Cellular Response to

Injury

By: Eyerusalem Fekade(MD)

CELLULAR RESPONSES TO STRESS AND
NOXIOUS STIMULI
 Cells are active participants in their environment and
any normal cell is in a steady state “Homeostasis.”
 As cells encounter physiologic stresses or pathologic
stimuli(change in homeostasis) they can undergo :-
i. Adaptation (adaptive responses) :- achieving a new
steady state and preserving viability and function,
if adaptive capability of a cell is exceeded,
ii. Cell Injury - Reversible / Irreversible(cell death)
develops.
 Adaptation, reversible injury, and cell death can be
considered stages of progressive impairment of the
cell's normal function and structure.

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CELLULAR RESPONSE…

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CELLULAR INJURY & ADAPTATION….

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CELLULAR ADAPTATION TO
STRESS
Adaptations are reversible changes in the
number, size, phenotype, metabolic activity, or
functions of cells in response to changes in their
environment. It can be:-

Physiologic adaptations usually

represent responses of cells to normal stimulation
by hormones or endogenous chemical mediators
(e.g., the hormone-induced enlargement of the
breast and uterus during pregnancy).

Pathologic adaptations are responses to

stress that allow cells to modulate their structure
and function and thus escape injury. 5
CELLULAR ADAPTATION TO
STRESS …
The principal Cellular adaptive responses are :-
 Hypertrophy
 Hyperplasia
 Atrophy
 Metaplasia
 Dysplasia

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HYPERTROPHY
 Hypertrophy refers to an increase in the size
of cells, resulting in an increase in the size of
the organ, often in response to increased
workload; induced by mechanical stress and by
growth factors.
 occurs in tissues incapable of cell division
(e.g. Cardiac muscle / myocardiocytes)
 The hypertrophied organ has no new cells,
just larger cells.
 The increased size of the cells is due not to
cellular swelling but to the synthesis of more
structural components.
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CONT’D…..
 Hypertrophy can be physiologic or pathologic and is
caused by increased functional demand or by
specific hormonal stimulation.
 The striated muscle cells in both the heart and the
skeletal muscles are capable of tremendous
hypertrophy, perhaps because they cannot
adequately adapt to increased metabolic demands
by mitotic division and production of more cells to
share the work.
 E.g - Physiologic hypertrophy

- weightlifter muscles due to mechanical workload.

- Enlarged breast & uterus in Pregnant due to
hormonal stimulation.
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 CONTD….
 E.g. of Pathologic hypertrophy
Cardiac hypertrophy due to Hypertension

Heart hypertrophy
in hypertension:

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MECHANISMS OF HYPERTROPHY
 Much of the understanding of hypertrophy is
based on studies of the heart.
 The mechanisms of cardiac muscle
hypertrophy involve many signal transduction
pathways, leading to the induction of a
number of genes, which in turn stimulate
synthesis of numerous cellular proteins.

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HYPERPLASIA
 Hyperplasia is an increase in the number of cells
in response to hormones and other growth factors
in an organ or tissue, usually resulting in
increased volume of the organ or tissue.
 occurs in tissues whose cells are able to divide
 Although hyperplasia and hypertrophy are two
distinct processes, frequently both occur
together, and they may be triggered by the same
external stimulus.
 Hyperplasia takes place if the cellular
population is capable of synthesizing DNA, thus
permitting mitotic division; by contrast,
hypertrophy involves cell enlargement without
cell division. 11
HYPERPLASIA
 Hyperplasia can be physiologic or pathologic.
 Physiological hyperplasia can be:-

i. Hormonal hyperplasia:- e.g. Breast enlargement

in females at puberty.
ii. Compensatory hyperplasia:- e.g. Liver
restoration after resection.
 Pathologic hyperplasia
e.g. Common skin wart due to HPV infection
- Endometrial hyperplasia

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ATROPHY

 Shrinkage in the size of the cell by loss of cell

substance is known as atrophy.
 It represents a form of adaptive response and
may culminate in cell death.
 When a sufficient number of cells are involved,
the entire tissue or organ diminishes in size, or
becomes atrophic.
 Atrophy can be physiologic or pathologic.

