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Outline of Lecture

Cell death in living tissue

Necrosis (Not specified)



Programmed cell death-suicide

Cell membrane remains intact

No inflammatory reaction

Natural in physiological embryogenesis

Induced in therapeutic radiotherapy / chemotherapy

Examples physiologic apoptosis

During growth development & Embryogenesis.

Homeostatic mechanisms maintains cell population.

In aging

Shedding of menstrual endometrium

Involution of breast after weaning.


Require activations signal →protein cleavage within  cell causing cell death.

Programmed & energy dependent process designed to switch off & eliminate cells.

Cell shrinkage.

Chromatin condensation

Formation of cytoplasmic blebs & apoptotic bodies

Phagocytosis of apoptotic bodies.

Activation pathways

Intrinsic mitochondrial pathway

↑ mitochondrial membrane permeability → cytochrome c & AIF →                                                activates caspases → death.

–    1.Withdrawal of GF

–    2.injury

Extrinsic death receptor pathway

–    1. FAS & TNF1 receptor families with death domain.

–    2. CTL CD8+

Intrinsic mitochondrial pathway

Examples withdrawal of positive signal.

–   GF for neuron

–   IL-2 for lymphocytes

Examples of receipt of negative signals.

–   ↑ ICF oxidants

–   UV light, X-rays, chemotherapeutic agents

–   Misfolded proteins

–   TNF-α, TNF-β (lymphokines).

–   Fas-ligand (Fas-L)

Intrinsic mitochondrial pathway

Normal Bcl-2 on outer (M) membrane inhibit apoptosis.

In damaged cell Bax protein inhibits
(M ) Bcl-2 , & punches hole in (M) membane causing release of cytochrome-c into cytoplasm.

Cytochrome-c binds Apaf-1 (apoptotic protease activating factor-1)

Activates caspases 9→3 →7.

Intrinsic mitochondrial pathway (AIF)

Neuron does not use caspase

AIF located intermembrane space of mitochondria.

Released from mitochondria like in (1).

AIF migrates to nucleus.

Binds to DNA.

Triggers destruction of DNA.

Triggering apoptosis
Extrinsic death receptor
(Receptor-L interaction)

FasL ,TNF receptor →caspase 8→       exec caspase.

CD8+CTL mediated lysis of their target cells.

Directly activates executioner caspases leading to apoptosis.

Does not use caspases cascade.

Apoptosis & cancer

HPV produces protein E6 which binds & inactivates apoptosis promoter p53.

EBV produces protein similar to Bcl-2 & ↑own Bcl-2 make infected cell more resistant to apoptosis.

B-cell lymphoma ↑ level of Bcl-2

Melanoma inhibit expression of Apaf-1

Colon & lung cancer cells produce blocking protein for Fas receptor CTL cannot kill these tumor cells.

Some cancer cell produce FasL which kill CTL directed against these tumor cells.

Apoptosis & Autoimmune system

Mutation is Fas , FasL or caspases result in auto reactive lymphocytes producing

Autoimmune Hemolytic anemia


Apoptosis & AIDS

Normal CD4 count is 1000/µml of blood

AIDS <200/µml of blood

< 1/100,000 of CD4 cells are infected by HIV.

Nef HIV gene in infected cell causes high level of FasL on its surface

While preventing  interaction of its own Fas receptor with FasL from self-destruction.

After contact of infected CD4+ T cell with uninfected CD4 +T cell. The Uninfected T-cells are killed by apoptosis.

Physiologic apoptosis

During growth development & Embryogenesis.

Homeostatic mechanism maintains cell population.

In aging

Shedding of menstrual endometrium

Involution of breast after weaning.

Pathologic apoptosis

Prostatic atrophy after castration.

Death of inflammatory cells after inflammation.

When cells damaged by disease or injurious agents.

DNA damage by radiation ,chemotherapy, cytotoxic drugs.

Viral hepatitis

Neoplasia tumor which regress or involute

Deletion of autoreactive T cells in thymus.

Transplant rejection.


Morphological features

Biochemical features

Physiological impact

Aging & cellular death

Cause by accumulation of injurious events

Genetically controlled developmental program.


Genetic , environmental, behavioral.

∆ regulatory mechanism

Degenerative alteration

Cellular aging

Genetic  failure of repair mechanism, clock genes ↑ antioxidative enzymes (Telomerase )

Telomerase activity stops in somatic cells but continues in stem cells & germ cells.

Enviromental generation of FR

Accumulation of multiple defects →aging

Aged cells show

lipofuscin pigment,

abnormally folded protein & advanced glycogenated end products (AGES)

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