3. • The morphologic hall mark of cell death is loss of nucleus that occurs
via nuclear condensation( pyknosis), fragmentation( karyorrhexis),
and dissolution( karyolysis)
4. Apoptosis
• Programmed cell death
• During growth and development, some cells serve a function
in the growth phase but need to be removed after their purpose
is fulfilled
5. Cont’d
• When DNA sustains irreparable damage (e.g., after low-dose radiation
exposure), the cell must be destroyed so mutations that have
developed will not be propagated.
• Apoptosis serves as a safety step by removing damaged cells from the
body
• Apoptotic cells break up into plasma membrane bound fragments
called apoptotic bodies, which contain portions of the cytoplasm and
nucleus
6. Causes of Apoptosis
Physiologic conditions
• The removal of supernumerary cells during development
• Involution of hormone-dependent tissues on hormone withdrawal
• Cell turnover in proliferating cell populations
• Elimination of potentially harmful self-reactive lymphocytes
• Death of host cells that have served their useful purpose. e.g.
neutrophils in an acute inflammatory response, and lymphocytes at
the end of an immune response
7. Cont’d
Pathologic conditions
• DNA damage
• Accumulation of misfolded proteins
• Induced during certain infections particularly viral infections, as a
result of the virus itself (as in adenovirus and HIV infections) or the
host immune response (as in viral hepatitis)
• Pathologic atrophy in parenchymal organs after duct obstruction, e.g.
in the pancreas, parotid gland, and kidney
8. Cont’d
• Phases of apoptosis
■ Initiation is the phase in which caspases (cysteine aspartic
acid proteases) become catalytically active
■ Execution is the phase in which the action of caspases causes death
of cell
• Caspases: lipid enzymes inducing apoptosis by activating cell death
9. Mechanism of apoptosis
• Apoptosis is initiated commonly by two pathways
• Extracellular and Intracellular pathways
• Both pathways share similar endpoints, culminating with the use of
caspases and prevention of inflammatory reaction.
10. Cont’d
Intrinsic (the mitochondrial) pathway of apoptosis
• Results from increased permeability of the mitochondrial outer
membrane with consequent release of death-inducing (pro-
apoptotic) molecules such as cytochrome c from the mitochondrial
intermembrane space into the cytoplasm
• Altered mitochondrial membrane = cytochrome c release = activates
protein = cell death
11.
12. Cont’d
• Several proteins regulate such mitochondrial permeability events
• Bcl-2 suppresses apoptosis in two ways: by direct action on
mitochondria to prevent increased permeability & by effects
mediated by interaction with other proteins
• P53 protein: accumulates within the nucleus if DNA is damaged. If the
DNA cannot be repaired then the P53 protein directs the cell for
apoptosis.
13. Cont’d
Extrinsic (Death receptor) pathway
• Initiated by engagement of plasma membrane death receptors
• Death receptors are members of the tumor necrosis factor (TNF) receptor
family that contain a cytoplasmic domain involved in protein-protein
interactions
• The best known death receptors are the type 1 TNF receptor (TNFR1)
and a related protein called Fas (CD95)
• In Fas-Fas ligand binding, the Fas ligand binds to a member of the tumor
necrosis factor family known as the Fas receptor
• The activated Fas receptor in turn activates FADD (Fas-associated death
domain), which in turn activates caspases
14.
15.
16.
17.
18. Morphology of apoptosis
• Cell shrinkage
• Chromatin condensation
• Formation of cytoplasmic blebs and apoptotic bodies
• Phagocytosis of apoptotic cells or cell bodies, usually by macrophages
* Apoptosis does not generate an inflammatory reaction as necrosis
does
22. Removal of Dead cells
• The formation of apoptotic bodies breaks cells up into "bite-sized”
fragments that are edible for phagocytes.
• The process of apoptotic cell phagocytosis is called efferocytosis
23. Necrosis
• Uncontrolled death of cells due to one of the various causes of
cellular injury
• Characterized by denaturation of cellular proteins, leakage of cellular
contents through damaged membranes, local inflammation, and
enzymatic digestion of the lethally injured cell.
24. Patterns of necrosis
Coagulative Necrosis
• Coagulative necrosis is the type of necrosis in which protein
denaturation is more prominent than enzymatic breakdown
• Microscopic morphology of coagulative necrosis:- There is increased
eosinophilia of the cytoplasm and decreased basophilia of the
nucleus; both are associated with preservation of the general cellular
architecture (the organ type is identifiable)
• Ischemia caused by obstruction in a vessel may lead to coagulative
necrosis of the supplied tissue in all organs except the brain
• A localized area of coagulative necrosis is called an infarct
26. Cont’d
Liquefactive Necrosis
• Liquefactive necrosis occurs in situations in which enzymatic
breakdown is more prominent than protein denaturation
• Characterized by digestion of the dead cells, resulting in
transformation of the tissue into a viscous liquid
• is seen in focal bacterial or occasionally in fungal infections, because
microbes stimulate the accumulation of leukocytes and the liberation
of enzymes from these cells
• The necrotic material is frequently creamy yellow because of the
presence of leukocytes and is called pus
• Seen in organs with high fat and low protein content e.g brain or in
organs with high enzymatic content e.g pancreas
27. hypoxic death of cells within the central nervous
system often manifests as liquefactive necrosis
28. Cont’d
Caseous Necrosis
• Caseous necrosis is a “cheesy-looking” necrosis associated with
tuberculosis infections
• Microscopically :- the necrotic area appears as a structureless
collection of fragmented or lysed cells and amorphous granular debris
enclosed within a distinctive inflammatory border
31. Cont’d
Fat Necrosis
• change in adipose tissue due to trauma or the release of enzymes
from adjacent organs (e.g., the pancreas)
• The trauma or enzymatic action causes a breakdown of lipid and a
release of fatty acids, which combine with calcium to form chalky
deposits
32. Fat necrosis. The areas of white chalky deposits represent foci of fat necrosis with calcium soap
formation (saponification) at sites of lipid breakdown in the mesentery
33. Cont’d
Gangrenous necrosis
• commonly used in clinical practice. It is usually applied to a limb,
generally the lower leg, that has lost its blood supply and has
undergone necrosis (typically coagulative necrosis)
• When bacterial infection is superimposed, there is more liquefactive
necrosis because of the actions of degradative enzymes in the
bacteria and the attracted leukocytes (giving rise to so-called wet
gangrene)
34. Cont’d
1. Dry Gangrene
• Usually seen on distal limbs of elderly
• Blood supply is little = ischemia
• Auto-amputation will happen
• There is clear demarcation between the gangrene and the normal
area
• If not amputated, might spread.
36. Cont’d
2. Wet Gangrene
• No clear demarcation
• Needs to be amputated (toxic otherwise)
• Most common
• Blood is a good growth media for bacteria
• Iron sulfide is formed (dark brown in color)
• Diabetic foot : high sugar content in the necrotized tissue which
favors growth of bacteria
38. Cont’d
3. Gas gangrene
• Formed by gas forming bacteria
• Can be demonstrated by physical examination :- when palpated it
forms a sound “cryptus” (the presence of gas in tissues)
• Caused by clostridium perfringens
40. Cont’d
Fibrinoid Necrosis
• vascular damage usually seen in immune reactions involving blood
vessels
• It typically occurs when complexes of antigens and antibodies are
deposited in the walls of arteries
• Microscopically :- bright pink and amorphous appearance in H&E
stains called “fibrinoid” (fibrin-like)
41. Fibrinoid necrosis in an artery. The wall of the artery shows
a circumferential bright pink area of necrosis with inflammation
