toxic metabolites and prote • Some forms of chronic inflammation may be important
ases extracellularly, causing tissue damage. During the in the pathogenesis of diseases that are not conven
damage, and in part as a result of the liberation of prosta tionally thought of as inflammatory disorders. These
glandins, neuropeptides, and cytokines, one of the local include neurodegenerative diseases such as Alzheimer
symptoms is pain (dolor). disease, metabolic syndrome and the associated type 2
diabetes, and certain cancers in which inflammatory
reactions promote tumor development. The role of
inflammation in these conditions is discussed in the rel
Chronic Inflammation evant chapters.
Chronic inflammation is a response of prolonged dura- Morphologic Features

tion (weeks or months) in which inflammation, tissue
injury and attempts at repair coexist, in varying combina- In contrast to acute inflammation, which is manifested by
tions. It may follow acute inflammation, as described vascular changes, edema, and predominantly neutrophilic
earlier, or chronic inflammation may begin insidiously, as infiltration, chronic inflammation is characterized by:
a low-grade, smoldering response without any manifesta • Infiltration with mononuclear cells, which include
tions of a preceding acute reaction. macrophages, lymphocytes, and plasma cells (Fig. 3-18)
Macrophages are professional phagocytes that act as filters

for particulate matter, microbes, and senescent cells. They
also function as effector cells that eliminate microbes in
cellular and humoral immune responses (Chapter 6). But
they serve many other roles in inflammation and repair.
Here we review the basic biology of macrophages, includ
ing their development and functional responses.
Macrophages are tissue cells derived from hematopoi-
* etic stem cells in the bone marrow and from progenitors

in the embryonic yolk sac and fetal liver during early
development (Fig. 3-19). Circulating cells of this lineage
are known as monocytes. Macrophages are normally dif
fusely scattered in most connective tissues. In addition,
they are found in specific locations in organs such as the
A liver (where they are called Kupffer cells), spleen and
lymph nodes (called sinus histiocytes), central nervous
system (microglial cells), and lungs (alveolar macrophages).
Together these cells comprise the mononuclear phagocyte
system, also known by the older (and inaccurate) name of
reticuloendothelial system.
Committed progenitors in the bone marrow give rise to
monocytes, which enter the blood, migrate into various
tissues and differentiate into macrophages. This is typical
of macrophages at sites of inflammation and in some
tissues such as the skin and intestinal tract. The half-life of
blood monocytes is about 1 day, whereas the life span of
tissue macrophages is several months or years. Most tissue
resident macrophages, such as microglia, Kupffer cells,
alveolar macrophages and macrophages in the spleen and
B connective tissues, may arise from yolk sac or fetal liver
very early in embryogenesis, populate the tissues, stay for
Figure 3-18 A, Chronic inflammation in the lung, showing all three charac- long periods in the steady state, and are replenished mainly
teristic histologic features: (1) collection of chronic inflammatory cells (*), (2) by proliferation of resident cells. As discussed earlier, in
destruction of parenchyma (normal alveoli are replaced by spaces lined by inflammatory reactions, monocytes begin to emigrate into
cuboidal epithelium, arrowheads), and (3) replacement by connective tissue extravascular tissues quite early, and within 48 hours they
(fibrosis, arrows). B, In contrast, in acute inflammation of the lung (acute may constitute the predominant cell type. Extravasation of
bronchopneumonia), neutrophils fill the alveolar spaces and blood vessels
are congested.
monocytes is governed by the same factors that are involved
in neutrophil emigration, that is, adhesion molecules and
chemical mediators with chemotactic and activating
properties.
• Tissue destruction, induced by the persistent offending There are two major pathways of macrophage activa-
agent or by the inflammatory cells
tion, called classical and alternative (Fig. 3-20). The
• Attempts at healing by connective tissue replacement

stimuli that activate macrophages by these pathways, and
of damaged tissue, accomplished by angiogenesis (prolif
the functions of the activated cells, are quite different.
eration of small blood vessels) and, in particular,
fibrosis
• Classical macrophage activation may be induced by
Because angiogenesis and fibrosis are also components microbial products such as endotoxin, which engage
of wound healing and repair, they are discussed later, in TLRs and other sensors; by T cell–derived signals,
the context of tissue repair. importantly the cytokine IFN-γ, in immune responses;
or by foreign substances including crystals and partic
Cells and Mediators of Chronic Inflammation ulate matter. Classically activated (also called M1)
macrophages produce NO and ROS and upregulate
The combination of leukocyte infiltration, tissue damage, lysosomal enzymes, all of which enhance their ability
and fibrosis that characterize chronic inflammation is the to kill ingested organisms, and secrete cytokines that
result of the local activation of several cell types and the stimulate inflammation. These macrophages are impor
production of mediators. tant in host defense against microbes and in many
inflammatory reactions. As discussed earlier in the
Role of Macrophages context of acute inflammation and leukocyte activation,
The dominant cells in most chronic inflammatory reac- the same activated cells are capable of injuring normal
tions are macrophages, which contribute to the reaction tissues.
by secreting cytokines and growth factors that act on • Alternative macrophage activation is induced by cyto