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ATROPHY….
 Physiologic atrophy is common during early
development.
 Some embryonic structures, such as the
notochord and thyroglossal duct, undergo
atrophy during fetal development.
 The uterus decreases in size shortly after
parturition, and this is a form of physiologic
atrophy.

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ATROPHY …
 Pathologic atrophy depends on the underlying
cause and can be local or generalized.
 The common causes of atrophy are the
following:
• Decreased workload (atrophy of disuse):
 When a broken limb is immobilized in a plaster
cast or when a patient is restricted to
complete bed rest, skeletal muscle atrophy
rapidly ensues.

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ATROPHY…
• Loss of innervation(denervation atrophy)
 Normal function of skeletal muscle is dependent
on its nerve supply. Damage to the nerves leads
to rapid atrophy of the muscle fibers supplied by
those nerves.
• Diminished blood supply:
 A decrease in blood supply (ischemia) to a tissue
as a result of arterial occlusive disease results in
atrophy of tissue owing to progressive cell loss.
 In late adult life, the brain undergoes
progressive atrophy, presumably as
atherosclerosis narrows its blood supply.
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ATROPHY …
• Inadequate nutrition: Profound protein-
calorie malnutrition.
• Loss of endocrine stimulation:
 Many endocrine glands, the breast, and the
reproductive organs are dependent on
endocrine stimulation for normal metabolism
and function.
 The loss of estrogen stimulation after
menopause results in physiologic atrophy of
the endometrium, vaginal epithelium, and
breast.

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ATROPHY …
 • Aging (senile atrophy):
 The aging process is associated with cell
loss, typically seen in tissues containing
permanent cells, particularly the brain and
heart.
• Pressure: Tissue compression for any
length of time can cause atrophy.

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ATROPHY….
 The fundamental cellular changes associated with
atrophy are identical in all of these settings.
 Atrophy results from a reduction in the structural
components of the cell.
 In atrophic muscle, the cells contain fewer
mitochondria and myofilaments and a reduced amount
of endoplasmic reticulum.
 By bringing into balance cell volume and lower levels
of blood supply, nutrition, or atrophic stimulation, a
new equilibrium is achieved.
 Although atrophic cells may have diminished function,
they are not dead. However, atrophy may progress to
the point at which cells are injured and die.

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MECHANISMS OF ATROPHY
 The biochemical mechanisms responsible for
atrophy are incompletely understood but are
likely to affect the balance between protein
synthesis and degradation.
 Increased protein degradation probably plays a
key role in atrophy.
 Mammalian cells contain multiple proteolytic
systems that serve distinct functions. Lysosomes
contain acid hydrolases (e.g., cathepsins) and
other enzymes that degrade endocytosed
proteins from the extracellular environment and
the cell surface as well as some cellular
components.
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METAPLASIA
 Metaplasia is a reversible change in which
one adult cell type (epithelial or
mesenchymal) is replaced by another adult
cell type.
 It may represent an adaptive substitution of
cells that are sensitive to stress by cell types
better able to withstand the adverse
environment.

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 METAPLASIA….
 The most common epithelial metaplasia is
columnar to squamous , as occurs in the
respiratory tract in response to chronic
irritation.
 In the habitual cigarette smoker, the normal
ciliated columnar epithelial cells of the
trachea and bronchi are often replaced focally
or widely by stratified squamous epithelial
cells.

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METAPLASIA …..
 Epithelial metaplasia is double-edged sword;
It is protective but, the influences that induce
metaplastic transformation, if persistent, may
predispose to malignant transformation of the
epithelium.

