Response to cell injury

Targets of cell injury
1. Aerobic respiration
  1. Mitochondrial oxidative phosphorylation and synthesis of ATP
2. Cell membrane integrity
  1. Maintains ionic and osmotic homeostasis
3. Protein synthesis
4. Cytoskeleton
5. Genetic aparatus of the cell
Mechanisms of cell injury
1. Despite numerous mechanisms - the pattern of response is limited and converges on common pathways
  1. Oxygen deprivation (hypoxia) - reduced O2 carrying capacity of the blood (e.g. anaemia or CO poisoning) or lack of blood supply (ischaemia)
  2. Chemical agents or drugs (poisons e.g. arsenic)
  3. Infectious agents
  4. Immunological reactions
  5. Physical agents (e.g. burns or trauma)
  6. Genetic defects (e.g. sickle cell anaemia)
2. In hypoxia...
  1. Decreased oxidative phosphorylation
    1. Decreased cell ATP
      1. Cell membrane ATP-dependent Na/K pump fails
        Accumulation of cytosolic Na(+)
        Water moves into cell down the concentration gradient
        The cell swells (particulalry the ER)
        Loss of cell membrane integrities
        Increase in intracellular Ca(2+) from the extracellular medium, ER and mitochondria
        Mitochondria also release pro-apoptotic molecules (cytochrome c)
        Apoptosis
        Activates
        Phospholipases
        Decreased phospholipids
        Proteases
        Disruption of membrane and ctoskeletal proteins
        Membrane damage
        Endonucleases
        Nuclear chromatin damage
      2. Increased anaerobic glycolysis
        Depletion of cell glycogen (liver/skeletal muscle)
        Decrease in cell pH
        Nuclear clumping
      3. Detachment of ribosomes from ER
        Reduced protein synthesis
        Lipid depletion
      4. Disruption of cytoskeleton/cell contacts
3. Mitochondria are the major target
  1. Source of energy for the cell
  2. Maintenance of the mitochondrial membrane is essential for oxidative phosphorylation
  3. Ca(2+) is an important mediator of cell injury (high intracellular Ca(2+) is bad for the cell)
    1. Low intracellular Ca(2+) is maintained by the Ca/Mg ATPase
      1. (Requires ATP)
Types of injury
1. Reversible
  1. Plasma membrane blebbing, loss of microvilli
  2. Mitochondrial swelling (small amorphous densites)
  3. Dialation of ER - with detachment of ribosomes
  4. Clumping of nuclear chromatin
  5. Then the damaging stimulus needs to cease - the cell can recover from this
    1. Otherwise...
      1. Irreversible
        Increased cell swelling
        Disruption of lysosomes
        Large amorphous densities in swollen mitochondria
        Disruption of the cell membrane
        Myelin figures (damaged membrane structures)
        Changes to the nucleus (condensation of chromatin - then fragmentation)
        Karyorrhexis (fragmentation of nuclear material)
        Karyolysis (complete lysis of the nucleus)
Cell death
1. Apoptosis
  1. See cancer revision notes
  2. Physiological
    1. Embryogenesis - during tissue morphogenesis
    2. Hormone-dependent involution (endometrium in menstrual cycle)
    3. Cell deletion in proliferating populations (intestinal crypt epithelium)
    4. Death of immune cells (following cytokine depletion and deletion of autoreactive T cells)
  3. Pathological
    1. Cell death induced by
      1. Radiation
      2. Anti-cancer drugs
      3. Viral diseases
      4. Organ atrophy secondary to duct obstruction (e.g. pancreas)
    2. Cell death in tumours
2. Necrosis
  1. The morphological changes that occur in living tissue following cell death
  2. Degradative action of lysosomal enzymes
  3. Infarction - large groups of necrotic cells due to impaired blood supply
  4. Different types of necrosis
    1. Coagulative
      1. Basic outline of cell shape preserved due to limited enzymatic destruction
      2. Eosinophilic anucleate cells fragment and debris is removed by local macrophages and neutrophils
      3. Macroscopically the tissue appears firm
      4. Most common pattern of tissue necrosis in
        Heart
        Kidney
        Spleen
    2. Liquefactive necrosis
      1. Characterised by complete lysis of cells with transformation of dead tissue into a liquid viscous mass
      2. Typical of ischaemic necrosis of the brain
        e.g. following a stroke
    3. Gangrenous necrosis
      1. Coagulative necrosis modified by liquefactive action of bacteria
      2. E.g. ischameic limbs, bowel necrosis, diabeteic ulcers -> gangrenous
    4. Caseous necrosis
      1. Specific form of coagulative necrosis seen almost exclusively in tuberculosis
      2. Tissue is destroyed, no cell outlines visible
      3. Macroscopically appers as a white 'cheesy' mass
      4. Granuloma formation
        Organised collection of modified macrophages (epithelioid cells)
        Immune reaction - frequently associated with the formation of multinucleate giant cells
        Granulomas in TB are caseating - other granulomas are typically 'non-caseating' (e.g. sarcoidosis)
    5. Fat necrosis
      1. Areas of fat destruction
      2. Acute pancreatitis
        Release of pancreatic enzymes into abdomen
        Destruction of fat in abdominal cavity
Effects of cell injury
1. Decreased organ function (mechanical (heart), synthetic (liver) and detoxification (liver))
2. Abnormal organ function (epilepsy, caridac arrhythmias)
3. Initiation of reaction to injury (inflammation and stress response)
4. Rupture of lysosomes in lethally damaged cells releases enzymes into the blood
  1. Cardiac muscle (alanie transaminase, creatinine kinase and lactate dehydrogenase)
  2. Pancreas (amylase)
  3. Important in diagnosis
5. Longer term effects of cell injury
  1. Injured tissues that survive become calcified
    1. Dystrophic calcification
      1. Scars
      2. Site of infection
      3. Heart valves
    2. If serum calcium is abnormally high (metastatic)
      1. Tissue calcification (but not at site of cell damage)
      2. Kidney, lung and skin affected
      3. Sites of acid-base balance

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Response to cell injury

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	Created by maisie_oj almost 11 years ago