Apoptosis

Definition

Causes / Significance

Morphology

Mechanism / Cellular events

Clinical significance

Definition

1. Pathway of cell death induced by a tightly regulated

intracellular program in which cells destined to die,

activate enzymes that degrade the cells own nuclear

DNA & nuclear & cytoplasmic proteins.

Definition:

2. Internally programmed cell death.

3.“A form of cell death, designed to eliminateunwanted host cells through activation ofcoordinated, internally programmed series ofevents effected by a dedicated set of geneproducts”.

Causes/significance

PHYSIOLOGICAL

PATHOLOGICAL

PHYSIOLOGICAL SITUATIONS:

Embryogenesis.

Hormone dependent involution in adults.

Cell deletion in proliferating populations.

Cell death by cytotoxic T cells.

Elimination of harmful self reactive lymphocytes.

Death of host cells that have served their useful purpose.

PATHOLOGICAL CONDITIONS

Injurious stimuli

Cell injury in viral diseases

Pathological atrophy in parenchymal organs after

duct obstruction

Cell death in tumours

MORPHOLOGY

Cell shrinkage

Chromatin condensation

Formation of cytoplasmic blebs & apoptotic

bodies

Phagocytosis of Apoptotic cell by macrophages

HISTOLOGICAL EXAMINATION

H&E STAIN

Apoptotic cell appears as an round/oval mass of

intensely eosinophilic cytoplasm with dense

nuclear chromatin fragments.

MECHANISM/CELLULAR EVENTS

1. SIGNALING

2. CONTROL & INTEGRATION

3. EXECUTION

4. REMOVAL OF DEAD CELLS

1. SIGNALING

Transmembrane signals

-suppress preexisting death programs

-initiate a death cascade

Tumour necrosis factor receptor (TNFR):

oligomerize leading to activation of initiator caspases & a

cascade of enzyme activation culminating in cell death.

2. CONTROL & INTEGRATION

Direct transmission of death signals by specific

adapter proteins to the execution mechanism.

Regulation of mitochondrial permeability by

members of BCL-2 family of proteins.

-mitochondrial permeability transition

Cytochrome c – apoptotic trigger

Cytochrome c binds to cytosolic proteins (e.g.,proapoptotic

protease activating factor/Apaf-1) & activates them triggering

execution caspases activation.

BCL-2 suppresses apoptosis by preventing increased

mitochondrial permeability.

Other members of BCL-2 family bind to BCL-2 &

modulate its antiapoptotic effect, thus BCL-Xl

inhibits apoptosis while BAX & BAD promote

programmed cell death.

3. EXECUTION

Protein cleavage

DNA breakdown

Protein cross-linking

Phagocytic recognition

Protein cleavage

Activation of caspases

-caspases – cleave cellular proteins (lamins) leads to break

up of nuclear scaffold & cytoskeleton

-activate DNase which degrade nuclear DNA.

DNA breakdown:

DNA breakdown into oligonucleosomes in multiples of 180-300

base pairs by Ca2+ & Mg2+ dependent endonucleaes.

DNA fragments identified by a technique agarose gel

electrophoresis.

Apoptosis-regular fragmentation associated with activation of

p53 gene.

Necrosis- “smeared” pattern.

Protein cross-linking

Via transglutaminase activation

-converts soluble cytoplasmic proteins into

covalently condensed shell leading to formation

of apoptotic bodies.

4. Phagocytic recognition

Apoptotic cells express phosphatidyl serine in the outer

layers of plasma membrane ‘flipped’ from the inner layers.

Some express thrombospondin an adhesive glycoprotein

Other proteins secreted by phagocytes may bind to

apoptotic cells & opsonize the cells for phagocytosis.

Tumours – apoptotic index as a measure of

proliferation

Apoptosis in tumours increases following irradiation &

immune responses.

Measurement of apoptosis in-vivo/ in-vitro following

treatment may predict effectiveness of therapy.

CLINICAL SIGNIFICANCE