various cells, by destroying foreign invaders and tissues, kines other than IFN-γ, such as IL-4 and IL-13, produced
and by activating other cells, notably T lymphocytes. by T lymphocytes and other cells. These macrophages
Bone marrow Hemopoietic Blood monocyte

stem cell
Activated macrophages in inflammation

Macrophages in skin, intestinal tract
Resident tissue macrophages

Yolk (Kupffer cells, alveolar macrophages,
sac microglia, etc.)
Liver
Progenitor in
yolk sac, fetal liver
A
B Monocyte Activated macrophage

Figure 3-19 Maturation of mononuclear phagocytes. A, In the steady state, some tissue macrophages, including microglia and alveolar macrophages, may
be derived from embryonic precursors and populate the tissues. The development of macrophages from hematopoietic precursors and monocytes may be
more prominent when tissue macrophages need to be increased or replenished, as after injury and during inflammation. B, The morphology of a monocyte
and activated macrophage.
are not actively microbicidal and the cytokines may in response to most injurious stimuli, the first activation
actually inhibit the classical activation pathway; instead, pathway is the classical one, designed to destroy the
the principal function of alternatively activated (M2) offending agents, and this is followed by alternative
macrophages is in tissue repair. They secrete growth activation, which initiates tissue repair. However, such
factors that promote angiogenesis, activate fibroblasts, a precise sequence is not well documented in most
and stimulate collagen synthesis. It seems plausible that inflammatory reactions.
Classically activated Alternatively activated

macrophage (M1) Microbes, macrophage (M2)
IFN-γ
IL-13,
IL-4
ROS, NO, IL-1, IL-12, Growth

IL-10,
lysosomal IL-23, factors,
TGF-β
enzymes chemokines TGF-β
Microbicidal actions:
phagocytosis and Tissue repair, Anti-inflammatory
Inflammation effects
killing of many fibrosis
bacteria and fungi
Figure 3-20 Classical and alternative macrophage activation. Different stimuli activate monocytes/macrophages to develop into functionally distinct populations.
Classically activated macrophages are induced by microbial products and cytokines, particularly IFN-γ. They phagocytose and destroy microbes and dead
tissues and can potentiate inflammatory reactions. Alternatively activated macrophages are induced by other cytokines and are important in tissue repair and
the resolution of inflammation.
The products of activated macrophages eliminate nature of the inflammatory reaction. These T cells greatly
injurious agents such as microbes and initiate the process amplify the early inflammatory reaction that is induced by
of repair, but are also responsible for much of the recognition of microbes and dead cells as part of innate
tissue injury in chronic inflammation. Several functions immunity. There are three subsets of CD4+ T cells that
of macrophages are central to the development and persis secrete different types of cytokines and elicit different
tence of chronic inflammation and the accompanying types of inflammation.
tissue injury.
• TH1 cells produce the cytokine IFN-γ, which activates
• Macrophages, like the other type of phagocyte, the macrophages by the classical pathway.
neutrophils, ingest and eliminate microbes and dead • TH2 cells secrete IL-4, IL-5, and IL-13, which recruit and

