necrosis and degeneration-cell degeneration

necrosis and degeneration

1. Necrosis and degeneration

2. necrosis Localized area of cell death followed by the degradation of the tissue by the hydrolytic enzymes. Always accompanied by inflammatory reaction

3. Causes of necrosis hypoxia Chemical agents Physical agents Microbiological agents Immunological agents

4. Basic mechanism Denaturation of intracellular proteins Enzymatic digestion of the cells

5. Morphology changes in cytoplasm Increased eosinophilia normal Loss of normal basophilia imparted bt DNA Binding of eosin to denatured protein Digestion of orgenelles Cytoplasmic vacuolation Dead cells replaced by mass of damaged membrane degraded in to fatty acid dystrophic calcification

6. Nuclear changes KARYOLYSIS BASOPHILIA OF THE CHROMATIN FADES REFLECTS DNAse ACTIVITY PYKNOSIS NUCLEAR SHRINKAGE AND INCREASED BASOPHILIA. DUE TO CONDENSATION OF DNA IN TO MASS KARYORRHEXIS PYKNOTIC NUCLEUS GETS FRAGMENTED DUE TO NON SPECIFIC CHANGES OF DNA NUCLEI DISAPPEARS

7. KARYOLYSIS PYKNOSIS KARYORRHEXIS NUCLEAR FADING NUCLEAR SHRINKAGE NUCLEAR FRAGMENTATION (chromatin dissolution (DNA condenses in to shrunken (pyknotic nuclei membrane ruptures & nucleus undergoes fragmentation) basophilic mass) due to DNAse and RNAse ) Anuclear necrotic cell

8. Several morphologic pattern Coagulative Liquefaction Caseous Fat fibrinoid

9. Coagulative necrosis Common type outline of dead tissues is preserved (at least for few days). Infarct is a localized area of coagulative necrosis seen in infarct of solid organs Causes : Ischemia caused by obstruction in a vessel • Mechanism : Ischemia denatures and coagulates structural proteins and enzymes.

10. • Gross: – Organs affected : All organs except the brain. More frequent in heart, kidney, spleen and limb (dry gangrene). Appearance: Involved region appear dry, pale, yellow and firm It is wedge shaped in organs like kidney and spleen.

11. Microscopy: Indistinct outline of dead tissue. Nucleus may be either absent or show karyolysis The cytoplasm is converted into homogeneous deeply eosinophilic and structureless material. The outlines of the affected cells are still discernible.

12. Liquefaction necrosis Seen in two situations: 1. Brain infarcts i.e. ischemic destruction of brain tissue. 2. Abscesses i.e. suppurative bacterial infections. Liquefaction necrosis is characterized by complete digestion of dead cells by enzymes and thus the necrotic area is eventually liquefied i.e. converted into a cyst filled with debris and fluid.

13. . Dead tissue rapidly undergoes softening and transforms into a liquid viscous mass. • Causes: – Ischemic injury to central nervous system Dead cells are transformed into a liquid viscous mass due to enzymes released from leukocytes accumulated at the site of necrosis

14. Suppurative infections: Infections by bacteria which stimulate the accumulation of leukocytes. • Mechanism: Liquefaction is due to digestive action of the hydrolytic enzymes released from dead cells (autolysis) and leukocytes (heterolysis) • Gross : Organs affected are Brain: Necrotic area is soft and center show liquefaction – Abscess anywhere: Localized collection of pus. It is also seen in wet gangrene and pancreatic necrosis. • Microscopy Pus consists of liquefied necrotic cell debris, dead leukocytes and macrophages (scavenger cells).

15. Caseous necrosis (caseation) This combines the features of coagulative and liquefactive necroses. found in the center of tuberculous granulomas. The morphologic unit of this is called granuloma. Grossly the caseous material is soft, friable, tan to whitish-gray cheesy material. Microscopically the area is surrounded by granulomatous inflammation. It has distinctive amorphous granular pinkish debris.

16. Caseous necrosis appears as eosinophilic, coarsely granular material. It is surrounded by epithelioid cells; Langerhans type giant cells (nuclei arranged in a horse-shoe pattern), lymphocytes and fibroblasts. Caseous necrotic material may undergo dystrophic calcification.