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MECHANISMS OF METAPLASIA
 Metaplasia does not result from a change in the
phenotype of a differentiated cell type; instead
it is the result of genetic reprogramming of
stem cells that are known to exist in normal
tissues, or of undifferentiated mesenchymal
cells present in connective tissue.
 In a metaplastic change, these precursor cells
differentiate along a new pathway.
 The differentiation of stem cells to a particular
lineage is brought about by signals generated
by cytokines, growth factors, and extracellular
matrix components in the cell's environment.
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CELL INJURY
 cell injury results when cells are stressed so
severely that they are no longer able to adapt or
when cells are exposed to inherently damaging
agents or suffer from intrinsic abnormalities. It
can be:-
 Reversible cell injury
 Cell swelling
 Accumulation of pigments
 Fatty change
 Irreversible cell injury(cell death)
 Apoptosis
 Necrosis

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CELL INJURY

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CELL INJURY…
 Causes of Cell Injury
 The causes of cell injury range from the
external gross physical violence of an
automobile accident to internal endogenous
causes, such as a subtle genetic mutation
causing lack of a vital enzyme that impairs
normal metabolic function.
 Most injurious stimuli can be grouped into
the following broad categories.

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CAUSE OF CELL INJURY…
 Oxygen Deprivation:
 Hypoxia is a deficiency of oxygen, which
causes cell injury by reducing aerobic
oxidative respiration.
 It is commonly due to low blood flow
(Ischemia) ,but can be also be due to poor
oxygenation of blood or decreased oxygen
carrying capacity of blood.
 Hypoxia is an extremely important and
common cause of cell injury and cell death.

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CELL INJURY…
 Physical Agents
 Physical agents capable of causing cell injury
include mechanical trauma, extremes of
temperature (burns and deep cold), sudden
changes in atmospheric pressure, radiation,
etc.

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CELL INJURY…
 Chemical Agents:
 Trace amounts of agents known as poisons,
such as arsenic, cyanide, or mercuric salts,
may destroy sufficient numbers of cells within
minutes to hours to cause death.
 Other substances, however, are our daily
companions: environmental and air pollutants,
insecticides, and herbicides; industrial and
occupational hazards, such as carbon
monoxide and asbestos; social stimuli, such as
alcohol and narcotic drugs; and the ever-
increasing variety of therapeutic drugs.
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CELL INJURY…
 Infectious Agents
 These agents range from the submicroscopic
viruses to the large tapeworms. In between
are the rickettsiae, bacteria, fungi, and
higher forms of parasites.

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CELL INJURY…
 The genetic injury may result in a
defect as severe as the congenital
malformations associated with Down
syndrome, caused by a chromosomal
abnormality, or as subtle as the decreased life
of red blood cells caused by a single amino
acid substitution in hemoglobin S in sickle cell
anemia.
 Variations in genetic makeup can also
influence the susceptibility of cells to injury
by chemicals and other environmental insults.

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CELL INJURY…
 Nutritional Imbalances
 Nutritional imbalances continue to be major
causes of cell injury. Protein-calorie
deficiencies cause an appalling number of
deaths, chiefly among underprivileged
populations.
 Deficiencies of specific vitamins are found
throughout the world

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CELL INJURY…
 Mechanisms of Cell Injury:
 The biochemical mechanisms responsible for
cell injury are complex.
 There are, however, a number of principles
that are relevant to most forms of cell
injury:

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MECHANISMS OF CELL INJURY:

 • The cellular response to injurious

stimuli depends on the type of injury, its
duration, and its severity.
 • The consequences of cell injury depend
on the type, state, and adaptability of the
injured cell.

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CELL INJURY…
 Cell injury results from functional and
biochemical abnormalities in one or more of
several essential cellular components.
 The most important targets of injurious
stimuli are: (1) aerobic respiration involving
mitochondrial oxidative phosphorylation and
production of ATP; (2) the integrity of cell
membranes, on which the ionic and osmotic
homeostasis of the cell and its organelles
depends; (3) protein synthesis; (4) the
cytoskeleton; and (5) the integrity of the
genetic apparatus of the cell.
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MECHANISMS OF CELL INJURY:

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MECHANISM OF CELL INJURY
 Main mechanism of cell
injury:
 1.ATP DEPLETION
 2. MITOCHONDRIAL DAMAGE
 3. INFLUX OF INTRACELLULAR CALCIUM AND LOSS
OF CALCIUM HOMEOSTASIS
 4. ACCUMULATION OF OXYGEN-DERIVED FREE
RADICALS (OXIDATIVE STRESS)
 5.DEFECTS IN MEMBRANE PERMEABILITY

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CELL INJURY
…ATP DPLN.