tissues. activate eosinophils and are responsible for the alterna
• Macrophages initiate the process of tissue repair and tive pathway of macrophage activation.
are involved in scar formation and fibrosis. These pro • TH17 cells secrete IL-17 and other cytokines, which
cesses are discussed later in the chapter. induce the secretion of chemokines responsible for
• Macrophages secrete mediators of inflammation, such
recruiting neutrophils (and monocytes) into the
as cytokines (TNF, IL-1, chemokines, and others) and reaction.
eicosanoids. Thus, macrophages are central to the initia
Both TH1 and TH17 cells are involved in defense against
tion and propagation of inflammatory reactions.
many types of bacteria and viruses and in autoimmune
• Macrophages display antigens to T lymphocytes and
diseases. TH2 cells are important in defense against helmin
respond to signals from T cells, thus setting up a feed thic parasites and in allergic inflammation. These T cell
back loop that is essential for defense against many subsets and their functions are described in more detail in
microbes by cell-mediated immune responses. These Chapter 6.
interactions are described further in the discussion of Lymphocytes and macrophages interact in a bidirec
the role of lymphocytes in chronic inflammation, below, tional way, and these interactions play an important role
and in more detail in Chapter 6 where cell-mediated in propagating chronic inflammation (Fig. 3-21). Macro
immunity is considered. phages display antigens to T cells, express membrane mol
Their impressive arsenal of mediators makes macro ecules (called costimulators), and produce cytokines (IL-12
phages powerful allies in the body’s defense against and others) that stimulate T-cell responses (Chapter 6).
unwanted invaders, but the same weaponry can also Activated T lymphocytes, in turn, produce cytokines,
induce considerable tissue destruction when macrophages described earlier, which recruit and activate macrophages,
are inappropriately or excessively activated. It is because promoting more antigen presentation and cytokine secre
of these activities of macrophages that tissue destruction is tion. The result is a cycle of cellular reactions that fuel and
one of the hallmarks of chronic inflammation. sustain chronic inflammation.
In some instances, if the irritant is eliminated, macro Activated B lymphocytes and antibody-producing
phages eventually disappear (either dying off or making plasma cells are often present at sites of chronic inflam-
their way into the lymphatics and lymph nodes). In others, mation. The antibodies may be specific for persistent
macrophage accumulation persists, as a result of continu foreign or self antigens in the inflammatory site or against
ous recruitment from the circulation and local proliferation altered tissue components. However, the specificity and
at the site of inflammation. even the importance of antibodies in most chronic inflam
matory disorders are unclear.
Role of Lymphocytes In some chronic inflammatory reactions, the accumu
Microbes and other environmental antigens activate T lated lymphocytes, antigen-presenting cells, and plasma
and B lymphocytes, which amplify and propagate chronic cells cluster together to form lymphoid tissues resembling
inflammation. Although the major function of these lym lymph nodes. These are called tertiary lymphoid organs; this
phocytes is as the mediators of adaptive immunity, which type of lymphoid organogenesis is often seen in the synovium
provides defense against infectious pathogens (Chapter 6), of patients with long-standing rheumatoid arthritis and in
these cells are often present in chronic inflammation and the thyroid in Hashimoto thyroiditis. It has been postu
when they are activated, the inflammation tends to be per lated that the local formation of lymphoid organs may
sistent and severe. Some of the strongest chronic inflam perpetuate the immune reaction, but the significance of
matory reactions, such as granulomatous inflammation, these structures is not established.
described later, are dependent on lymphocyte responses.
Lymphocytes may be the dominant population in the Other Cells in Chronic Inflammation
chronic inflammation seen in autoimmune and other Other cell types may be prominent in chronic inflammation
hypersensitivity diseases. induced by particular stimuli.
Antigen-stimulated (effector and memory) T and B lym
phocytes use various adhesion molecule pairs (selectins, • Eosinophils are abundant in immune reactions medi
integrins and their ligands) and chemokines to migrate into ated by IgE and in parasitic infections (Fig. 3-22). Their
inflammatory sites. Cytokines from activated macrophages, recruitment is driven by adhesion molecules similar to
mainly TNF, IL-1, and chemokines, promote leukocyte those used by neutrophils, and by specific chemokines
recruitment, setting the stage for persistence of the inflam (e.g., eotaxin) derived from leukocytes and epithelial
matory response. cells. Eosinophils have granules that contain major basic
By virtue of their ability to secrete cytokines, CD4+ T protein, a highly cationic protein that is toxic to parasites
lymphocytes promote inflammation and influence the but also causes lysis of mammalian epithelial cells. This
T lymphocyte Cytokines
(e.g., IL-12,
IL-6, IL-23)
Activated
T lymphocyte Activated
(TH1, TH17) macrophage
Presents
antigen to
T cells TNF,
IL-17,
TNF IL-1,
chemokines
IFN-γ Leukocyte
Leukocyte Other recruitment,
Other inflammation
recruitment, inflammatory inflammatory
inflammation mediators Classical
macrophage mediators
activation
Macrophage
Figure 3-21 Macrophage-lymphocyte interactions in chronic inflammation. Activated T cells produce cytokines that recruit macrophages (TNF, IL-17, chemo-
kines) and others that activate macrophages (IFN-γ). Activated macrophages in turn stimulate T cells by presenting antigens and via cytokines such as IL-12.
is why eosinophils are of benefit in controlling parasitic T lymphocytes. In chronic bacterial infection of bone
infections, yet they also contribute to tissue damage in (osteomyelitis), a neutrophilic exudate can persist for
immune reactions such as allergies (Chapter 6). many months. Neutrophils are also important in the
• Mast cells are widely distributed in connective tissues chronic damage induced in lungs by smoking and other
and participate in both acute and chronic inflammatory irritant stimuli (Chapter 15). This pattern of inflamma
reactions. Mast cells express on their surface the recep tion has been called acute on chronic.
tor (FceRI) that binds the Fc portion of IgE antibody. In
immediate hypersensitivity reactions, IgE antibodies Granulomatous Inflammation
bound to the cells’ Fc receptors specifically recognize
antigen, and the cells degranulate and release media Granulomatous inflammation is a form of chronic inflam-
tors, such as histamine and prostaglandins (Chapter 6). mation characterized by collections of activated macro-
This type of response occurs during allergic reactions phages, often with T lymphocytes, and sometimes
to foods, insect venom, or drugs, sometimes with associated with central necrosis. Granuloma formation is
catastrophic results (e.g., anaphylactic shock). Mast a cellular attempt to contain an offending agent that is dif
cells are also present in chronic inflammatory reactions, ficult to eradicate. In this attempt there is often strong
and because they secrete a plethora of cytokines, activation of T lymphocytes leading to macrophage activa
they may promote inflammatory reactions in different tion, which can cause injury to normal tissues. The acti
situations. vated macrophages may develop abundant cytoplasm and
• Although neutrophils are characteristic of acute
begin to resemble epithelial cells, and are called epithelioid
inflammation, many forms of chronic inflammation, cells. Some activated macrophages may fuse, forming mul
lasting for months, continue to show large numbers of tinucleate giant cells.
neutrophils, induced either by persistent microbes or There are two types of granulomas, which differ in their
by mediators produced by activated macrophages and pathogenesis.
• Foreign body granulomas are incited by relatively

