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    براءة أحمد السلامات
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    The document summarizes various mechanisms of cell injury, including defects in membrane permeability caused by ischemia, toxins, or physical/chemical damage. It also discusses mechanisms of membrane damage like lipid peroxidation and breakdown. Consequences include damage to mitochondria, plasma membranes, and lysosomes. DNA and protein damage can also occur, potentially leading to apoptosis. Ischemic and hypoxic injury lower ATP and allow ion pump failure, while reperfusion can exacerbate injury through reactive oxygen species and inflammation. Chemicals may directly damage cells or require metabolic activation to toxic metabolites. Apoptosis is an programmed cell death pathway.

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    5. Mechanisms of Cell Injury

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    The document summarizes various mechanisms of cell injury, including defects in membrane permeability caused by ischemia, toxins, or physical/chemical damage. It also discusses mechanisms of membrane damage like lipid peroxidation and breakdown. Consequences include damage to mitochondria, plasma membranes, and lysosomes. DNA and protein damage can also occur, potentially leading to apoptosis. Ischemic and hypoxic injury lower ATP and allow ion pump failure, while reperfusion can exacerbate injury through reactive oxygen species and inflammation. Chemicals may directly damage cells or require metabolic activation to toxic metabolites. Apoptosis is an programmed cell death pathway.

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    169 views21 pages

    Mechanisms of Cell Injury

    Uploaded by

    براءة أحمد السلامات
    The document summarizes various mechanisms of cell injury, including defects in membrane permeability caused by ischemia, toxins, or physical/chemical damage. It also discusses mechanisms of membrane damage like lipid peroxidation and breakdown. Consequences include damage to mitochondria, plasma membranes, and lysosomes. DNA and protein damage can also occur, potentially leading to apoptosis. Ischemic and hypoxic injury lower ATP and allow ion pump failure, while reperfusion can exacerbate injury through reactive oxygen species and inflammation. Chemicals may directly damage cells or require metabolic activation to toxic metabolites. Apoptosis is an programmed cell death pathway.

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    Mechanisms of cell injury

    Hussam Telfah, MBBS,FRCPath

    Defects in membrane permeability


    Selective and overt membrane damage is a constant feature in all forms of cell injury except apoptosis. Causes include ischemia (ATP depletion and calcium mediated activation of phospholipases), direct damage (bacterial toxins, viral proteins, lytic complement components, physical and chemical agents).

    Mechanisms of membrane damage


    Reactive oxygen species: lipid peroxidation. Decreased phospholipids synthesis: as a consequence of defective mitochondrial function or hypoxia. This affects all cellular membranes including mitochondria themselves. Increased phospholipids breakdown: activation of endogenous phospholipases due to Ca resulting in accumulation of lipid breakdown

    Mechanisms of membrane damage


    Lipid Breakdown products include unesterified free fatty acids, acyl carnitine and lysophospholipids which have a detergent effect on membranes causing changes in permeability and electrophysiologic alterations. Cytoskeletal abnormalities: activation of proteases by high Ca causes damage to the elements of cytoskeleton.

    Consequences of membrane damage


    Most important sites of membrane damage: mitochondrial, plasma membrane and lysosomal. Lysosomes contain many degrading enzymes like RNases, DNases, proteases.....

    Damage to DNA and proteins


    Usually cells have mechanisms to repair DNA damage but if the damage is severe the cells initiate a suicide program results in cell death by apoptosis.

    Concluding points
    The identification of factors that determine when reversible injury becomes irreversible and progresses to cell death would be very useful so we may be able to identify strategies to prevent permanent consequences of cell injury. Leakage of intracellular proteins into blood through damaged membranes provides a means of detecting tissue damage. CK & troponin in MI and ALT,

    Ischemic and hypoxic injury


    Most common type of injury in clinical medicine. Hypoxia: anaerobic glycolysis Ischemia: delivery of substrates is also compromise. Ischemia is more rapidly damaging than hypoxia in the absence of ischemia.

    Mechanisms of ischemic injury


    Low O2 leads to loss of oxidative phosphorylation and decreased generation of ATP. Na/K and Ca pumps failure. Progressive loss of glycogen and decreased protein synthesis. Loss of function though the cell is not yet dead.

    Mechanisms of ischemic injury


    Cytoskeleton abnormalities; blebs and loss of villi. Formation of myelin figures and swollen organelles. To this point changes are reversible. After that, severe swelling to the mitochondria, extensive damage to the plasma membranes, myelin figures formation and swelling of lysosomes.

    Mechanisms of ischemic injury


    Large densities develop in the mitochondria. Massive influx of Ca happens especially if the ischemic area is reperfused. Death is mainly by necrosis but apoptosis also takes place. Dead cells may become replaced by large masses of myelin figures which are either phagocytosed or degraded more into fatty acids.

    Mechanisms of ischemic injury


    Protective responses: Hypoxiainducible factor-1; promotes new blood vessel formation, stimulates cell survival pathways and enhances anaerobic glycolysis. Still no reliable therapeutic measure to reduce consequences of ischemia clinically. Induction of hypothermia (33.4) in ischemic brain and spinal injuries may help in reducing the effects of

    Ischemia- reperfusion injury


    Restoration of blood flow to ischemic tissues can promote recovery if they are reversibly injured. In certain situations, reperfusion paradoxically exacerbates injury (more dead cells in addition to the already irreversibly injured cells). Mechanisms:

    Ischemia- reperfusion injury


    Reoxygenation: increased regeneration of reactive oxygen and nitrogen species from parenchymal and endothelial cells and leukocytes. Ca influx. Inflammation response mediated by cytokines which recruits more leukocytes and more injury. Applying of Anti-cytokines might aid in decreasing the unwanted effects of inflammation.

    Ischemia- reperfusion injury


    Activation of the complement system: Some IgM antibodies are deposited in ischemic tissues for unknown reasons and once the blood is restored complement proteins bind to those antibodies and lead to more injury.

    Chemical injury
    Major problem. Drugs. Liver as a major site of drug metabolism is a target for drug toxicity. Mechanisms: Directly by combining with critical molecular component. Example mercuric chloride poisoning bind to the sulfhydryl groups of cell membrane proteins causing increased permeability. More in GIT

    Chemical injury
    Cyanide poisons mitochondrial cytochrome oxidase and inhibits oxidative phosphorelation Most chemicals are not biologically active and need to be converted into active forms (toxic metabolites) which usually takes place in liver ( cytochrome P-450 mixed-function oxidases). Free radical formation and lipid peroxidation. CCl4 is converted to CCl3 which causes lipid

    Chemical injury
    Acetaminophen (paracetamol) converted to to toxic products in liver leading to injury.

    Apoptosis
    Pathway of cell death induced by a suicide program in which activation of degrading enzymes takes place. Apoptotic cells break up into fragments called apoptotic bodies which contain portions of the cytoplasm and nucleus. Become targets for phagocytosis before their contents leak out and so there would be no inflammatory reaction.

    Apoptosis
    Occurs normally during development and adulthood and in pathologic conditions. Physiologic situations: Embryogenesis, involution of hormone-dependent tissues upon hormone withdrawal, cell loss in proliferating cell populations and death of host cells after serving their usful function.

    Apoptosis
    Pathologic situations: (no host reaction) DNA damage, accumulation of misfolded proteins (Excessive accumulation of these proteins in the ER called ER stress), certain infections (viral ones), pathologic atrophy in parenchymal organs after duct obstruction (pancreas, parotid and kidney)

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