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MORPHOLOGY OF CELL INJURY:
 Reversible Injury
 Two patterns of reversible cell injury can be
recognized under the light microscope:
 cellular swelling and fatty change.
 Cellular swelling appears whenever cells are
incapable to maintaining ionic and fluid
homeostasis and is the result of loss of
function of plasma membrane energy-
dependent ion pumps.
 Fatty change occurs in hypoxic injury and
various forms of toxic or metabolic injury.
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MORPHOLOGY…
I. Cellular swelling:- is the first manifestation of
almost all forms of injury to cells.
 It is a difficult morphologic change to
appreciate with the light microscope; it may
be more apparent at the level of the whole
organ.
 When it affects many cells in an organ, it
causes some pallor, increased turgor, and
increase in weight of the organ.

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CELL INJURY…
II. Intracellular Accumulations:
 One of the manifestations of metabolic derangements in
cells is the intracellular accumulation of abnormal amounts
of various substances.
 The stockpiled substances fall into three categories:
 (1) a normal cellular constituent accumulated in excess,
such as water, lipids, proteins, and carbohydrates.
 (2) an abnormal substance, either exogenous, such as a
mineral or products of infectious agents, or endogenous,
such as a product of abnormal synthesis or metabolism; and
 (3) a pigment.
 These substances may accumulate either transiently or
permanently, and they may be harmless to the cells, but on
occasion they are severely toxic. 42
INTRACELLULAR
ACCUMULATIONS…
 Many processes result in abnormal
intracellular accumulations, but most
accumulations are attributable to three
types of abnormalities:
 1.A normal endogenous substance is
produced at a normal or increased rate, but
the rate of metabolism is inadequate to
remove it (example-fatty change).

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INTRACELLULAR
ACCUMULATIONS…
 2.A normal or abnormal endogenous
substance accumulates because of genetic or
acquired defects in the metabolism,
packaging, transport, or secretion of these
substances(example-storage disease).
 3.An abnormal exogenous substance is
deposited and accumulates because the cell
has neither the enzymatic machinery to
degrade the substance nor the ability of
transport it to other sites.

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INTRACELLULAR
ACCUMULATIONS…
A. Steatosis (Fatty Change)
 The terms steatosis and fatty change describe
abnormal accumulations of triglycerides within
parenchymal cells.
 Fatty change is often seen in the liver because it
is the major organ involved in fat metabolism,
but it also occurs in heart muscle, and kidney.
 The cause of steatosis include toxins, protein
malnutrition, diabetes mellitus, obesity, and
anoxia.
 In industrialized nations, by far the most
common cause of significant fatty change in the
liver (fatty liver) is alcohol abuse.
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INTRACELLULAR
ACCUMULATIONS…
 Different mechanisms account for triglyceride
accumulation in the liver.
 Free fatty acids from adipose tissue or ingested food
are normally transported into hepatocytes.
 In the liver, they are esterified to triglycerides,
converted into cholesterol or phospholipids, or
oxidized to ketone bodies.
 Release of triglycerides from the hepatocytes requires
association with apoproteins to form lipoproteins,
which may then traverse the circulation.
 Excess accumulation of triglycerides within the liver
may result from defects in any one of the events in
the sequence from fatty acid entry to lipoprotein
exit.
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INTRACELLULAR
ACCUMULATIONS…

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FATTY CHANGE…
 Morphology
 Fatty change in most often seen in the liver
and heart. In all organs, fatty change appears
as clear vacuoles within parenchymal cells.
 In the liver, mild fatty change may not affect
the gross appearance.
 With progressive accumulation, the organ
enlarges and becomes increasingly yellow
until, in extreme instances, the liver may
weigh 3 to 6 kg and be transformed into a
bright yellow, soft, greasy organ.

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FATTY CHANGE…

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INTRACELLULAR
ACCUMULATIONS…
B. PIGMENTS
 Pigments are colored substances, some of
which are normal constituents of cells (e.g.,
melanin), whereas others are abnormal and
collect in cells only under special
circumstances.
 Pigments can be exogenous, coming from
outside the body, or endogenous, synthesized
within the body itself.

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INTRACELLULAR
ACCUMULATIONS…
 Exogenous Pigments
 The most common exogenous pigment is
carbon or coal dust, which is a ubiquitous air
pollutant of urban life.
 When inhaled, it is picked up by
macrophages within the alveoli and is then
transported through lymphatic channels to
the regional lymph nodes in the
tracheobronchial region.

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INTRACELLULAR
ACCUMULATIONS…
 Accumulations of this pigment blacken the
tissues of the lungs (anthracosis) and the
involved lymph nodes.
 In coal miners, the aggregates of carbon dust
may induce a fibroblastic reaction or even
emphysema and thus cause a serious lung
disease known as coal worker's
pneumoconiosis.
 Tattooing is a form of localized, exogenous
pigmentation of the skin.

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INTRACELLULAR
ACCUMULATIONS…
 Endogenous Pigments
 Bilirubin is the normal major pigment found
in bile.
 It is derived from hemoglobin but contains no
iron.
 Its normal formation and excretion are vital
to health, and jaundice is a common clinical
disorder caused by excesses of this pigment
within cells and tissues.

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 ENDOGENOUS PIGMENTS…
 Hemosiderin is a hemoglobin-derived, golden
yellow-to-brown, granular or crystalline pigment
accumulates in tissues when there is a local or
systemic excess of iron due to excessive red blood
cell break down . E.g. in hemorrhage.
 In most instances of systemic hemosiderosis, the
pigment does not damage the parenchymal cells or
impair organ function.
 The more extreme accumulation of iron, however,
in a disease called hemochromatosis, is associated
with liver, heart, and pancreatic damage, resulting
in liver fibrosis, heart failure, and diabetes
mellitus. 54
HEMOSIDERIN GRANULES IN LIVER CELLS.
A, H&E SECTION SHOWING GOLDEN-BROWN, FINELY GRANULAR PIGMENT.

B, PRUSSIAN BLUE REACTION, SPECIFIC FOR IRON .

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PATHOLOGIC CALCIFICATION
 Pathologic calcification is the abnormal
tissue deposition of calcium salts, together
with smaller amounts of iron, magnesium,
and other mineral salts.
 It is a common process occurring in a variety
of pathologic conditions.
 There are two forms of pathologic
calcification.

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PATHOLOGIC CALCIFICATION…
 1.When the deposition occurs locally in dying
tissues, it is known as dystrophic
calcification; it occurs despite normal serum
levels of calcium and in the absence of
derangements in calcium metabolism.
 2.In contrast, the deposition of calcium salts
in otherwise normal tissues is known as
metastatic calcification, and it almost
always results from hypercalcemia secondary
to some disturbance in calcium metabolism.

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IRREVERSIBLE CELL INJURY
 Irreversibly injured cells invariably undergo
morphologic changes that are recognized as
cell death.
 There are two types of cell death, necrosis
and apoptosis, which differ in their
morphology, mechanisms, and roles in
disease and physiology.
 When damage to membranes is severe,
lysosomal enzymes enter the cytoplasm and
digest the cell, and cellular contents leak
out, resulting in necrosis.
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 IRREVERSIBLE CELL INJURY…
 Necrosis is the major pathway of cell death in
many commonly encountered injuries, such as
those resulting from ischemia, exposure to toxins,
various infections, and trauma.
 When a cell is deprived of growth factors or the
cell's DNA or proteins are damaged beyond repair,
the cell kills itself by another type of death, called
apoptosis, which is characterized by nuclear
dissolution without complete loss of membrane
integrity.

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 IRREVERSIBLE CELL INJURY…
 There may be some overlaps and common
mechanisms between these two pathways. In
addition, at least some types of stimuli may induce
either apoptosis or necrosis, depending on the
intensity and duration of the stimulus, the rapidity
of the death process, and the biochemical
derangements induced in the injured cell.
 Whereas necrosis is always a pathologic process,
apoptosis serves many normal functions and is
not necessarily associated with cell injury.

