Cell Death Dr. Sadaf Mumtaz 19/12/11

Cell Injury Reversible cell injury Irreversible cell injury ‘The functional and morphologic changes are reversible if the damaging stimulus is removed’ Irreversible cell injury ‘With continuing damage the injury becomes irreversible, at which time the cell cannot recover and it dies’

Causes of cell injury Oxygen deprivation Cardiorespiratory failure, anemia, after blood loss Physical agents Mechanical trauma, temperature, electric shock Chemical agents and drugs Arsenic, cyanide, alcohol, insectisides Infectious agents Viruses, bacteria, fungi Immunological reactions Autoimmune diseases, microbes and enviromental substances Genetic derrangements Sickle cell anaemia Nutritional imbalances Vitamin deficiencies, Atherosclerosis

Cell Death Necrosis Apoptosis ‘Loss of membrane integrity, enzymatic digestion of cells, leakage of cellular contents and frequently a host reaction’ Apoptosis ‘Nuclear dissolution, fragmentation of cell without complete loss of membrane integrity and rapid removal of cellular debris’

‘Programmed cell death’ Apoptosis ‘Programmed cell death’ Process was identified in 1972 Named after the Greek designation for ‘falling off’ Physiological Pathological Eliminates cells that are no longer needed and to maintain a steady number of various cell population in tissues Eliminates cells that are injured beyond repair without eliciting a host reaction, thus limiting collateral tissue damage

Apoptosis in physiological and pathological conditions The programmed destruction of cells during embryogenesis DNA damage Involution of hormone dependent tissues upon hormone withdrawal Accumulation of misfolded proteins Cell loss in proliferating cell populations Cell death in certain infections, particularly viral infection, tumors and cellular rejection of transplant Elimination of potentially harmful self-reactive lymphocytes Pathological atrophy in parenchymal organs after duct obstruction, such as occurs in pancreas, parotid gland and kidney. Death of host cells that have served their useful purpose

Morphological changes in apoptosis

Biochemical features of apoptosis Activation of caspases ‘C’ refers to ‘cysteine proteases’ and ‘aspase’ refers ‘to the unique ability of these enzymes to cleave after aspartic acid residues’

Biochemical features of apoptosis DNA and Protein breakdown Ca2+ and Mg2+ dependent endonucleases

Biochemical features of apoptosis Membrane alterations and recognition by phagocytes ‘Annexin V Staining’ The exposed lipids are detectable by binding of a protein called ‘Annexin V’

Mechanisms of apoptosis C Elegans Intrinsic or mitochondrial pathway The extrinsic or death receptor-initiated pathway

The Intrinsic (mitochondrial pathway) of apoptosis

The extrinsic (death receptor-initiated) pathway of apoptosis Bid Activation of mitochondrial pathway FLIP

Removal of dead cells Phospholipids fliping Release of soluble factors by apoptotic cells Thrombospondin Macrophages may themselves produce proteins Apoptotic cells may be coated with antibodies

Disorders associated with dysregulated apoptosis Defective apoptosis and increased cell survival Increased apoptosis and excessive cell death Neurodegenerative diseases (mutations and misfolded proteins) Ischemic injury, (MI and stroke) Death of virus infected cells Cancers & autoimmune diseases

Autophagy Cell eats its own contents Occurs in times of nutrient deprivation Autophagic vacuole---Autophagolysosome

Laboratory assesments of apoptosis DNA laddering Annexin 5 staining Flow cytometry

Thankyou

FLIP FLICE like inhibitory protein ‘Fas-associated death domain-like interleukin 1β-converting enzyme’