Today’s Quranic verse

1. Today’s Quranic verse But to those who believe and do deeds of righteousness, He will give their (due) rewards, and more, out of His bounty: But those who are disdainful and arrogant, He will punish with a grievous penalty; Nor will they find, besides God, any to protect or help them. [004:173] 

2. CELL INJURY

8. Principles of Cell Injury • Dependent upon the etiology, duration, and severity of the inciting injury • Dependent upon cell type, stage of cell cycle, and cell adaptability • Cellular membranes, mitochondria, endoplasmic reticulum, and the genetic apparatus are particularly vulnerable • Injury at one focus often has a cascade effect • Morphologic reactions occur only after critical biochemical (molecular) damage

9. Normal cell is in a steady state “Homeostasis” Change in Homeostasis due to stimuli - Injury Response to Injury – Reversible (adaptation)/ Irreversible (cell death) Adaptive Responses: • Atrophy • Hypertrophy • Hyperplasia • Metaplasia

10. Reversible vs. Irreversible Injury Cell injury is a continuum, and it is not possible to identify the exact point at which injury becomes irreversible. However, some ultrastructural and light microscopic changes are associated with each form of injury. Once an irreversible injury occurs, the cell undergoes necrosis, which is the light-microscopic hallmark of cell death.

11. In general, permanent organ injury is associated with the death of individual cells. By contrast, the cellular response to persistent sub-lethal injury, whether chemical or physical, reflects adaptation of the cell to a hostile environment. These changes are, for the most part, reversible on discontinuation of the stress” If the acute stress to which a cell must react exceeds its ability to adapt, the resulting changes in structure and function lead to the death of the cell

12. Causes of Cell Injury • Hypoxia • Physical agents including Radiations • Chemicals and Drugs • Microbiologic Agents • Immunologic Reactions • Genetic Defects • Nutritional Imbalances

13. Mechanisms of Cell Injury

14. Mechanisms of Cell Injury • Ischemia/Hypoxia • Activated Oxygen Species(O2.-, H2O2, OH. ) • Radiation • Inflammation • Oxygen toxicity • Chemicals • Reperfusion injury Others Chemicals Infectious agents Mechanical disruption Deficiency of essential metabolites Damage to DNA

16. MECHANISMS OF CELL INJURY

17. ISCHEMIC AND HYPOXIC INJURY

18. Reversible Injury - Decreased oxidative phosphorylation • reduced ATP increased cytosolic free calcium • reduced activity of “sodium pump” accumulation of sodium by cell is-osmotic gain of water (swelling) diffusion of potassium from cell

19. - Increased Cytosolic Calcium (activates enzymes) • ATPase decreased ATP • Phospholipase decreased phospholipids • Endonuclease nuclear chromatin damage • Protease disruption of membrane and cytoskeletal proteins

21. - Increased anaerobic glycolysis • glycogen depletion • lactic acid accumulation • accumulation of inorganic phosphates • reduced intracellular pH

22. - Detachment of ribosomes • reduced protein synthesis - Worsening mitochondrial function - Increasing membrane permeability - Cytoskeleton dispersion • loss of microvilli • formation of cell surface blebs

23. Reversible Injury results in • Swelling of mitochondria, endoplasmic reticulum, and entire cells

25. Irreversible Injury • Mitochondrial changes • severe vacuolization • amorphous calcium-rich densities • Extensive plasma membrane damage • Prominent swelling of lysosomes • Massive influx of calcium (on reperfusion) • Continued loss of cell proteins, coenzymes, ribonucleic acids and other metabolites • Leakage of enzymes measured in serum

26. Injury to lysosomal membranes • leakage of degradative enzymes • activation of acid hydrolases due to reduced intracellular pH with degradation of cell components • Prominent leakage of cellular enzymes • Influx of macromolecules from interstitium • “Myelin figures”-whorled phospholipid masses

31. FREE RADICAL MEDIATION OF CELL INJURY

32. Free Radical Injury Contributes to: • Chemical and radiation injury • Oxygen and other gaseous toxicity • Cellular aging • Microbial killing by phagocytic cells • Inflammatory damage • Tumor destruction by macrophages • Others

33. Definition Of Free Radicals • Extremely unstable, highly reactive chemical species with a single unpaired electron in an outer orbital • Examples Of Free Radicals • OH., H., O2.-

34. Source of Free Radicals • Hydrolysis of water into OH. and H. by ionizing radiation • Redox reactions in normal physiology • respiration • intracellular oxidase action • transition metal reactions • Metabolism of exogenous chemicals

35. Free Radical Injury Mechanisms • Lipid peroxidation of membranes • double bonds in polyunsaturated lipids • Lesions in DNA • reactions with thymine with single-strand breaks • Cross-linking of proteins • sulfhydryl-mediated protein cross-linking

36. Free Radical Degradation • Unstable with spontaneous decay • Decay accelerated by • superoxide dismutase • glutathione • Catalase • Antioxidants (vitamin E, ceruloplasmin) • block formation or scavenge

38. CHEMICAL INJURY

39. Can cause: •       Injury to cell membrane and other cell structures •       Block enzyme pathways (e.g cyanide) •       Coagulate cell proteins •       Upset concentration gradients and pH Direct action or Conversion to reactive toxic metabolite

40. RADIATION INJURY

41. Causes: Immediate cell death Interuption of cell replication (cancer cells) Mutation (thymidine dimers) Non-ionizing radiations can cause thermal injury

42. BIOLOGICAL AGENTS CAUSING INJURY

43. Viral injury • Direct cytotoxicity • Indirect cytotoxicity, via the immune system (activated killer T cells identify viral proteins on the cell surface and kill the cell) Bacterial injury • Mostly due to their metabolic products & secretions • Host inflammatory reaction