Pathology
Pathology
Pathology
Disease
Robbins and Cotran
Pathologic Basis of Disease
Introduction to Pathology
Pathology is devoted to the study of the
• structural,
• biochemical,
• functional
changes in cells, tissues, and organs
Rudolf Virchow,
father of modern pathology
Cellular Responses to Stress and Toxic
Insults: Adaptation, Injury, and Death
Cellular Responses to Stress and Toxic
Insults: Adaptation, Injury, and Death
Cellular Responses to Stress and Toxic
Insults: Adaptation, Injury, and Death
Lecture 2
Cellular Adaptations in Disease
Overview
• Adaptability of cells to an altered environment
• Physiological and pathological stimuli
• Changes in growth pattern
• Hyperplasia, hypertrophy, atrophy, involution,
metaplasia
• Apoptosis
• Growth factors
• Role in altered environment
Why is this important?
• Extremely common responses in disease
• Certain adaptations in growth act as a fertile
ground for the later development of neoplasia -
cancer formation…
• Nomenclature is used in clinical work.
Adaptability of cells to an altered environment
• Infections
Immune
• Anoxia
Endocrine
• Genetic
Physical agents
Metabolic regulation
• Cells may adapt by metabolic regulation
• Induction of enzyme
• Downregulation of enzyme
• Increased synthesis of product
• Reduced secretion of product
• Metabolic adaptation is usually not associated
with morphological changes
Cell stress response
• The cell stress response allows cells to survive
pathological stimuli
• Housekeeping genes switched off
• Cell stress genes switched on
• Cells stress proteins are expressed in cells (also
called heat shock proteins)
• Cell stress proteins are cytoprotective
Cell stress proteins
• Small cell stress proteins act as molecular
chaperones and prevent misfolding of proteins
• Ubiquitin links to damaged proteins and flags them
for elimination by the cell
• Other groups of cell stress proteins have roles in
the nucleus.
Ubiquitin system
Free
ubiquitin
Degraded
Activated protein
proteosome
ubiquitin
Damaged protein
Ubiquitinated protein
Increased functional demand
• Increased functional demand can be met by
two main responses
hypertrophy
• Increase in cell size:
LV=left ventricle
Pathological hypertrophy
Myocardium in hypertensive heart disease
Physiological hyperplasia
Endometrium in the menstrual cycle
Physiological hyperplasia
Pregnant uterus
Normal uterus
Pathological hyperplasia
RP = rete peg
DP = dermal papilla
Hyperplasia may be nodular
• Hyperplasia may occur in a non-uniform pattern in
an organ or tissue - termed nodular hyperplasia
• Examples include
• hyperplasia of the prostate gland
• hyperplasia of the breast
Nodular hyperplasia of prostate
• Aerobic respiration –
• ATP depletion or decreased synthesis.
• Cell membranes - plasma membranes, mitochondrial,
lysosomal and other organelle membranes.
• Protein synthesis.
• Cytoskeleton.
• Genetic apparatus.
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© 2005 Elsevier
ATP DEPLETION - HYPOXIA/ISCHAEMIA
• Mitochondria - reduced oxidative phosphorylation.
• Cell membrane - reduced sodium pump.
• Sodium and water enter the cell; potassium exits.
• Endoplasmic reticulum dilates, the cell swells, blebs appear.
• Anaerobic glycolysis occurs with loss of glycogen, accumulation of lactic
acid, acid pH which interferes with enzymes.
• Failure of the calcium pump leads to influx of Ca++ into the cell, activate
various enzymes to the detriment of the cell.
• RER loses ribosomes and protein synthesis falls - structural proteins
(membranes,cytoskeleton) and enzymes.
• Misfolded proteins lead to the unfolded protein response which may
further injure the cell.
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© 2005 Elsevier
THE IMPORTANCE OF CALCIUM
• Influx of calcium to the cytosol comes from the extracellular
fluid and stores in mitochondria and endoplasmic reticulum.
• Ca++ activates phospholipases (damages cell
membranes),proteases (damages cell membranes and
cytoskeleton) and endonucleases (damages DNA).
• This is one of the main mechanisms of cell death, either
through severe damage to membranes of lysosomes and
leakage of lysosomal enzymes or triggering apoptosis.
• Occurs particularly in hypoxia and ischaemia and with certain
toxins. Preventing the rise in Ca++ or restoring to normal levels
prevents cell death.
© 2005 Elsevier
THE IMPORTANCE OF FREE
RADICALS
• Free radicals have a single unpaired electron in the outer
orbit. They are highly reactive with adjacent molecules.
• Are usually derived from oxygen to produce reactive oxygen
species, superoxide, hydroxyl radicals,H2O2,etc.
• Are normally produced during cellular respiration.
Protective molecules include superoxide dismutase,
glutathione peroxidase, vitamin E, vitamin C, catalase.