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61
IRREVERSIBLE CELL INJURY…
 Cells undergo sequential biochemical and
morphologic changes as they are
progressively injured and ultimately die by
necrosis.
 Cellular function may be lost long before cell
death occurs, and the morphologic changes
of cell injury (or death) lag far behind both .

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63
1. NECROSIS

 Necrosis refers to a spectrum of morphologic

changes that follow cell death in living tissue,
largely resulting from the progressive
degradative action of enzymes on the lethally
injured cell (cells placed immediately in
fixative are dead but not necrotic).
 As commonly used, necrosis is the gross and
histologic correlate of cell death occurring in
the setting of irreversible exogenous injury.
 Necrotic cells are unable to maintain
membrane integrity and their contents often
leak out. This may elicit inflammation in the
surrounding tissue 64
MORPHOLOGY OF NECROSIS…
 The morphologic appearance of necrosis is
the result of denaturation of intracellular
proteins and enzymatic digestion of the cell.
 The enzymes are derived either from the
lysosomes of the dead cells themselves, in
which case the enzymatic digestion is
referred to as autolysis, or from the
lysosomes of immigrant leukocytes, during
inflammatory reactions.

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 MORPHOLOGY OF NECROSIS…
 Morphology In one common pattern of cell death
resulting from lack of oxygen, the necrotic cells
show increased eosinophilia (i.e., pink staining
from the eosin dye, the "E" in "H&E"). This is
attributable in part to increased binding of eosin
to denatured cytoplasmic proteins and in part to
loss of the basophilia that is normally imparted
by the ribonucleic acid (RNA) in the cytoplasm
(basophilia is the blue staining from the
hematoxylin dye, the "H" in "H&E"). The cell may
have a more glassy homogeneous appearance
than viable cells, mostly because of the loss of
glycogen particles.

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 PATTERNS OF TISSUE NECROSIS
 There are several morphologically distinct
patterns of tissue necrosis, which may provide
clues about the underlying cause. These are:-
 Coagulative necrosis – Eg. Infarction
 Liquifactive necrosis - Brain, abscess
 Caseous necrosis - Bacterial / Tuberculosis
 Fat necrosis

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MORPHOLOGY OF NECROSIS…
 When denaturation is the primary pattern,
coagulative necrosis develops.
 In the instance of dominant enzyme
digestion, the result is liquefactive necrosis;
in special circumstances, caseous necrosis
and fat necrosis may occur.

68
 MORPHOLOGY OF NECROSIS…
A. Coagulative necrosis implies preservation of
the basic outline of the coagulated cell for a
span of at least some days.
 The affected tissues exhibit a firm texture.
 Coagulative necrosis is characteristic of
infarcts (areas of ischemic necrosis) in all solid
organs except the brain.

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COAGULATIVE NECROSIS

70
 LIQUEFACTIVE NECROSIS
B. Liquefactive necrosis is characteristic of focal
bacterial or, occasionally, fungal infections, because
microbes stimulate the accumulation of inflammatory
cells and the enzymes of leukocytes digest ("liquefy")
the tissue.
 For obscure reasons, hypoxic death of cells within
the central nervous system often evokes liquefactive
necrosis.
 Whatever the pathogenesis, liquefaction completely
digests the dead cells.
 The end result is transformation of the tissue into a
liquid viscous mass. If the process was initiated by
acute inflammation , the material is frequently
creamy yellow because of the presence of dead white
cells and is called pus. 71
LIQUEFACTIVE NECROSIS

72
 CASEOUS NECROSIS
C. Caseous necrosis, a distinctive form of
coagulative necrosis, is encountered most often in
foci of tuberculous infection.
 The term caseous is derived from the cheesy white
gross appearance of the area of necrosis.
 On microscopic examination, the necrotic focus
appears as amorphous granular debris seemingly
composed of fragmented, coagulated cells and
amorphous granular debris enclosed within a
distinctive inflammatory border known as a
granulomatous reaction.
 Unlike coagulative necrosis, the tissue architecture
is completely obliterated 73
CASEOUS NECROSIS

74
FAT NECROSIS
 Fat necrosis is a term that is well fixed in
medical parlance but does not in reality
denote a specific pattern of necrosis.
 Rather, it is descriptive of focal areas of fat
destruction, typically occurring as a result of
release of activated pancreatic lipases into
the substance of the pancreas and the
peritoneal cavity.
 This occurs in the calamitous abdominal
emergency known as acute pancreatitis.