17. Fat Necrosis focal areas of fat destruction, which affects adipose tissue. Types: Enzymatic fat necrosis : Occurs in adipose tissue around acutely inflamed pancreas (in acute pancreatitis). Mechanism: In pancreatitis, the enzymes (one of them is lipase) leak from acinar cells and causes tissue damage. Lipase destroys fat cells and liberates free fatty acids which combine with calcium and form calcium soaps ( fat saponification ).

18. Gross: Appears as chalky-white areas Microscopy: The necrotic fat cells appear pale with shadowy outlines surrounded by an inflammatory reaction

19. 2. Traumatic fat necrosis Occurs in tissues with high fat content (like in breast and thigh) following severe trauma.

20. Gangrene (Gangrenous Necrosis) It is massive necrosis with superadded putrefaction. Types: Two types, namely dry and wet gangrene. A variant of wet gangrene known as gas gangrene is caused by clostridia (gram-positive anaerobic bacteria). Dry Gangrene • Causes: Arterial occlusion (e.g. atherosclerosis). • Sites: It is usually involves a limb, generally the distal part of lower limb (leg, foot, and toe)

21. Dry Gangrene Causes: Arterial occlusion (e.g. atherosclerosis). Sites: It is usually involves a limb, generally the distal part of lower limb (leg, foot, and toe)

22. Gross: Affected part is dry, shrunken (shriveled) and dark brown or black resembling the foot of a mummy. The black color is due to the iron sulfide. A line of demarcation is seen between gangrenous and adjacent normal area Microscopy: The necrosis (coagulative type) shows smudging of soft tissue and overlying skin. The line of demarcation consists of granulation tissue with inflammatory cells

23. Wet Gangrene Causes: Due to the venous blockage (e.g. strangulated hernia, intussusception or volvulus). • Sites: Occurs in moist tissues or organs (e.g. bowel, lung, mouth, etc)

24. Gross: The affected part is soft, swollen, putrid and dark. No clear line of demarcation. Microscopy Liquefactive type of necrosis.

25. Fibrinoid Necrosis COMMONLY OCCUR IN SMALL VESSELS INSUDATION AND DEPOSITION OF FIBRIN LIKE MATERIAL IN THE VESSEL WALL. MAINLY IN IMMUNOLOGICAL INJURIES. FIBRIN IS THE RESULT OF POLYMERIZATION OF PRE EXISTING SOLUBLE PLASMA PROTEIN(FIBRINOGEN) MICROSCOPIC; BRIGHTLY EOSINOPHILIC , HYALINE LIKE DEPOSITION IN THE VESSEL WALL. NECROTIC FOCI IS DORROUNDED BY NUCLEAR DEBRIS

26. APOPTOSIS Apoptosis is a type of (programmed) cell death. It is characterized by activation of cell enzymes that degrade its own nuclear DNA and proteins (nuclear and cytoplasmic).

27. DISCOVERED IN THE YEAR 1972 BY JOHN KERR , ANDREW H WYLLIE AND ALASTAIR CURRIE. GREEK MEAN ‘’FALLINGOFF ’’ (LIKE LEAVES FALLING FROM A TREE)

28. PHYSIOLOGICAL CONDITIONS 1.EMBRYOGENESIS

29. 2 . Involution of hormone-dependent tissues upon hormone withdrawal endometrial cell breakdown during the menstrual cycle ovarian follicular atresia in menopause the regression of the lactating breast after weaning

30. 3.Cell loss in proliferating cell populations immature lymphocytes in the bone marrow and thymus Continuously dividing cells to maintain a constant number

31. 4 . Elimination of potentially harmful self-reactive lymphocytes to prevent reactions against one’s own tissues 5.Death of inflammatory cells after their functions are over.

