general pathology

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5. Apoptosis
Apoptosis is a pathway of cell
death that is induced by a tightly
regulated suicide program in which
cells destined to die activate
intrinsic enzymes that degrade the
cells’ own nuclear DNA and nuclear
and cytoplasmic proteins.

6. Apoptosis
Apoptotic cells break up into
fragments, called apoptotic bodies,
which contain portions of the
cytoplasm and nucleus.
It was quickly appreciated that
apoptosis was a unique mechanism of
cell death, distinct from necrosis
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7. Apoptosis
Because it is genetically regulated,
apoptosis is sometimes referred to as
programmed cell death.
As already alluded to, certain forms of
necrosis,called necroptosis, are also
genetically programmed, but by a distinct
set of genes.
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8. Causes of Apoptosis
Apoptosis occurs normally both
during development and through
out adulthood,
It is also a pathologic event when
diseased cells become damaged
beyond repair and are eliminated.
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9. Apoptosis in Physiologic Situations
Death by apoptosis is a normal phenomenon
that serves to eliminate cells that are no
longer needed, and to maintain a steady
number of various cell populations in tissues.
It is important in the following physiologic
situations:
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10. Apoptosis in Physiologic
Situations
The destruction of cells during embryogenesis,
including implantation, organogenesis,
developmental involution,and metamorphosis
Involution of hormone-dependent tissues upon
hormone with drawal,such as endometrial cell
breakdown during the menstrual cycle, ovarian
follicular atresia in menopause,the regression
of the lactating breast after weaning, and
prostatic atrophy after castration. 10

11. Apoptosis in Physiologic Situations
Cell loss in proliferating cell populations,
such as immature lymphocytes in the
bone marrow
Elimination of potentially harmful self-
reactive lymphocytes, either before or
after they have completed their
maturation,so as to prevent reactions
against one’s own tissues 11

12. Apoptosis in Physiologic
Situations
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.
In these situations cells undergo apoptosis
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13. Apoptosis in Pathologic Conditions
Apoptosis eliminates cells that
are injured beyond repair without
eliciting a host reaction,
Death by apoptosis is responsible
for loss of cells in a variety of
pathologic states:
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14. Apoptosis in Pathologic Conditions
DNA damage. Radiation, cytotoxic anticancer
drugs, and hypoxia can damage DNA, either
directly or via production of free radicals.
In these situations elimination of the cell
may be a better alternative than risking
mutations in the damaged DNA, which may
result in malignant transformation.
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15. Accumulation of misfolded proteins
Apoptosis caused by the
accumulation of misfolded
proteins has been invoked as the
basis of several degenerative
diseases of the central nervous
system and other organs
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16. • Cell death in certain infections, particularly
viral infections,in which loss of infected cells
is largely due to apoptosis that may be
induced by the virus (as in adenovirus and
HIV infections) or by the host immune
response (as in viral hepatitis).
• Pathologic atrophy in parenchymal organs
after duct obstruction,such as occurs in the
pancreas, parotid gland, and kidney
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17. Morphologic and Biochemical Changes
in Apoptosis
Cell shrinkage. The cell is
smaller in size, the
cytoplasm is dense and the
organelles, although
relatively normal, are more
tightly packed
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18. Morphologic and Biochemical Changes
in Apoptosis
• MORPHOLOGY
• Cell shrinkage. The cell is
smaller in size, the
cytoplasm is
• dense and the organelles,
although relatively
• normal, are more tightly
packed
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20. Chromatin condensation.
chromatin aggregates
peripherally, under the
nuclear membrane, into
dense masses of various
shapes and sizes
• The nucleus itself may
break up
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21. cytoplasmic blebs and apoptoticbodies
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22. Phagocytosis of apoptotic cells or cell bodies, usually
by macrophages
• The apoptotic bodies are rapidly ingested
• by phagocytes and degraded by the
phagocyte’s lysosomal enzymes.
• Plasma membranes are thought to
remain intact during apoptosis, until the
last stages, when they become
permeable to normally retained solutes.
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23. histologic examination, in tissues stained with hematoxylin and eosin
apoptotic cell appears as a round or oval
mass of intensely eosinophilic cytoplasm
with fragments of dense nuclear chromatin
• does not elicit inflammation,
• making it more difficult to
• detect histologically
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31. Apoptosis results from the
activation of enzymes called
caspases (so named because
they are cysteine proteases)
Like many proteases, caspases
exist as inactive proenzymes,
or zymogens,
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32. must undergo enzymatic
cleavage to become active.
The presence of cleaved,
active caspases is a marker for
cells undergoing apoptosis
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33. The process of apoptosis may be
divided into an initiation phase,
during which some caspases
become catalytically active,
and an execution phase, during
which other caspases trigger the
degradation of critical cellular
components.
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34. The activation of
caspases depends on a
finely tuned balance
between production of
pro-apoptotic and anti-
apoptotic proteins
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35. Two distinct pathways
converge on caspase
activation:
the mitochondrial
pathway and the death
receptor pathway
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36. The two pathways of
apoptosis differ in
their induction and
regulation, and both
culminate in the
activation of caspases.
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37. In the mitochondrial pathway,
proteins of the BCL2 family,
which regulate mitochondrial
permeability, become
imbalanced and leakage of
various substances from
mitochondria leads to caspase
activation.
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38. In death receptor pathway,
signals from plasma membrane
receptors lead to the assembly
of adaptor proteins into a
“death-including signaling
complex,” which activates
caspases, and the end result is
the same.
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40. The Intrinsic (Mitochondrial)
Pathway of Apoptosis
The mitochondrial pathway is
the major mechanism of
apoptosis
It results from increased
permeability of the mitochondrial
outer membrane cont
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41. with consequent release of death-
inducing (pro-apoptotic) molecules from
the mitochondrial intermembrane
space into the cytoplasm
Mitochondria are remarkable organelles
in that they contain proteins such as
cytochrome c that are essential for life
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42. when released into the cytoplasm
(an indication that the cell is not
healthy), initiate the suicide
program of apoptosis.
The release of mitochondrial pro-
apoptotic proteins is tightly
controlled by the BCL2 family of
proteins
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43. Anti-apoptotic.
BCL2, BCL-XL, and MCL1 are the principal members of
this group; they possess four BH domains (called BH1-
4). These proteins reside in the outer mitochondrial
membranes as well as the cytosol and ER membranes.
By keeping the mitochondrial outer membrane
impermeable they prevent leakage of cytochrome c
and other death-inducing proteins into the cytosol
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44. • Pro-apoptotic. BAX and BAK
• They also have four BH domains
• Upon activation, promote
mitochondrial outer membrane
permeability.
• They form a channel in the outer
mitochondrial membrane, allowing
leakage of cytochrome c from the
intermembranous space.
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45. • Sensors.
• contain only one BH domain, the
third of the four BH domains, and
hence are sometimes called BH3-
only proteins.
• BH3-only proteins act as sensors of
cellular stress and damage, and
regulate the balance between the
other two groups, thus acting as
arbiters of apoptosis.
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46. The intrinsic (mitochondrial) pathway
of apoptosis.
A, Cell viabilityis maintained by the
induction of anti-apoptotic proteins
such as BCL2 by survival signals.
These proteins maintain the
integrity of mitochondrial
membranes and prevent leakage of
mitochondrial proteins.
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48. B, Loss of survival signals, DNA damage, and
other insults activate sensors that antagonize
the anti-apoptotic proteins and activate the
pro-apoptotic proteins BAX and BAK, which
form channels in the mitochondrial membrane.
The subsequent leakage of cytochrome c (and
other proteins, not shown) leads to caspase
activation and apoptosis.
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