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Cell injuryadaptation 4


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for Undergraduate medical students (MBBS)

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Cell injuryadaptation 4

  1. 1. SDUMC-Path-CSBRP ApoptosisApoptosis Dr.CSBR.Prasad, M.D.
  2. 2. SDUMC-Path-CSBRP Cell injuryCell injury • Reversible injuryReversible injury 1-Cell swelling 2-Fatty change 3-Mitochondrial swelling 4-ER disruption 5-Membrane blebs 6-Cytoskeletal disruption • Irreversible injuryIrreversible injury 1-Apoptosis 2-Necrosis
  3. 3. SDUMC-Path-CSBRP Examples for irreversible injuryExamples for irreversible injury 1. Apoptosis 2. Necrosis
  4. 4. SDUMC-Path-CSBRP ApoptosisApoptosis • Initially recognized in 1972 • Greek term meaning “falling offfalling off” • It occurs in many situations (Physiological / Pathological)(Physiological / Pathological) • It’s a mechanism to eliminate…. –Unwanted cells –Potentially harmful cells –Useless cells –Cells damaged beyond repair
  5. 5. SDUMC-Path-CSBRP ApoptosisApoptosis Apoptosis is “Programmed cell death” Planned self destruction
  6. 6. SDUMC-Path-CSBRP ApoptosisApoptosis Clinical implications for this knowledge: 1. Apoptosis is very essential for our survival 2. Increased or decreased apoptosis is associated with diseases
  7. 7. SDUMC-Path-CSBRP ApoptosisApoptosis Apoptosis in Physiologic Situations: • Destruction of cells during embryogenesis • Hormone-dependent involution in the adult • Death of host cells that have served their useful purpose • Elimination of potentially harmful self-reactive lymphocytes • Cell death induced by cytotoxic T cells
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  9. 9. SDUMC-Path-CSBRP ApoptosisApoptosis Apoptosis in Pathological Conditions: • Cell death produced by a variety of injurious stimuli • Cell injury in certain viral diseases • Pathologic atrophy in parenchymal organs after duct obstruction • Cell death in tumors
  10. 10. SDUMC-Path-CSBRP ApoptosisApoptosis NOTENOTE:: Even in situations in which cell death is mainly by necrosis, the pathway of apoptosis may contribute Eg: Injurious stimuli that cause increased mitochondrial permeability trigger apoptosis
  11. 11. Activation of caspasesActivation of caspases is theis the basisbasis forfor apoptosisapoptosis SDUMC-Path-CSBRP
  12. 12. SDUMC-Path-CSBRP Activation of caspases is the basis for apoptosisActivation of caspases is the basis for apoptosis
  13. 13. • In radiation injury which will be altered, Bax or Bcl2? • In cancer cells which one you think will be altered Bax or Bcl2? SDUMC-Path-CSBRP
  14. 14. SDUMC-Path-CSBRP ApoptosisApoptosis MorphologyMorphology. Cell shrinkage. The cell is smaller in size; the cytoplasm is dense; and the organelles are more tightly packed Chromatin condensation. The chromatin aggregates peripherally, under the nuclear membrane, into dense masses of various shapes and sizes. The nucleus itself may break up, producing two or more fragments. Formation of cytoplasmic blebs and apoptotic bodies. The apoptotic cell first shows extensive surface blebbing, then undergoes fragmentation into membrane-bound apoptotic bodies composed of cytoplasm and tightly packed organelles, with or without nuclear fragments Phagocytosis of apoptotic cells or cell bodies, usually by macrophages. The apoptotic bodies are rapidly degraded within lysosomes, and the adjacent healthy cells migrate or proliferate to replace the space occupied by the now deleted apoptotic cell.