• Produced in excess, they react with, and damage proteins,
lipids, carbohydrates, nucleic acids.
• These damaged molecules may themselves be reactive
species with a chain reaction being set up with widespread
damage.
FREE RADICALS
• Mitochondria –
• mitochondrial permeability transition;
• this non-selective pore may be reversible or become permanent leading to cell
death.
• Leakage of cytochrome c can trigger apoptosis.
• Plasma membrane –
• mechanisms include those occuring with hypoxia/ischaemia and free radicals,
but also
• immune mechanisms as with complement activation and
• perforin from lymphocyte attack on cells infected with a virus.
• All membranes may be damaged and ruptured by
• mechanical force as in trauma, or by
• ice crystals as in extreme cold.
• Damage to lysosomal membranes can lead to cell death by necrosis.
CHEMICAL & BIOLOGICAL AGENTS
• Fat necrosis:
• enzymatic digestion of fat.
• Example: necrosis of fat by pancreatic enzymes.
• Gangrenous necrosis:
• Necrosis (secondary to ischemia)
• usually with superimposed infection.
• Example: necrosis of distal limbs, usually foot and toes in diabetes.
Caseous Necrosis
• Microscopically, caseous
necrosis is characterized
by acellular pink areas of
necrosis, as seen here at
the upper right,
surrounded by a
granulomatous
inflammatory process.
• Caseous necrosis hilar lymph
node lung
Fat Necrosis
• This is fat necrosis of the
pancreas. Cellular injury to
the pancreatic acini leads to
release of powerful enzymes
which damage fat by the
production of soaps, and
these appear grossly as the
soft, chalky white areas seen
here on the cut surfaces.
Gangrenous Necrosis
• In this case, the toes
were involved in a
frostbite injury. This is an
example of "dry"
gangrene in which there
is mainly coagulative
necrosis from the anoxic
injury.
• Gummatous necrosis is restricted to necrosis involving
spirochaetal infections (e.g. syphilis).
• Haemorrhagic necrosis is due to blockage of the venous
drainage of an organ or tissue (e.g. in testicular torsion).
• Fibrinoid necrosis is caused by immune-mediated
vascular damage. It is marked by deposition of fibrin-like
proteinaceous material in arterial walls, which appears
smudgy and eosinophilic on light microscopy.
•END lecture
Morphological Forms of
Programmed Cell Death
Type I = Apoptosis
Type II = Autophagic Cell Death
Type III = Non-lysosomal
Kerr, Wyllie, and Currie, 1972; Schweicheland Merker, 1973; Clarke 1990Kerr,
Wyllie, and Currie, 1972; Schweicheland Merker, 1973
Apoptosis
• Shrinkage of cells
• Condensation of nuclear chromatin peripherally under nuclear
membrane
• Formation of apoptotic bodies by fragmentation of the cells and nuclei.
The fragments remain membrane-bound and contain cell organelles
with or without nuclear fragments.
• Phagocytosis of apoptotic bodies by adjacent healthy cells or
phagocytes.
• Unlike necrosis, apoptosis is not accompanied by inflammatory reaction
Apoptosis
• In this fetal thymus there is involution
of thymic lymphocytes by the
mechanism of apoptosis.
• Individual cells fragment and are
consumed by phagocytes to give the
appearance of clear spaces filled with
cellular debris.
• Apoptosis is controlled by many
mechanisms.
• Genes such as Bcl-2 are turned off and
Bax genes turned on.
• Proteolytic enzymes called caspases
produce much cellular breakdown.
Apoptosis
• Apoptosis is a more orderly
process of cell death in
which there is individual cell
necrosis, not necrosis of
large numbers of cells.
• In this example, liver cells
are dying individually
(arrows) from injury by viral
hepatitis.
• The cells are pink and
without nuclei.
Autophagy
• When cells are faced with an inadequate supply of
nutrients in their extracellular fluid (ECF), they may
begin to cannibalize some of their internal
organelles (e.g. mitochondria) for re-use of their
components.
• Autophagy refers to a set of diverse processes
whereby intracytoplasmic material is delivered to
lysosomes.
Autophagy
Autophagy is a regulated process for the removal of
damaged proteins and organelles.
Autophagy occurs under basal conditions and is
stimulated by environmental factors such as
starvation.
There is evidence that proteins that are linked to
tumorigenesis can regulate the rate of autophagy,
with oncogenes in general blocking and tumour
suppressors stimulating the process.
The removal of damaged cellular components,
especially damaged mitochondria, might decrease
the level of reactive oxygen species (ROS), which
in turn might reduce genomic instability or
forestall cellular senescence.
Such mechanisms might allow moderate increases in
autophagy to reduce the incidence of cancer and
prolong lifespan.
Autophagy involves: