Outline of Lecture
Cell death in living tissue
Necrosis (Not specified)
Apoptosis
Apoptosis
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.
Apoptosis
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
Thrombocytopenia.
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.
Comparison
Morphological features
Biochemical features
Physiological impact
Aging & cellular death
Cause by accumulation of injurious events
Genetically controlled developmental program.
Mechanism
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)
