Necrosis and apoptosis

1. (Foundation Block, pathology) Lecturer name: Dr. MahaArafah Lecture Date: 25-9-2011 Necrosis and apoptosis Cell injury L2

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

3. Reference book and the relevant page numbers.. • Robbins Basic Pathology 8th edition, • pages: 9-22.

4. Cell Death • Death of cells occurs in two ways: • Necrosis--changes produced by enzymatic digestion ofcells after irreversible injury • Apoptosis--vital process that helps eliminate unwanted cells--an internally programmed series of events effected by dedicated gene products Autolysis Autolysis is the death of individual cells and tissues after the death of the whole organism. The cells are degraded by the post-mortem release of digestive enzymes from the cytoplasmiclysosomes.

5. Cell Death • Apoptosis • Vital process. • Programmed cell death. • Can occurs in physiological or pathological conditions.

6. 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

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

8. Apoptosis B. Pathologic • To remove damaged cells by virus • Atrophy (virtually never accompanied by necrosis). • To eliminate cells after DNA damage by radiation, cytotoxic agents etc. • Cell death in tumors.

9. Morphology of Apoptosis • Shrinkage of cells • Condensation of nuclear chromatin peripherally under nuclear membrane • 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. • Phagocytosis of apoptotic bodies by adjacent healthy cells or phagocytes. • Unlike necrosis, apoptosis is not accompanied by inflammatory reaction

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

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

13. Skin, apoptotic Keratinocyte

14. MECHANISMS OF APOPTOSIS 1. Chromatin condensation is mediated by calcium-sensitive endonuclease leading to internucleosomalDNA fragmentation. 2. Alteration in cell volume (shrinkage) 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-myconcogene and p53.

15. Apoptosis summary

17. Apoptosis regulating genes

18. 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 • Bcl-2 overexpression is found in follicular lymphoma. Tumor suppressor gene p-53 • Will cause cells with DNA damage (eg amplified myc) to go apoptosis • Induce bax expression • Reversed by overexpression of bcl-2

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

20. Necrosis • Necrosis is defined as the morphological changes that result from cell death within living tissues. • In necrosis, death of a large number of cells in one area occurs. • These changes occur because of digestion and denaturation of cellular proteins.

21. Morphology of necrosis: • Cellular swelling or rupture • Denaturation  and coagulation of cytoplasmic proteins • Breakdown of cell organelles • Breakdown of nuclear DNA

22. The results of cell death can include: • Cessation of function of a tissue or organ. • Release of cellular enzymes, these can sometimes be detected in the blood and used as markers of the extent or timing of damage to a particular organ, e.g. cardiac enzyme after myocardial infarction. • Initiation of the inflammatory response (vital reaction).

23. Patterns of Necrosis: In Tissues or Organs • As a result of cell death the tissues or organs display one of these six macroscopic changes: • Coagulative necrosis • Liquifactive necrosis • Caseous necrosis • Fat necrosis • Gangrenous necrosis • Fibrinoid necrosis

24. Patterns of Necrosis In Tissues or Organs • Coagulative necrosis: • Denaturation of intracellular protein leads to the pale firm nature of the tissues affected. The cells show the microscopic features of cell death but the general architecture of the tissue and cell ghosts remain discernible for a short time. • The outline of the dead cells are maintained and the tissue is somewhat firm. • Example: kidney and heart injury caused by ischaemia.

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

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

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

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

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

30. Coagulative necrosis: • Remember: True coagulation necrosis involves groups of cells, and is almost always accompanied, by acute inflammation (infiltrate)

31. Patterns of Necrosis In Tissues or Organs 2. Liquefactive necrosis: • The dead cells undergo disintegration and affected tissue is liquefied. • This results from release of hydrolytic lysosomal enzymes and leads to an accumulation of semi-fluid tissue. Example: • cerebral infarction. • Abscess

32. Cerebral infarction - this will liquefy eventualy

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

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

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

36. … 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

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

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

39. Patterns of Necrosis In Tissues or Organs 3. Caseous necrosis: • A form of coagulative necrosis but appear cheese-like. • The creamy white appearance of the dead tissue is probably a result of the accumulation of partly digested waxy lipid cell wall components of the TB organisms. The tissue architecture is completely destroyed. • Example: • tuberculosis lesions • fungal infections • Coccidioidomycosis • blastomycosis • histoplasmosis

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

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

42. 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

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

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

45. Patterns of Necrosis In Tissues or Organs 4. Fat necrosis: • This can result from direct trauma or enzyme released from the diseased pancreas. • Example: • Necrosis of fat by pancreatic enzymes. • Traumatic fat necrosis in breast Adipocytes rupture and the released fat undergoes lipolysis catalyzed by lipases. Macrophages ingest the oily material and a giant cell inflammatory reaction may follow. Another consequence is the combination of calcium with the released fatty acids.

46. Fat necrosis secondary to acute pancreatitis

47. 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.

48. Patterns of Necrosis In Tissues or Organs 5. Gangrenous necrosis: • This life-threatening condition occurs when coagulative necrosis of tissue is associated with superadded infection by putrefactive bacteria. • These are usually anaerobic gram-positive Clostridia spp. Derived from the gut or soil which thrive in conditions of low oxygen tension.

49. Patterns of Necrosis In Tissues or Organs 5. Gangrenous necrosis: • Gangrenous tissue is foul smelling and black. • The bacteria produce toxins which destroy collagen and enable the infection to spread rapidly. If fermentation occurs, gas gangrene ensues. • Infection can become systemic (i.e. reach the bloodstream, septicaemia). • The commonest clinical situation is gangrene of the lower limb caused by poor blood supply and superimposed bacterial infection. This is a life-threatening emergency and the limb should be amputated.

50. Example: necrosis of distal limbs, usually foot and toes in diabetes. • “Wet" gangrene “ of the lower extremity in patient with diabetes mellitus: • liquefactive component from superimposed infection on • coagulative necrosis from loss of blood supply.