inert foreign bodies, in the absence of T cell–mediated
immune responses. Typically, foreign body granulomas
form around materials such as talc (associated with
intravenous drug abuse) (Chapter 9), sutures, or other
fibers that are large enough to preclude phagocytosis by
a macrophage and do not incite any specific inflamma
tory or immune response. Epithelioid cells and giant
cells are apposed to the surface of the foreign body. The
foreign material can usually be identified in the center
of the granuloma, particularly if viewed with polarized
light, in which it appears refractile.
• Immune granulomas are caused by a variety of agents
that are capable of inducing a persistent T cell–mediated
immune response. This type of immune response pro
duces granulomas usually when the inciting agent is
difficult to eradicate, such as a persistent microbe or a
Figure 3-22 A focus of inflammation containing numerous eosinophils. self antigen. In such responses, macrophages activate
T cells to produce cytokines, such as IL-2, which acti Table 3-8 Examples of Diseases with Granulomatous Inflammation
vates other T cells, perpetuating the response, and IFN- Disease Cause Tissue Reaction
γ, which activates the macrophages. It is not established
Tuberculosis Mycobacterium Caseating granuloma (tubercle):
which macrophage-activating cytokines (IL-4 or IFN-γ) tuberculosis focus of activated macrophages
transform the cells into epithelioid cells and multinucle (epithelioid cells), rimmed by
ate giant cells. fibroblasts, lymphocytes,
histiocytes, occasional Langhans
giant cells; central necrosis with
MORPHOLOGY amorphous granular debris;
acid-fast bacilli
In the usual hematoxylin and eosin preparations (Fig. 3-23), the Leprosy Mycobacterium Acid-fast bacilli in macrophages;
activated macrophages in granulomas have pink granular cyto- leprae noncaseating granulomas
plasm with indistinct cell boundaries and are called epithelioid
Syphilis Treponema Gumma: microscopic to grossly
cells because of their resemblance to epithelia. The aggregates pallidum visible lesion, enclosing wall of
of epithelioid macrophages are surrounded by a collar of lym- histiocytes; plasma cell infiltrate;
phocytes. Older granulomas may have a rim of fibroblasts and central cells are necrotic without
connective tissue. Frequently, but not invariably, multinucleated loss of cellular outline
giant cells 40 to 50 µm in diameter are found in granulomas; Cat-scratch Gram-negative Rounded or stellate granuloma
these are called Langhans giant cells. They consist of a large disease bacillus containing central granular
mass of cytoplasm and many nuclei, and they derive from the debris and recognizable
fusion of multiple activated macrophages. In granulomas asso- neutrophils; giant cells
ciated with certain infectious organisms (most classically uncommon
Mycobacterium tuberculosis), a combination of hypoxia and Sarcoidosis Unknown etiology Noncaseating granulomas with
free radical–mediated injury leads to a central zone of necrosis. abundant activated macrophages
Grossly, this has a granular, cheesy appearance and is there- Crohn disease Immune reaction Occasional noncaseating
fore called caseous necrosis. Microscopically, this necrotic (inflammatory against granulomas in the wall of the
material appears as amorphous, structureless, eosinophilic, bowel intestinal intestine, with dense chronic
granular debris, with complete loss of cellular details. The gran- disease) bacteria, inflammatory infiltrate
possibly self
ulomas in Crohn disease, sarcoidosis, and foreign body reac-
antigens
tions tend to not have necrotic centers and are said to be
noncaseating. Healing of granulomas is accompanied by fibro-
sis that may be extensive.
diseases, notably Crohn disease, which is one type of
inflammatory bowel disease and an important cause of
granulomatous inflammation in the United States, and in
Granulomas are encountered in certain specific patho a disease of unknown etiology called sarcoidosis. Tuber
logic states; recognition of the granulomatous pattern is culosis is the prototype of a granulomatous disease
important because of the limited number of conditions caused by infection and should always be excluded as the
(some life-threatening) that cause it (Table 3-8). In the cause when granulomas are identified. In this disease the
setting of persistent T-cell responses to certain microbes granuloma is referred to as a tubercle. The morphologic
(e.g., M. tuberculosis, Treponema pallidum, or fungi), T cell– patterns in the various granulomatous diseases may be
derived cytokines are responsible for chronic macrophage sufficiently different to allow reasonably accurate diagno
activation and granuloma formation. Granulomas may sis by an experienced pathologist (see Table 3-8); however,
also develop in some immune-mediated inflammatory there are so many atypical presentations that it is always
necessary to identify the specific etiologic agent by special
stains for organisms (e.g., acid-fast stains for tubercle
bacilli), by culture methods (e.g., in tuberculosis and fungal
diseases), by molecular techniques (e.g., the polymerase
chain reaction in tuberculosis), and by serologic studies
(e.g., in syphilis).
KEY CONCEPTS
Chronic Inflammation
■ Chronic inflammation is a prolonged host response to per-
sistent stimuli.
■ It is caused by microbes that resist elimination, immune
responses against self and environmental antigens, and