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  16. 16. Cytoplasmic blebs SDUMC-Path-CSBRP
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  18. 18. SDUMC-Path-CSBRP Apoptosis of epidermal cells in an immune-mediated reaction. The apoptotic cells are visible in the epidermis with intensely eosinophilic cytoplasm and small, dense nuclei.
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  23. 23. SDUMC-Path-CSBRP ApoptosisApoptosis BIOCHEMICAL FEATURES OF APOPTOSIS Protein Cleavage: by activation of caspases DNA Breakdown: DNAses, Endonucleases Phagocytic Recognition: Apoptotic cells express Phosphatidylserine [Annexin V ] Thrombospondin other proteins secreted by phagocytes may bind to apoptotic cells
  24. 24. SDUMC-Path-CSBRP Agarose gel electrophoresis of DNA extracted from culture cells A-Control, B-Extensive apoptosis, C-Cells showing massive necrosis
  25. 25. SDUMC-Path-CSBRP ApoptosisApoptosis MECHANISMS OF APOPTOSISMECHANISMS OF APOPTOSIS There are mainly two mechanismsThere are mainly two mechanisms 1- The extrinsic Pathway (Death Receptor-Initiated) 2- The Intrinsic Pathway (Mitochondrial)
  26. 26. SDUMC-Path-CSBRP Activation of caspases is the basis for apoptosisActivation of caspases is the basis for apoptosis
  27. 27. SDUMC-Path-CSBRP The extrinsic Pathway (Death Receptor-Initiated) Fas: death receptor FasL: Fas Ligand eg: TNF1 FADD: Fas-associated death domain FLIP: is a naturally occuring preventer of apoptosis
  28. 28. SDUMC-Path-CSBRP The Intrinsic (Mitochondrial) PathwayThe Intrinsic (Mitochondrial) Pathway
  29. 29. SDUMC-Path-CSBRP Extrinsic & Mitochondrial Pathways -Extrinsic & Mitochondrial Pathways - SimplifiedSimplified
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  31. 31. SDUMC-Path-CSBRP EXAMPLES OF APOPTOSISEXAMPLES OF APOPTOSIS • Apoptosis After Growth FactorApoptosis After Growth Factor DeprivationDeprivation • DNA Damage-Mediated ApoptosisDNA Damage-Mediated Apoptosis • Apoptosis Induced by Tumor NecrosisApoptosis Induced by Tumor Necrosis Factor Family of ReceptorsFactor Family of Receptors • Cytotoxic T-Lymphocyte-MediatedCytotoxic T-Lymphocyte-Mediated ApoptosisApoptosis
  32. 32. SDUMC-Path-CSBRP
  33. 33. Apoptosis detection methods: • Caspase-3 is a marker of early apoptosis • Annexin-V SDUMC-Path-CSBRP
  34. 34. IHC for TUNEL in murine liver, brown cell is apoptotic. SDUMC-Path-CSBRP
  35. 35. Main differences between apoptosis and necrosis SDUMC-Path-CSBRP
  36. 36. SDUMC-Path-CSBRP Figure 1-16 Timing of biochemical and morphologic changes in cell injury.
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  38. 38. SDUMC-Path-CSBRP Differences between Apoptosis and NecrosisDifferences between Apoptosis and Necrosis Feature Apoptosis Necrosis Cell membrane Intact Leaky Inflammation Absent Present Cytosolic proteins Normal Altered Cell death Programmed Unregulated Leakage of contents No leakage Leakage occurs Setting Occurs normally also Always pathological Mechanisms Similarities exist Similarities exist Number of cells involved Single cell or a few cells Numerous cells Cell death Final event Initial event
  39. 39. “Fallen leaf sign” Unicameral bone cyst SDUMC-Path-CSBRP
  40. 40. SDUMC-Path-CSBRP E N DE N D
  41. 41. • Falling leaves animation • Chip away the unwanted o give a shape • Dropout necrosis – liver • Effete cells in endometrium • Alzhemer’s disease. • Apoptosis video • Organogenesis • Fallen leaf sign of unicameral bone cyst • Apoptosis is the feature of anoxic brain necrosis in infants • Include the man who described apoptosis SDUMC-Path-CSBRP