Dr.

Meena Patil
 Definition
 Morphological changes
 Types- Physiological
 - Pathological
 Mechanisms-
 Diff. between necrosis & apoptosis
 “ A form of cell death designed to eliminate
unwanted host cells through activation of
coordinated , internally programmed series
of events regulated by a set of gene products ”

“ Falling off ”
 Apoptosis- Coordinated and internally
programmed cell death in physiological and
pathological conditions.

Differs from necrosis.

No inflammatory reaction.
 Physiological  Pathological

During embryogenesis Injury due to heat

Hormone dependant- Radiation
endometrial shedding Cytotoxic drugs for
Lactating breast after cancer
weaning Tumour cells
Atrophy of thymus Autoimmune diseases
Involves single cell usually
Oval masses with intensely pink cytoplasm.
Nuclear chromatin condensed and aggregated
peripherally under nuclear membrane in
various shapes and sizes.
Ultimately karyorrhexis occurs.
Cells shrink, form cytoplasmic buds and
fragment into apoptotic bodies.
There is no inflammatory reaction but
apoptotic bodies are phagocytosed by
macrophages.
 Fig 1-18
A) Initiators of apoptosis-
1. Withdrawal of signals required for normal cell
survival-
e.g. Absence of certain hormones, growth factors,
cytokines
2. Extracellular signals- e.g. activation of FAS receptor
3. Intracellular stimuli- e.g. heat, radiation, hypoxia

B) Process of programmed cell death-

1. Activation of caspases- Protein-splitting enzymes
2. Activation of death receptors- FAS receptor (CD95) ,
a cell surface receptor present on cytotoxic (CD8+) T
cells.
3. Activation of growth controlling genes ( BCL-2 & p53)-
BCL-2 gene family includes both activators & inhibitors of
apoptosis.
Activators – BAX & BAD. Inhibitors- BCL-X

4. Cell death-
Above mechanisms lead to proteolytic actions on nucleus,
chromatin clumping, cytoskeletal damage, disruption of E.R.,
mitochondrial damage, & disturbed cell membrane.

C. Phagocytosis-
Membrane changes in apoptotic cells promote phagocytosis
Phosphotidylserine & thrombospondin molecules which
normally present on inside of cell memb., appear on outer
surface of cells , which promote phagocytosis
Not ass. with inflammation
 The withdrawal of positive signals; that is, signals
needed for continued survival, and
 The receipt of negative signals.

 The continued survival of most cells requires that they

receive continuous stimulation from other cells and,
for many, continued adhesion to the surface on which
they are growing.
 Withdrawal of Positive signals:

 Growth factors for neurons

 Interleukin-2 , an essential factor for the mitosis of
lymphocytes
 Receipt of negative signals-
 Increased levels of oxidants within the cell
 Damage to DNA by these oxidants or other agents like
• Ultraviolet rays
• x-rays
• Chemotherapeutic drugs

 Accumulation of proteins that failed to fold properly into their

proper tertiary structure
 Molecules that bind to specific receptors on the cell surface
and signal the cell
 Apoptosis triggered by internal signals:
 1. The intrinsic or mitochondrial pathway
 In a healthy cell, the outer membranes of its mitochondria
display the protein BCL-2 on their surface. Bcl-2 inhibits
apoptosis.
 2. Internal damage to the cell (e.g.from reactive oxygen species)
causes -
• Related proteins, Bad and Bax, to migrate to the surface
of the mitochondrion where they bind to Bcl-2 —
blocking its protective effect — and punch holes in the
outer mitochondrial membrane, causing ---
• Cytochrome C to leak out.
 The released cytochrome c binds to the protein Apaf-1 ("apoptotic
protease activating factor-1").

 Using the energy provided by ATP, these complexes aggregate to

form apoptosomes.

 The apoptosomes bind to and activate caspase-9.

 Caspase-9 is one of a family of over a dozen caspases.

 They are all proteases They get their name because they cleave
proteins at aspartic acid (Asp) residues.

 . Caspase-9 cleaves and, activates other caspases (caspase-3 and -7).

 The activation of these caspases creates an expanding cascade of
proteolytic activity ,which leads to digestion of structural proteins in
the cytoplasm, degradation of chromosomal DNA, and phagocytosis
of the cell.
 triggered by external signals: the
 2. Apoptosis
extrinsic or death receptor pathway
 Fasand the TNF receptor are integral membrane
proteins with their receptor domains exposed at
the surface of the cell

 Binding of the complementary death activator

(FasL and TNF respectively) transmits a signal to
the cytoplasm that leads to activation of caspase 8

 Caspase 8 (like caspase 9) initiates a cascade of

caspase activation leading to phagocytosis of the
cell.
 Necrosis Apoptosis

Stimuli Hypoxia Physiological

Toxins Pathological

Histology Cell swelling Single cell

condensation of chromatin
Disruption of Apoptotic bodies
organelles
Coagulation N
 Necrosis Apoptosis

Mechanism Mitochondrial Gene activation

damage, Endonuclease,
Membrane Caspase,
injury, Phosphatidylserine
Free radicals Thrombospondin

Tissue Inflammation No inflammation

reaction Phagocytosis of
apoptotic bodies
 Regulated mechanism of cell death that serves to eliminate
unwanted & irreparably damaged cells, with least possible host
reaction

 Characterized by:- 1. Enzymatic degradation of proteins & DNA,

initiated by caspases
 2. Recognition & removal of dead cell by
phagocytosis
 Initiated
by two pathways:-
 1. Mitochondrial (Intrinsic) pathway-
 is triggered by loss of survival signals, DNA damage &
accumulation of misfolded proteins; ass. with leakage of
proapoptotic proteins from mitochondrial memb. into the
cytoplasm, trigger caspase activation

 2. Death receptor (Extrinsic) pathway-

 Elimination of self-reactive lymphocytes & damage by
cytotoxic T lymphocytes; is initiated by engagement of death
receptors (TNF receptor family)by ligands on adjacent cells.
 Definition
 Morphological changes
 Types- Physiological
 - Pathological
 Mechanisms-
 Diff. between necrosis & apoptosis