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Cell Death, Necrosis & Calcification, Screenshot 2023-06-21 at 11.25…

- - - - Anemia
      - Ischaemia
      - Hypoxia
    - - Radiation
      - Electric shock
      - Temp extremes
      - Mechanical trauma
      - Changes in atmospheric pressure
    - - Poisons e.g. arsenic, cyanide, mercury
      - Excess oxygen
      - Alcohol
      - Pollutants
    - - Protein-calorie deficiencies
      - Vit deficiencies
      - Anorexia
      - Food shortages
      - Obesity
    - - Parasites
      - Protozoa
      - Fungi
      - Bacteria
      - Prions
      - Viruses
    - - Autoimmune diseases
        
        Diabetes mellitus
        
        Hypothyroidism
        
        Immune-mediated hemolytic anemia
    - - Base pair substitution
      - Chromosomal e.g. Down's syndrome
  - - - Swelling of cell (hydropic degeneration)
      - Fatty change
  - - - Necrosis (oncotic necrosis)
        
        Plasma membrane disrupted
        
        Enzymatic digestion; may leak out of cell
      - Apoptosis (condensation & shrinkage)
        
        Programmed cell death
        
        Cells break up into fragments - apoptotic bodies
        
        Apoptotic bodies removed by phagocytes - no leakage of cellular content i.e. no inflammation
        
        Pathological or physiological
        
        Morphologic features
        
        Cell shrinkage
        
        Chromatin condensation
        
        Formation of cytoplasmic blebs & apoptotic bodies
        
        Phagocytosis of apoptotic bodies by macrophages
        
        Physiologic situations
        
        Eliminate cells that are no longer needed
        
        Development
        
        Maintenance in adults
        
        Removal of supernumerary cells during development
        
        Cell turnover in proliferating cell populations
        
        Elimination of self-reactive lymphocytes
        
        Removal of cells that have served their purpose
        
        Mechanisms
        
        Apoptosis results from activation of enzymes known as "caspases"
        
        Caspases exist as inactive proenzymes and undergo enzymatic cleave to become active
        
        Regulation of caspases depends on balance between pro-apoptotic and anti-apoptotic proteins
        
        Pathways of apoptosis
        
        Mitochondrial (intrinsic) pathway
        
        BCL2 (anti-apoptotic) keeps mitochondrial membrane impermeable
        
        Lack of survival signals, DNA damage or accumulation of misfolded proteins upregulate BH3-only proteins
        
        BH3-only proteins activate pro-apoptotic proteins BAX & BAK
        
        BH3-only proteins also blocks functions of BCL2
        
        Net result: Increase permeability of mitochondria
        
        Release of cytochrome c into cytoplasm
        
        Cytochrome c binds to apoptosis-activating factor 1 (APAF-1) to form apoptosome
        
        Apoptosome binds to caspase-9 (initiator caspase)
        
        Enter executioner phase
        
        Death Receptor Initiated (extrinsic) pathway
        
        Initiated by activation of membrane death receptors
        
        Bindings of FasL to FAS forms FADD (Fas-associated death domain)
        
        Generates active caspase-8 or capase-10 (initiator caspases)
        
        Enter executioner phase
        
        Executioner phase
        
        Intrinsic (caspase-9) and extrinsic pathways (capases 8 or 10) converge to activate executioner phase
        
        Initiator caspases activate executioner caspases, such as caspase-3 and caspase 6 (36)
        
        Executioner caspases cleave an inhibitor of DNAase --> DNAase becomes active --> DNA degradation
        
        Caspases also proteolyze components of nuclear matrix --> fragmentation of nuclei
        
        Apoptotic cells express "eat me" signals to phagocytes. Phagocytosis of apoptotic cells "efferocytosis"
        
        Other mechanisms of cell death
        
        Necroptosis
        
        Autophagy
- - - - Hypereosinophilic (pink)
      - Swells/shrinks, loses adherence
      - Eventually ruptures
    - - Pyknosis
      - Karyorrhexis
      - Karyolysis
      - Absence of nucleus
  - - - Common with ischaemia e.g. infarction & in some toxic/metabolic injuries
      - Common in kidney, liver & muscle
      - Gross appearance: pallor of affected tissue - solid appearance
    - - Architecture lost
      - Due to digestion of dead tissue by lytic enzymes
      - Gross appearance: cavity containing thick fluid
    - - Necrotic centre composed of fragmented/lysed cells
      - Granuloma
      - Gross appearance: Affected tissue becomes pale tan & friable with a caseous (cheese-like) texture
    - - Not a specific pattern
      - Death of tissue within a living body
      - 3 Types
        
        Dry gangrene
        
        Predominately coagulative necrosis
        
        No significant bacterial decomposition
        
        Wet (moist) gangrene
        
        Predominately liquefactive necrosis
        
        Secondary to decrease blood supply
        
        Bacterial infection
        
        Gas gangrene
        
        Necrosis complicated by infection with gas-producing anaerobic bacteria e.g. Clostridia spp.
        
        Secondary to penetrating wounds
        
        Severe pain, swelling, serosanguineous exudate
    - - Adipose tissue destroyed
      - Pancreatitis: action of lipases on triglycerides --> FFAs + glycerol. FFAs complex with Ca2+ --> Ca2+ soaps precipitate
      - Gross appearance: Chalky white deposits
- - - - Deposition of calcium at sites of cell injury & necrosis
      - Fine, white granules or clumps
    - - Hypercalcemia
        
        Increased secretion of parathyroid hormone (PTH)
        
        Resorption of bone tissue, secondary to primary tumours of bone marrow
        
        Vit-D related disorders
        
        Renal failure
        
        Retention of phosphate
      - May occur widely throughout body
        
        Principally affects interstitial tissues of gastric mucosa, kidneys, lungs, systemic arteries
        
        Deposition of calcium in normal tissues