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II. APOPTOSIS

Apoptosis is a pathway of cell death that is induced by a
tightly regulated sucide program in which cells destined
to die activate enzymes that degrade the cells' own
nuclear DNA and nuclear and cytoplasmic proteins.
 The cell's plasma membrane remains intact, but its
structure is altered in such a way that the apoptotic cell
becomes an avid target for phagocytosis.
 The dead cell is rapidly cleared, before its contents have
leaked out, and therefore cell death by this pathway
does not elicit an inflammatory reaction in the host.
 Thus, apoptosis differs from necrosis, which is
characterized by loss of membrane integrity, enzymatic
digestion of cells, leakage of cellular contents, and
frequently a host reaction
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APOPTOSIS…
 Apoptosis in Physiologic Situations
 Death by apoptosis is a normal phenomenon
that serves to eliminate cells that are no
longer needed, as, for example, during
development, and to maintain a steady
number of various cell populations in tissues.
 It is important in the following physiologic
situations:

77
APOPTOSIS…
 • The programmed destruction of cells
during embryogenesis, including
implantation, organogenesis, developmental
involution and metamorphosis.
• Hormone-dependent involution in the
adult, such as endometrial cell breakdown
during the menstrual cycle, ovarian follicular
atresia in the menopause, the regression of
the lactating breast after weaning, and
prostatic atrophy after castration.

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 APOPTOSIS…
 • Cell deletion in proliferating cell
populations, such as intestinal crypt epithelia,
in order to maintain a constant number.
• Death of host cells that have served their
useful purpose, such as neutrophils in an acute
inflammatory response, and lymphocytes at
the end of an immune response.

79
APOPTOSIS…
 Apoptosis in Pathologic Conditions
 • Elimination of potentially harmful self-
reactive lymphocytes, either before or after
they have completed their maturation.
• Cell death induced by cytotoxic T
cells, a defense mechanism against viruses
and tumors that serves to eliminate virus-
infected and neoplastic cells.

80
 APOPTOSIS…
Mechanisms of Apoptosis
The fundamental event in apoptosis is the
activation of enzymes called caspases
Activated caspases cleave numerous targets,
culminating in activation of nucleases that
degrade DNA and other enzymes that
presumably destroy nucleoproteins and
cytokeletal proteins.

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MORPHOLOGY OF APOPTOSIS
 The following morphologic features, some best seen
with the electron microscope, characterize cells
undergoing apoptosis.
• Cell shrinkage. The cell is smaller in size; the
cytoplasm is dense; and the organelles, although
relatively normal, are more tightly packed.
• Chromatin condensation. This is the most
characteristic feature of apoptosis. The chromatin
aggregates peripherally, under the nuclear membrane,
into dense masses of various shapes and sizes.
• Formation of cytoplasmic blebs and apoptotic
bodies
• Phagocytosis of apoptotic cells or cell bodies,
usually by macrophages.
82
Feature Necrosis Apoptosis
Cell size Enlarged (swelling) Reduced (shrinkage)
Plasma membrane Disrupted Intact; altered
structure, especially
orientation of lipids

Cellular contents Enzymatic digestion; Intact; may be

may leak out of cell released in apoptotic
bodies
Adjacent Frequent No
inflammation
Severe ATP depletion Active, No ATP
ATP depletion
Physiologic or Invariably pathologic Often physiologic,
pathologic role (culmination of means of eliminating
irreversible cell injury) unwanted cells; may
be pathologic after
some forms of cell
injury, especially DNA
damage 83
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t ’s
h a
T 84