1. Irreversible cell injury Dr Heyam Awad FRCPath

2. Irreversible injury Necrosis Apoptosis.

3. Necrosis Morphologic changes that follow cell death in living tissues.

4. NECROSIS Denaturation of intracellular proteins. Digestion of cells by lysosomal enzymes of dying cells ( autolysis) and leukocytes (heterolysis).

5. Protein denaturation

6. denaturation

7. LM changes 1) Increased cytoplasmic eosinophilia. Cause? 2) Vacoulation of cytoplasm, moth eaten. Cause? 3) Nuclear changes 4) Calcification

8. Nuclear changes one of three patterns 1. karyolysis: decreased chromatin basophilia secondary to deoxyribonuclease (DNAase) activity. 2. pyknosis: nuclear shrinkage and increased basophilia (DNA condenses into a solid shrunken mass. 3. karyorrhexis, fragmentation then disappearance of nucleus.

9. EM changes 1)Discontinuities in plasma and organelle membranes. 2) Marked dilation of mitochondria and large amorphous densities. 3)Disruption of lysosomes. 4) Intracytoplasmic myelin figures

10. Myelin figures Myelin figures: aggregates of damaged cell membranes (phospholipids). Fate of Myelin figures: phagocytosed by other cells or further degraded into fatty acids and calcify

12. Patterns of necrosis Denaturation of protein predominates…. Coagulative necrosis. Enzymatic digestion predominates… liquefactive necrosis. Special circumstances: caseous necrosis and fat necrosis.

14. Coagulative necrosis preserved architecture of dead tissue. Denaturation of structural proteins and enzymes… so no cellular proteolysis. Eosiniphilic anucleated cells Cells are removed by inflammatory cells.

15. Ischemia in all solid organs except the brain may lead to coagulative necrosis.

16. Coagulative necrosis

18. Liquifactive necrosis digestion of the dead cells resulting into a liquid jelly-like mass. In focal bacterial or fungal infections and in hypoxic death in central nervous system.

20. Caseous necrosis White cheese like friable necrosis. Prototype: Tuberculosis Typical finding is granuloma :Collection of fragmented or lysed cells with amorphous granular eosinophilic debris surrounded by macrophages.

21. Caseous necrosis

22. Fat necrosis used as a clinical terms and not a specific type. Necrosis of fat. Typical example: pancreatic enzymes (lipases) release in acute pancreatitis.

24. Fate of necrotic tissue Phagocytosis. Replacement by scar. Regeneration. Calcification.

25. Apoptosis

26. cell death induced by a tightly regulated suicide program in which cells activate enzymes capable of degrading the cells' own nuclear DNA and nuclear and cytoplasmic proteins. Fragments of the apoptotic cells then break off, giving the appearance that is responsible for the name (apoptosis, "falling off")..

27. apoptosis The plasma membrane remains intact. Apoptotic bodies (contain portions of the cytoplasm and nucleus) become targets for phagocytosis before their contents leak out and so there would be no inflammatory reaction.

28. Causes of Apoptosis Physiologic situations: To eliminate cells that are no longer needed OR to maintain a steady number of various cell populations in tissues.

29. Physiologic apoptosis Embryogenesis. involution of hormone-dependent tissues upon hormone withdrawal. (endometrium and breast after pregnancy) Cell loss in proliferating cell populations. (GIT) Death of host cells after serving their useful function. (neutrophils and lymphocytes in inflammation) Elimination of potentially harmful self-reactive lymphocytes. Cell death induced by cytotoxic T lymphocytes (tumor cells and viraly infected cells)

30. Pathologic situations Examples: DNA damaged cells,. Cells with accumulation of misfolded proteins, Certain infections (viral ones): may be induced by the virus (as in human immunodeficiency virus infections) or by the host immune response (as in viral hepatitis). Pathologic atrophy in parenchymal organs after duct obstruction (pancreas, parotid and kidney)

31. Morphology Cell shrinkage: dense cytoplasm, tightly packed organelles. Chromatin condensation: peripherally under the nuclear membrane. Formation of cytoplasmic blebs apoptotic bodies: blebbing then fragmentation into membrane bound apoptotic bodies composed of cytoplasm and tightly packed organelles with or without nuclear fragments.

32. Morphology Phagocytosis of apoptotic cells or cell bodies by macrophages (quickly hence no inflammation).

34. Mechanisms of Apoptosis Activation of enzymes called caspases. Two main pathways: 1- Mitochondrial pathway (intrinsic) 2- Death receptor pathway (extrinsic)

35. 1- mitochondrial pathway (intrinsic) Leak of cytochrome c out of mitochondria and activation of caspase 9… 2- death receptor pathway (extrinsic) Involved in elimination of self-reactive lymphocytes and in killing of target cells by some cytotoxic T lymphocytes. Activation of caspase 8.

37. FeatureNecrosisApoptosis Cell size Enlarged (swelling)Reduced (shrinkage) Nucleus Pyknosis → karyorrhexis → karyolysis Fragmentation into nucleosome-size fragments Plasma membrane Disrupted Intact; altered structure, especially orientation of lipids Cellular content Enzymatic digestion; may leak out of cell Intact; altered structure, especially orientation of lipids Adjacent inflammation Frequent No Physiologic or pathologic role Invariably pathologic (culmination of irreversible cell injury) Often physiologic, means of eliminating unwanted cells; may be pathologic after some forms of cell injury, especially DNA damage