Ans. is 'a' i.e., ATP; 'b' i.e., is Cytosolic Ca'; 'c' i.e., Membrane damage; Cell injury o Cell injury results when cells are stressed so severly that they are no longer able to adapt i.e., when the limits of adaptive response to a stimulus are exceeded, cell injury occurs. o Cell injury is reversible up to a ceain point, but if the stimulus persists or is severe enough from the beginning, the cell reaches a "point of no return" and suffers irreversible injury and ultimate cell death. o Adaptation, reversible injury and irrversible injury & cell death are stages of progressive impairment of the cell's normal function and structure. Mechanism of injury o Regardless of the nature of injurious agents, there are a number of common biochemical themes or mechanisms responsible for cell injury:? A. Diminished generation ofATP o Diminished generation of ATP constitutes the critical mechanism of cellular injury and occurs in both reversible and irreversible phases. o Depletion of ATP to < 5% to 10% of normal levels has widespread effects on many critical cellular system : ? Activity of Na+ K+ ATPase is reduced. It is ATP dependent pump that cause effux of Na+ and influx of K+. Decreased activity of this pump leads to intracellular accumulation of sodium. The net gain in solute is accompnied by isoosmotic water gain, causing cell swelling. Normally Na+ inhibits efflux of Ca' and promotes influx of Ca+2. When activity of Na+K+ ATPase is reduced, there is increased intracellular Na+--> T influx and efflux of Ca' --> T intracellular calclium. 3Decreased ATP synthesis results in an increased rate of anaerobic glycolysis --> T Lactic acid accumulation .1, pH --> decreased activity of many cellular enzymes and clumping of nuclear chromatin. 4.Depletion of ATP results in structural disruption of protein synthetic apparatus Detachment of ribosomes from rough endoplasmic reticulum (ER) reduction in protein synthesis. B. Increased intracellular calcium o Sustained rise in intracellular calcium activates a number of enzymes ATPase fuher ATP depletion Phospholipases Membrane damage Proteases --> Damage to membrane and cystoskeleton proteins. Endonulcease --> Damage to DNA. C. Membrane damage o It occurs due to Mitochondrial dysfunction --> Defective mitochondrias function results in decrease phospholipid synthesis which is an impoant constituent of cell membrane and mitochondrial membrane. Increased intracellular Ca' activates phospholipase --> Damage to cell membrane, mitochondrial membrane and membrane of other organelles. Increase in intracellular Ca' results in activation of proteases --> damage to cystoskeletal filaments that serve as anchors connecting the plasma membrane to the cell interior. Free radicals cause damae to cell membrane. D. Release of lysosomal enzymes o The membrane damage combined with low pH cause leakage of lysosomal enzymes (RNases, DNases, phosphatases, proteases, glucosidases, Cathepsins) that leads to enzymatic digestion of cell component, resulting in loss of ribonucleoprotein (RNP), deoxyribonucleoprotein & glycogen, and the cells die by necrosis.