2. Objectives  Define necrosis and apoptosis  List the different types of necrosis, examples of each and its features  List the different conditions associated with apoptosis, its morphology and its mechanism  Know the difference between apoptosis and necrosis

3. Objectives  Define necrosis and apoptosis  List the different types of necrosis, examples of each and its features  List the different conditions associated with apoptosis, its morphology and its mechanism  Know the difference between apoptosis and necrosis

4. Cell Death Death of cells occurs in two ways: 1.Necrosis--(irreversible injury) changes produced by enzymatic digestion of dead cellular elements 2.Apoptosis--vital process that helps eliminate unwanted cells--an internally programmed series of events effected by dedicated gene products

5. Objectives  Define necrosis and apoptosis  List the different types of necrosis, examples of each and its features  List the different conditions associated with apoptosis, its morphology and its mechanism  Know the difference between apoptosis and necrosis

6. Morphology of necrosis : 1.Cellular swelling or rupture 2.Denaturation and coagulation of cytoplasmic proteins 3.Breakdown of cell organelles 4.Breakdown of nuclear DNA

7. Patterns of Necrosis In Tissues or Organs As a result of cell death the tissues or organs display one of these six macroscopic changes: 1.Coagulative necrosis 2.Liquifactive necrosis 3.Caseous necrosis 4.Fat necrosis 5.Gangrenous necrosis 6.Fibrinoid necrosis

8. Patterns of Necrosis In Tissues or Organs 1.Coagulative necrosis: the outline of the dead cells are maintained and the tissue is somewhat firm. Example: myocardial infarction 1.Liquefactive necrosis: the dead cells undergo disintegration and affected tissue is liquefied. Example: cerebral infarction.

9. Patterns of Necrosis In Tissues or Organs 3. Caseous necrosis: a form of coagulative necrosis (cheese-like). Example: tuberculosis lesions. 4. Fat necrosis: enzymatic digestion of fat. Example: necrosis of fat by pancreatic enzymes. 5. Gangrenous necrosis: Necrosis (secondary to ischemia) usually with superimposed infection. Example: necrosis of distal limbs, usually foot and toes in diabetes. 6. Fibrinoid necrosis: typically seen in vasculitis and glomerular autoimmune diseases

10. Coagulative Necrosis Changes in the cytoplasm and the nucleus Karyolysis Pyknosis Karyorrhexis

11. Necrosis of the liver induced by herpesvirus. Herpesvirus invades liver cell nuclei producing nuclear ('ground glass') mildly basophilic inclusions.

12. Acute renal tubular necrosis (ischemia) : increased eosinophilia and pyknosis in necrotic cells Normal Necrotic

13. Ischemic neuronal injury:acidophilic cytoplasm & nuclear pyknosis

14. … a mess - so many cells have died - the tissue is not recognizable. Nuclei have become pyknotic (shrunken and dark), undergone karorrhexis (fragmentation) and karyolysis(dissolution) Necrotic myocardium

15. Kidney: ischemia and infarction (loss of blood supply and resultant tissue anoxia). Coagulative necrosis Removal of the dead tissue leaves behind a scar

16. Infarcts (vascular distribution) are wedge-shaped with a base on the organ capsule. Coagulative necrosis: is due to loss of blood supply Spleen

17. Depending on circumstances: 1.necrotic tissue may be walled off by scar tissue, 2.totally converted to scar tissue, 3.get destroyed (producing a cavity or cyst), 4.get infected (producing an abscess or "wet gangrene"), 5.or calcify. If the supporting tissue framework does not die, and the dead cells are of a type capable of regeneration, you may have complete healing. Remember: True coagulation necrosis involves groups of cells, and is almost always accompanied, by acute inflammation (infiltrate)

18. Liquefactive Necrosis Rate of dissolution of the necrotic cells is faster than the rate of repair. Usually results in an abscess secondary to bacterial infection. Liquefactive necrosis : hydrolysis of dead tissues or cells (rapidly destroyed by lysosomal enzymes from neutrophilic leukocytes (i.e., bacterial infections), or clostridia or snake poison. Liquefactive necrosis that is caused by neurophilic leukocytes is called pus.

19. Liquefactive necrosis: two lung abscesses Removal of the dead tissue leaves behind a cavity or scar

20. Localized liquefactive necrosis liver abscess Removal of the dead tissue leaves behind a scar

21. Cerebral infarction - this will liquefy eventualy

22. Liquefactive necrosis in the brain: in a patient suffered a "stroke"

23. Liquefactive necrosis of the brain: macrophages cleaning up the necrotic cellular debris Removal of the dead tissue leaves behind a cavity

24. Liquefactive necrosis in brain leads to resolution with cystic spaces.

25. Fat Necrosis Specific to adipose tissue with triglycerides. With enzymatic destruction(lipases) of cells, fatty acids are precipitated as calcium soaps. Grossly- chalky white deposits in the tissue. Microscopically – amorphous, basohilic /purple deposits at the periphery of necrotic adipocytes.