some toxic substances (e.g., silica); underlies many medi-
cally important diseases.
Figure 3-23 Typical tuberculous granuloma showing an area of central necro- ■ It is characterized by coexisting inflammation, tissue injury,
sis surrounded by multiple Langhans-type giant cells, epithelioid cells, and attempted repair by scarring, and immune response.
lymphocytes.
Systemic effects of inflammation 99
Fibrinogen binds to red cells and causes them to form

■ The cellular infiltrate consists of macrophages, lympho-
stacks (rouleaux) that sediment more rapidly at unit
cytes, plasma cells, and other leukocytes.
gravity than do individual red cells. This is the basis for
■ It is mediated by cytokines produced by macrophages and
measuring the erythrocyte sedimentation rate as a simple
lymphocytes (notably T lymphocytes); bidirectional inter- test for an inflammatory response caused by any stimu
actions between these cells tend to amplify and prolong lus. Acute-phase proteins have beneficial effects during
the inflammatory reaction. acute inflammation, but prolonged production of these
■ Granulomatous inflammation is a pattern of chronic inflam-
proteins (especially SAA) in states of chronic inflamma
mation induced by T cell and macrophage activation in tion causes secondary amyloidosis (Chapter 6). Elevated
response to an agent that is resistant to eradication. serum levels of CRP have been proposed as a marker
for increased risk of myocardial infarction in patients
with coronary artery disease. It is postulated that
Systemic Effects of Inflammation inflammation involving atherosclerotic plaques in the
coronary arteries may predispose to thrombosis and
Inflammation, even if it is localized, is associated with subsequent infarction. Another peptide whose produc
cytokine-induced systemic reactions that are collectively tion is increased in the acute-phase response is the iron-
called the acute-phase response. Anyone who has suffered regulating peptide hepcidin. Chronically elevated plasma
through a severe bout of a viral illness (e.g.., influenza) has concentrations of hepcidin reduce the availability of
experienced the systemic manifestations of acute inflam iron and are responsible for the anemia associated with
mation. These changes are reactions to cytokines whose chronic inflammation (Chapter 14).
production is stimulated by bacterial products such as LPS
and by other inflammatory stimuli. The cytokines TNF,
• Leukocytosis is a common feature of inflammatory
reactions, especially those induced by bacterial infec
IL-1, and IL-6 are important mediators of the acute-phase tions. The leukocyte count usually climbs to 15,000 or
reaction; other cytokines, notably type I interferons, also 20,000 cells/mL, but sometimes it may reach extraordi
contribute to the reaction. narily high levels of 40,000 to 100,000 cells/mL. These
The acute-phase response consists of several clinical and extreme elevations are referred to as leukemoid reactions,
pathologic changes: because they are similar to the white cell counts observed
in leukemia and have to be distinguished from leuke
• Fever, characterized by an elevation of body tempera mia. The leukocytosis occurs initially because of acceler
ture, usually by 1° to 4°C, is one of the most prominent
ated release of cells from the bone marrow postmitotic
manifestations of the acute-phase response, especially
reserve pool (caused by cytokines, including TNF and
when inflammation is associated with infection.
IL-1) and is therefore associated with a rise in the
Substances that induce fever are called pyrogens. The
number of more immature neutrophils in the blood,
increase in body temperature is caused by prostaglan
referred to as a left shift. Prolonged infection also induces
dins that are produced in the vascular and perivascular
proliferation of precursors in the bone marrow, caused
cells of the hypothalamus. Bacterial products, such as
by increased production of colony-stimulating factors.
LPS (called exogenous pyrogens), stimulate leukocytes to
Thus, the bone marrow output of leukocytes is increased
release cytokines such as IL-1 and TNF (called endoge-
to compensate for the loss of these cells in the inflam
nous pyrogens) that increase the enzymes (cyclooxy
matory reaction. (See also the discussion of leukocytosis
genases) that convert AA into prostaglandins. In the
in Chapter 13.) Most bacterial infections induce an
hypothalamus, the prostaglandins, especially PGE2,
increase in the blood neutrophil count, called neutro-
stimulate the production of neurotransmitters that reset
philia. Viral infections, such as infectious mononucleo
the temperature set point at a higher level. NSAIDs,
sis, mumps, and German measles, cause an absolute
including aspirin, reduce fever by inhibiting prostaglan
increase in the number of lymphocytes (lymphocytosis).
din synthesis. An elevated body temperature has been
In some allergies and parasitic infestations, there is
shown to help amphibians ward off microbial infec
an increase in the absolute number of eosinophils, creat
tions, and it is assumed that fever is a protective host
ing an eosinophilia. Certain infections (typhoid fever
response in mammals as well, although the mechanism
and infections caused by some viruses, rickettsiae, and
is unknown. One hypothesis is that fever may induce
certain protozoa) are associated with a decreased
heat shock proteins that enhance lymphocyte responses
number of circulating white cells (leukopenia).
to microbial antigens.
• Acute-phase proteins are plasma proteins, mostly syn • Other manifestations of the acute-phase response
thesized in the liver, whose plasma concentrations may include increased pulse and blood pressure; decreased
increase several hundred-fold as part of the response to sweating, mainly because of redirection of blood flow
inflammatory stimuli. Three of the best-known of these from cutaneous to deep vascular beds, to minimize heat
proteins are C-reactive protein (CRP), fibrinogen, and loss through the skin; rigors (shivering), chills (search
serum amyloid A (SAA) protein. Synthesis of these mol for warmth), anorexia, somnolence, and malaise, prob
ecules in hepatocytes is stimulated by cytokines, espe ably because of the actions of cytokines on brain cells.
cially IL-6 (for CRP and fibrinogen) and IL-1 or TNF (for • In severe bacterial infections (sepsis), the large amounts
SAA). Many acute-phase proteins, such as CRP and of bacteria and their products in the blood stimulate the
SAA, bind to microbial cell walls, and they may act as production of enormous quantities of several cytokines,
opsonins and fix complement. They also bind chroma notably TNF and IL-1. High blood levels of cytokines
tin, possibly aiding in clearing necrotic cell nuclei. cause various widespread clinical manifestations such
as disseminated intravascular coagulation, hypotensive NORMAL

shock, and metabolic disturbances including insulin
resistance and hyperglycemia. This clinical triad is
known as septic shock; it is discussed in more detail in
Chapter 4.
KEY CONCEPTS
Systemic Effects of Inflammation
■ Fever: cytokines (TNF, IL-1) stimulate production of pros- Mild, superficial injury Severe injury
taglandins in hypothalamus
■ Production of acute-phase proteins: C-reactive protein,
others; synthesis stimulated by cytokines (IL-6, others)

acting on liver cells
■ Leukocytosis: cytokines (colony-stimulating factors) stimu-
late production of leukocytes from precursors in the bone

marrow
■ In some severe infections, septic shock: fall in blood pres-
sure, disseminated intravascular coagulation, metabolic

abnormalities; induced by high levels of TNF and other REGENERATION SCAR FORMATION
cytokines
Excessive inflammation is the underlying cause of many