32. Pathologic condition injured cells which cant be repaired Dna damage Misfolded protein accumulation Viral infections Duct obstructions

33. pathogenesis Caspases C ysteine dependent asp artate directed prote ases

34. family of protease enzymes Have proteolytic activity Cystein at its active site Cleave their target proteins at specific aspartic acids

35. caspases INITIATOR CASPASES caspases: 2, 8, 9, 10 EXECUTIONER CASPASES caspases: 3, 6, 7

36. ALL CASPASES ARE IN INACTIVE FORM CALLED PROCASPASES INITIATOR CASPASES ARE ACTIVATED BY EXTRINSIC OR INTRINSIC PATHWAY EXECUTIONER CASPASES ARE ACTIVATED BY INTRINSIC PATHWAY

37. INITIATOR CASPASES EXTRINSIC OR INTRINSIC PATHWAY

38. EXECUTIONER CASPASES INTRINSIC PATHWAY

39. APOPTOSIS EXTRINSC PATHWAY INTRINSIC PATHWAY ACTIVATION OF EXECUTIONER CASPASES SUBSTRATES ARE CLEAVED MORPHOLOGICAL FEATURES OF APOPTOSIS INITIATION EXECUTION

40. DEATH RECEPTORS TNFR , Fas DEATH LIGAND Fas -L V DEATH RECEPTOR / EXTRINSIC PATHWAY

41. DEATH RECEPTORS TNFR , Fas DEATH LIGAND Fas -L V DEATH RECEPTOR / EXTRINSIC PATHWAY DEATH DOMAIN Fas ASSOCIATED DEATH DOMAIN ( FADD) PROCASPASE 8 ACTIVATED CASPASE 8 ACTIVATED CASPASE 3 6 & 7

42. ACTIVATED CASPASE 3 6 & 7 EXECUTIONER CASPASES NUCLEAR BREAKDOWN BY ENDONUCLEASE ACTIVATION BREAKDOWN OF CYTOSKELETON

43. = EXECUTION

44. DEATH RECEPTORS TNFR , Fas DEATH LIGAND Fas -L V DEATH RECEPTOR / EXTRINSIC PATHWAY DEATH DOMAIN Fas ASSOCIATED DEATH DOMAIN ( FADD) PROCASPASE 8 ACTIVATED CASPASE 8 ACTIVATED CASPASE 3 6 & 7 INITIATION

45. INTRINSIC / MITOCHONDRIAL PATHWAY CYTOCHROME C APAF - 1 CYTOCHROM C APOPTOSOME ACTIVATED CASPASE 3 6 & 9 ACTIVATED CASPASE 9 PROCASPASE 9 RELEASE OF Smac ,Diablo Neutralize IAP’S

46. REGULATION OF APOPTOSIS

47. Bcl-2 family of genes chromosome 18 Proapoptotic antiapoptotic bax,bak,bcl-xS bcl -2 , bcl –xl , mcl-1 cv GROWTH FACTOR CESSATION OF GF cv SENSORS Bad , bim,bid,puma INACTIVATES ANTIAPOPTOTIC GENES . ACTIVATES PROAPOPTOTIC GENES

48. Diagnosis OF Apoptosis 1.HISTOPATHOLOGY SPECIAL STAIN:-FEULGEN AND ACRIDINRE ORANGE ROUND OR OVAL MASS OF INTENSE EOSINOPHILIC CYTOPLASM ALONG WITH FRAGMENTS OF CONDENSED NUCLEAR CHROMATIN

49. Estimation of: Cytosolic cytochrome c Activated caspase Annexin V Apoptotic cells express phosphatidylserine on the outer layer of plasma membrane because of which these cells are recognized by the dye Annexin

50. 2. Terminal deoxynucleotidyl transferase biotin d-UTP Nick End LabeLling (TUNEL) technique for detection of DNA FRAGMENTATION.

51. Disorders Associated with Dysregulated Apoptosis Disorders with reduced apoptosis: It may allow the survival of abnormal cells. – Cancer – Autoimmune disease.

52. Disorders with increased apoptosis : This will cause an excessive loss of cells. – Neurodegenerative diseases (Alzheimer, Parkinson disease). – Ischemic injury: In myocardial infarction and stroke. – Death of virus-infected cells: Many viral infections, important being acquired immune deficiency syndrome (AIDS).