Response to cell injury

Response to cell injury

1. Targets of cell injury

   • Aerobic respiration
     • Mitochondrial oxidative phosphorylation and synthesis of ATP
   • Cell membrane integrity
     • Maintains ionic and osmotic homeostasis
   • Protein synthesis
   • Cytoskeleton
   • Genetic aparatus of the cell

2. Mechanisms of cell injury

   • Despite numerous mechanisms - the pattern of response is limited and converges on common pathways
     • Oxygen deprivation (hypoxia) - reduced O2 carrying capacity of the blood (e.g. anaemia or CO poisoning) or lack of blood supply (ischaemia)
     • Chemical agents or drugs (poisons e.g. arsenic)
     • Infectious agents
     • Immunological reactions
     • Physical agents (e.g. burns or trauma)
     • Genetic defects (e.g. sickle cell anaemia)
   • In hypoxia...
     • Decreased oxidative phosphorylation
       • Decreased cell ATP
         • 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
         • Increased anaerobic glycolysis
           • Depletion of cell glycogen (liver/skeletal muscle)
           • Decrease in cell pH
             • Nuclear clumping
         • Detachment of ribosomes from ER
           • Reduced protein synthesis
             • Lipid depletion
         • Disruption of cytoskeleton/cell contacts
   • Mitochondria are the major target
     • Source of energy for the cell
     • Maintenance of the mitochondrial membrane is essential for oxidative phosphorylation
     • Ca(2+) is an important mediator of cell injury (high intracellular Ca(2+) is bad for the cell)
       • Low intracellular Ca(2+) is maintained by the Ca/Mg ATPase
         • (Requires ATP)

3. Types of injury

   • Reversible
     • Plasma membrane blebbing, loss of microvilli
     • Mitochondrial swelling (small amorphous densites)
     • Dialation of ER - with detachment of ribosomes
     • Clumping of nuclear chromatin
     • Then the damaging stimulus needs to cease - the cell can recover from this
       • Otherwise...
         • 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)

4. Cell death

   • Apoptosis
     • See cancer revision notes
     • Physiological
       • Embryogenesis - during tissue morphogenesis
       • Hormone-dependent involution (endometrium in menstrual cycle)
       • Cell deletion in proliferating populations (intestinal crypt epithelium)
       • Death of immune cells (following cytokine depletion and deletion of autoreactive T cells)
     • Pathological
       • Cell death induced by
         • Radiation
         • Anti-cancer drugs
         • Viral diseases
         • Organ atrophy secondary to duct obstruction (e.g. pancreas)
       • Cell death in tumours
   • Necrosis
     • The morphological changes that occur in living tissue following cell death
     • Degradative action of lysosomal enzymes
     • Infarction - large groups of necrotic cells due to impaired blood supply
     • Different types of necrosis
       • Coagulative
         • Basic outline of cell shape preserved due to limited enzymatic destruction
         • Eosinophilic anucleate cells fragment and debris is removed by local macrophages and neutrophils
         • Macroscopically the tissue appears firm
         • Most common pattern of tissue necrosis in
           • Heart
           • Kidney
           • Spleen
       • Liquefactive necrosis
         • Characterised by complete lysis of cells with transformation of dead tissue into a liquid viscous mass
         • Typical of ischaemic necrosis of the brain
           • e.g. following a stroke
       • Gangrenous necrosis
         • Coagulative necrosis modified by liquefactive action of bacteria
         • E.g. ischameic limbs, bowel necrosis, diabeteic ulcers -> gangrenous
       • Caseous necrosis
         • Specific form of coagulative necrosis seen almost exclusively in tuberculosis
         • Tissue is destroyed, no cell outlines visible
         • Macroscopically appers as a white 'cheesy' mass
         • 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)
       • Fat necrosis
         • Areas of fat destruction
         • Acute pancreatitis
           • Release of pancreatic enzymes into abdomen
           • Destruction of fat in abdominal cavity

5. Effects of cell injury

   • Decreased organ function (mechanical (heart), synthetic (liver) and detoxification (liver))
   • Abnormal organ function (epilepsy, caridac arrhythmias)
   • Initiation of reaction to injury (inflammation and stress response)
   • Rupture of lysosomes in lethally damaged cells releases enzymes into the blood
     • Cardiac muscle (alanie transaminase, creatinine kinase and lactate dehydrogenase)
     • Pancreas (amylase)
     • Important in diagnosis
   • Longer term effects of cell injury
     • Injured tissues that survive become calcified
       • Dystrophic calcification
         • Scars
         • Site of infection
         • Heart valves
       • If serum calcium is abnormally high (metastatic)
         • Tissue calcification (but not at site of cell damage)
         • Kidney, lung and skin affected
         • Sites of acid-base balance