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  1. Second form of morphological pattern of cell death. 
    1. Specialized form, of programmed cell death.Q
  2. The characteristic features are -
    1. Cell shrink in size with tight packing of organelles    
    2. Nuclear chromatin condensation
    3. Formation of cytoplasmic membrane blebs                               
    4. Break down of the cell into fragments or apoptotic bodies
    5. Phagocytosis of apoptotic bodies by macro phages
    6. A lack of inflammatory response Q (differentiate it from necrosis)
  3. Some Noteworthy Points :
    1. Initial Phase of Apoptosis
  1. The plasma membranes remain intact during the process of apoptosis. Only in the last stage, they become permeable to normally retained solutes.
  2. On histologic examination, the cell appears as a round or oval mass of intensely eosinophilic cytoplasm with denser nuclear chromatin.
  3. The shrinkage and formation of apoptotic bodies are rapid and fragments are rapidly phagocytosed and extruded in the lumen.
  4. Considerable apoptosis may occur in the tissues before it becomes apparent in the histologic sections.
  1. Stimulus for Apoptosis
  1. DNA damage by radiation toxins and free radicals stimulates p53
  2. Lack of hormones, cytokines, or growth factors starts the intrinsic pathway (mitochondrial pathway) of apoptosis.­
  3. Receptor ligand signals start the extrinsic (death receptor initiated pathway) which includes Fas binding to the Fas ligand - Tumor necrosis factor binding to TNF receptor 1
  1. Apoptosis is regulated' by genes (Fig3):                                                                                              
  1. Bcl-2 family Q regulates apoptosis. Bcl -2 and bcl-X reside in the mitochondrial membrane and they inhibit     apoptosis. Bak, Bax, and Bim stimulate apoptosis. When cell does not get hormones or growth factors, bcl-2 and bcl-X are replaced by Bax, Bak and Bim. They increase the permeability of mitochondrial membrane which results in leakage of cytochrome c of respiratory chain. This binds Apaf-1 (Apoptosis activating factor -1), which in turn activates caspases → initiate caspases..
  2. p-53 (stimulates apoptosis) Q increased due to DNA injury and arrests the cell in G1 phase of cell cycle. If DNA repair is impossible. P-53 stimulates apoptosis.
  1. Execution of apoptosis
  1. Mediated by CaspasesQ
  2. Caspases digest nuclear and cytoplasmic proteins
  3. Caspases also activate endonucleases
  • A caspase antagonist called FLIP, block activation of caspases downstream of death receptors.
  • Some viruses produce homologues of FLIP, and this is one of the mechanism that viruses use to keep infected cells alive
Propoptic Anti-apoptic
Apaf- 1 (Apoptosis activating factor - 1)
cytochrome C
P53 gene
Fas [CD95]
FADD (Fas associated death domain)
BH3 only proteins (Bim, Bid, Bad)
  1. Examples of Apoptosis
    1. Apoptosis is seen in following scenarios :- (Pathological factors)
      1. Growth Factor Deprivation 
      2. DNA Damage
      3. Accumulation of Misfolded Proteins  Intracellular accumulation of abnormally folded proteins, caused by mutations, aging, etc responsible for Alzheimer, Huntington, and Parkinson diseases, and possibly type II diabetes.Q 
      4. Apoptosis of Self-Reactive Lymphocytes
      5. Cytotoxic T Lymphocyte-Mediated Apoptosis
  2. Examples are: (Physiological factors)
    1. EmbryogenesisQ: Organogenesis and development
    2. Hormone dependent Q Apoptosis i.e endometrial shedding in menstruation.
    3. ThymusQ: Selective death of lymphocytes
    4. Viral diseases Q: viral hepatitis (councilman bodies)
    5. Cystic fibrosis Q    and pancreatic atrophy
Features of Necrosis and Apoptosis Q
Feature Necrosis Apoptosis
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 contents Enzymatic digestion; may leak out of cell Intact; may be released in apoptotic bodies
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

Fig 3: Mechanisms of apoptosis.

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