human diseases, described throughout this book. Con
versely, defective inflammation is responsible for increased
susceptibility to infections. The most common cause of
defective inflammation is leukocyte deficiency resulting
from replacement of the bone marrow by leukemias and Figure 3-24 Mechanisms of tissue repair: regeneration and scar formation.
metastatic tumors, and suppression of the marrow by ther Following mild injury, which damages the epithelium but not the underlying
apies for cancer and graft rejection. Inherited genetic tissue, resolution occurs by regeneration, but after more severe injury with
damage to the connective tissue, repair is by scar formation.
abnormalities of leukocyte adhesion and microbicidal
function are rare but very informative; these are described
in Chapter 6, in the context of immunodeficiency diseases. occurs by proliferation of cells that survive the injury
Deficiencies of the complement system are mentioned and retain the capacity to proliferate, for example, in the
earlier and are described further in Chapter 6. rapidly dividing epithelia of the skin and intestines, and
We next consider the process of repair, which is a healing in some parenchymal organs, notably the liver. In other
response to tissue destruction caused by inflammatory or cases, tissue stem cells may contribute to the restoration
non-inflammatory causes. of damaged tissues. However, mammals have a limited
capacity to regenerate damaged tissues and organs, and
only some components of most tissues are able to fully
Tissue Repair restore themselves.
• Connective tissue deposition (scar formation). If the
Overview of Tissue Repair injured tissues are incapable of complete restitution, or
if the supporting structures of the tissue are severely
Repair, sometimes called healing, refers to the restora- damaged, repair occurs by the laying down of connec
tion of tissue architecture and function after an injury. tive (fibrous) tissue, a process that may result in scar
(By convention, the term repair is often used for parenchy formation. Although the fibrous scar is not normal, it
mal and connective tissues and healing for surface epithelia, provides enough structural stability that the injured
but these distinctions are not based on biology and we tissue is usually able to function. The term fibrosis is
use the terms interchangeably.) Critical to the survival of most often used to describe the extensive deposition
an organism is the ability to repair the damage caused by of collagen that occurs in the lungs, liver, kidney, and
toxic insults and inflammation. Hence, the inflammatory other organs as a consequence of chronic inflamma
response to microbes and injured tissues not only serves to tion, or in the myocardium after extensive ischemic
eliminate these dangers but also sets into motion the necrosis (infarction). If fibrosis develops in a tissue
process of repair. space occupied by an inflammatory exudate, it is
Repair of damaged tissues occurs by two types of reac- called organization (as in organizing pneumonia affect
tions: regeneration by proliferation of residual (unin- ing the lung).
jured) cells and maturation of tissue stem cells, and the
deposition of connective tissue to form a scar (Fig. 3-24). After many common types of injury, both regeneration
and scar formation contribute in varying degrees to the
• Regeneration. Some tissues are able to replace the ultimate repair. Both processes involve the proliferation of
damaged components and essentially return to a normal various cells, and close interactions between cells and the
state; this process is called regeneration. Regeneration extracellular matrix (ECM). We first discuss the general
Tissue repair 101
mechanisms of cellular proliferation and regeneration, and capacity may exist in these tissues, it is insufficient to
then the salient features of regeneration and healing by produce tissue regeneration after injury. Skeletal muscle
scar formation, and conclude with a description of cutane is usually classified as a permanent tissue, but satellite
ous wound healing and fibrosis (scarring) in parenchymal cells attached to the endomysial sheath provide some
organs as illustrations of the repair process. regenerative capacity for muscle. In permanent tissues,
repair is typically dominated by scar formation.
Cell and Tissue Regeneration
Although it is believed that most mature tissues contain
The regeneration of injured cells and tissues involves cell variable proportions of continuously dividing cells, quies
proliferation, which is driven by growth factors and is cent cells that can return to the cell cycle, and nondividing
critically dependent on the integrity of the extracellular cells, it is actually difficult to quantify the proportions of
matrix, and by the development of mature cells from these cells in any tissue. Also, we now realize that cell
stem cells. Before describing examples of repair by regen proliferation is only one pathway of regeneration and that
eration, the general principles of cell proliferation are stem cells contribute to this process in important ways.