26. Fat necrosis secondary to acute pancreatitis

27. Caseous necrosis:  A form of coagulative necrosis but appear cheese-like  Example:  tuberculosis lesions  fungal infections  Coccidioidomycosis  blastomycosis  histoplasmosis

28. Caseous necrosis in a hilar pulmonary lymp node infected with tuberculosis.

29. Caseous necrosis: confluent cheesy tan granulomas in the lung in a patient with tuberculosis

30. Caseous necrosis: confluent cheesy tan granulomas in the lung in a patient with tuberculosis. This is characteristic of a poorly - understood subtype of immune injury, seen in certain granulomatous diseases (tuberculosis and certain fungal infections (coccidioidomycosis, blastomycosis and histoplasmosis) The macrophage-derived protein tumor-necrosis factor alpha ("cachectin") is the principal toxin that causes cells to undergo caseous necrosis

31. Pulmonary tuberculosis:tubercle contains amorphous finely granular, caseous ('cheesy') material typical of caseous necrosis. Removal of the dead tissue leaves behind a scar

32. Caseous necrosis is characterized by acellular pink areas of necrosis, surrounded by a granulomatous inflammatory process. N

33. Gangrenous necrosis Necrosis (secondary to ischemia) usually with superimposed infection. Example: necrosis of distal limbs, usually foot and toes in diabetes

34. “Wet" gangrene “ of the lower extremity in patient with diabetes mellitus: 1.liquefactive component from superimposed infection on 2.coagulative necrosis from loss of blood supply.

35. Fibrinoid necrosis: fibrin appear bright red amorphous material affect blood vessels and the glomerulus, infiltrated with fibrin

36. Fibrinoid necrosis: afferent arteriole and part of the glomerulus are infiltrated with fibrin, (bright red amorphous material)

37. Fibrinoid necrosis of artery

39. Objectives  Define necrosis and apoptosis  List the different types of necrosis, examples of each and its features  List the different conditions associated with apoptosis, its morphology and its mechanism  Know the difference between apoptosis and necrosis

40. Cell Death Apoptosis vital process that helps eliminate unwanted cells an internally programmed series of events effected by dedicated gene products

41. Apoptosis Physiologic process to die This process helps to eliminate unwanted cells by an internally programmed series of events effected by dedicated gene products. It serves several vital functions and is seen under various settings. Remember: apoptosis require energy to die

42. Apoptosis SEEN IN THE FOLLOWING CONDITIONS: A. Physiologic 1.During development for removal of excess cells during embryogenesis 2.To maintain cell population in tissues with high turnover of cells, such as skin, bowels. 3.To eliminate immune cells after cytokine depletion, and autoreactive T-cells in developing thymus. 4.Hormone-dependent involution - Endometrium, ovary, breasts etc.

43. Apoptosis SEEN IN THE FOLLOWING CONDITIONS: B. Pathologic 1.To remove damaged cells by virus 2.To eliminate cells after DNA damage by radiation, cytotoxic agents etc. 3.Cell death in tumors.

44. Morphology of Apoptosis 1.Shrinkage of cells 2.Condensation of nuclear chormatin peripherally under nuclear membrane 3. 4.Formation of apoptotic bodies by fragmentation of the cells and nuclei. The fragments remain membrane-bound and contain cell organelles with or without nuclear fragments. 5.Phagocytosis of apoptotic bodies by adjacent healthy cells or phagocytes. 6.Unlike necrosis, apoptosis is not accompanied by inflammatory reaction

45. Apoptosis: liver cells are dying individually from injury by viral hepatitis.

46. Liver biopsy - viral hepatitis: acidophilic body (councilman body) (apoptosis, i.e., induced, or programmed, individual cell death). Vacuolar change is reversible.

47. Skin, apoptotic Keratinocyte

48. MECHANISMS OF APOPTOSIS 1. Cause of chromatin condensation is internucleosomal DNA fragmentation mediated by calcium-sensitive endonuclease. 2. Alteration in cell volume due to action of transglutaminase. 3. Phagocytosis of apoptotic bodies is mediated by receptors on the macrophages. 4. Apoptosis is dependent on gene activation and new protein synthesis, e.g. bcl-2, c-myc oncogene and p53.

49. Apoptosis regulating genes

50. Genes that regulate apoptosis: Oncogene Bcl-2  Bcl-2 overexpression prevents apoptosis  Antagonized by cell death (ced) genes & others (bax,bad)  Localized to mitochondria, nuclear envelope and ER Tumor suppresor gene p-53  Will cause cells with DNA damage (eg amplified myc) to go apoptosis  Induce bax expression  Reversed by overexpression of bcl-2

53. Apoptosis summary

54. Objectives  Define necrosis and apoptosis  List the different types of necrosis, examples of each and its features  List the different conditions associated with apoptosis, its morphology and its mechanism  Know the difference between apoptosis and necrosis

55. Difference between apoptosis and necrosis Coagulation NecrosisApoptosis StimuliHypoxia, ToxinsPhysiologic and pathologic conditions Histologic appearance Cell swelling, coagulation necrosis disruption of organelles Single cell, chromatin condensation, apoptotic bodies DNA breakdown Random and diffuseinternucleosomal MechanismATP depletion membrane injuryGene activation, endonucleases, proteases Tissue reactionInflammationNo inflammation, phagocytosis of apoptotic bodies