discussed. Cell proliferation is driven by signals provided by
growth factors and from the extracellular matrix. Many
Cell Proliferation: Signals and Control Mechanisms different growth factors have been described; some act on
Several cell types proliferate during tissue repair. These multiple cell types and others are cell-selective (Chapter 1,
include the remnants of the injured tissue (which attempt Table 1-1). Growth factors are typically produced by cells
to restore normal structure), vascular endothelial cells (to near the site of damage. The most important sources of
create new vessels that provide the nutrients needed for these growth factors are macrophages that are activated by
the repair process), and fibroblasts (the source of the fibrous the tissue injury, but epithelial and stromal cells also
tissue that forms the scar to fill defects that cannot be cor produce some of these factors. Several growth factors bind
rected by regeneration). to ECM proteins and are displayed at high concentrations.
The ability of tissues to repair themselves is deter- All growth factors activate signaling pathways that ulti
mined, in part, by their intrinsic proliferative capacity. mately induce the production of proteins that are involved
Based on this criterion, the tissues of the body are divided in driving cells through the cell cycle and other proteins
into three groups. that release blocks on the cell cycle (checkpoints) (Chapter
1). In addition to responding to growth factors, cells use
• Labile (continuously dividing) tissues. Cells of these integrins to bind to ECM proteins, and signals from the
tissues are continuously being lost and replaced by integrins can also stimulate cell proliferation.
maturation from tissue stem cells and by proliferation In the process of regeneration, proliferation of resid-
of mature cells. Labile cells include hematopoietic cells ual cells is supplemented by development of mature cells
in the bone marrow and the majority of surface epithe from stem cells. In Chapter 1 we introduced the major
lia, such as the stratified squamous epithelia of the skin, types of stem cells. In adults, the most important stem cells
oral cavity, vagina, and cervix; the cuboidal epithelia of for regeneration after injury are tissue stem cells. These
the ducts draining exocrine organs (e.g., salivary glands, stem cells live in specialized niches, and it is believed
pancreas, biliary tract); the columnar epithelium of the that injury triggers signals in these niches that activate
gastrointestinal tract, uterus, and fallopian tubes; and quiescent stem cells to proliferate and differentiate into
the transitional epithelium of the urinary tract. These mature cells that repopulate the injured tissue.
tissues can readily regenerate after injury as long as the
pool of stem cells is preserved. Mechanisms of Tissue Regeneration
• Stable tissues. Cells of these tissues are quiescent (in the
The importance of regeneration in the replacement of
G0 stage of the cell cycle) and have only minimal prolif injured tissues varies in different types of tissues and with
erative activity in their normal state. However, these the severity of injury.
cells are capable of dividing in response to injury or loss
of tissue mass. Stable cells constitute the parenchyma of • In labile tissues, such as the epithelia of the intestinal
most solid tissues, such as liver, kidney, and pancreas. tract and skin, injured cells are rapidly replaced by pro
They also include endothelial cells, fibroblasts, and liferation of residual cells and differentiation of tissue
smooth muscle cells; the proliferation of these cells is stem cells provided the underlying basement mem
particularly important in wound healing. With the brane is intact. The growth factors involved in these
exception of liver, stable tissues have a limited capacity processes are not defined. Loss of blood cells is cor
to regenerate after injury. rected by proliferation of hematopoietic stem cells in the
• Permanent tissues. The cells of these tissues are consid
bone marrow and other tissues, driven by growth
ered to be terminally differentiated and nonproliferative factors called colony-stimulating factors (CSFs), which
in postnatal life. The majority of neurons and cardiac are produced in response to the reduced numbers of
muscle cells belong to this category. Thus, injury to the blood cells.
brain or heart is irreversible and results in a scar, because • Tissue regeneration can occur in parenchymal organs
neurons and cardiac myocytes cannot regenerate. with stable cell populations, but with the exception of
Limited stem cell replication and differentiation occur the liver, this is usually a limited process. Pancreas,
in some areas of the adult brain, and there is some evi adrenal, thyroid, and lung have some regenerative
dence that heart muscle cells may proliferate after myo capacity. The surgical removal of a kidney elicits in
cardial necrosis. Nevertheless, whatever proliferative the remaining kidney a compensatory response that

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82 C H A P T E R 3

Inflammation and Repair

Table 3-4 Principal Mediators of Inflammation

Cell membrane phospholipids

Prostaglandin G2 (PGG2) 5-HPETE 5-HETE

cyclooxgenases, called COX-1 and COX-2. COX-1 is pro­ Lipoxins

Table 3-6 Cytokines in Inflammation

LOCAL INFLAMMATION SYSTEMIC PROTECTIVE EFFECTS SYSTEMIC PATHOLOGICAL EFFECTS

C5a, C3a: Inflammation

Recruitment and Destruction of microbes

C3b C3a C3b: Phagocytosis

When Lewis discovered the role of histamine in inflamma­ Fibrinous Inflammation

act at short range; mediate multiple effects, mainly in leu-

system by microbes or antibodies leads to the generation

mediate vascular reaction, pain

Morphologic Patterns of Acute Inflammation

Purulent (Suppurative) Inflammation, Abscess Ulcers

ACUTE INFLAMMATION RESOLUTION

Chronic inflammation is a response of prolonged dura- Morphologic Features

Macrophages are professional phagocytes that act as filters

* etic stem cells in the bone marrow and from progenitors

Bone marrow Hemopoietic Blood monocyte

Activated macrophages in inflammation

Resident tissue macrophages

B Monocyte Activated macrophage

Classically activated Alternatively activated

ROS, NO, IL-1, IL-12, Growth

• Foreign body granulomas are incited by relatively

responses against self and environmental antigens, and

Fibrinogen binds to red cells and causes them to form

as disseminated intravascular coagulation, hypotensive NORMAL

others; synthesis stimulated by cytokines (IL-6, others)

late production of leukocytes from precursors in the bone

sure, disseminated intravascular coagulation, metabolic

Excessive inflammation is the underlying cause of many

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cyclooxgenases, called COX-1 and COX-2. COX-1 is pro Lipoxins

When Lewis discovered the role of histamine in inflamma Fibrinous Inflammation