Cell injury

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  • Normal cell has relative narrow range of functions and structure Limited changes in metabolism = homeostasis (increased Glc and TG metabolism in active contracting muscle) Stress = demands in excess of normal homeostatic changes leads to adaptations If stress exceeds adaptive response of cell -  injury In addition, a variety of agents can directly injure cells (ie CN, , Hg, pH, temp, etc)
  • Cell injury

    1. 1. Overview + Stress Normal Adapted cell - Stress Cell ess Injury + Str es sReversibly - Strinjured cell ApoptosisIrreversibly Dead cell Injured cell Necrosis
    2. 2. Causes of Cell Injury• Oxygen Deprivation• Physical Agents• Chemical Agents and Drugs• Infectious Agents• Immunologic Reactions• Genetic Derangements• Nutritional Imbalances
    3. 3. Oxygen Deprivation• Hypoxia – deficiency of oxygen• Ischemia – loss of blood supply (arterial flow or reduced venous drainage)
    4. 4. Physical Agents• Mechanical trauma• Extremes of temperature – burns, deep cold• Radiation• Electric shock
    5. 5. Chemical Agents and Drugs• Hypertonic concentration of salt – deranging electrolyte homeostasis• Poisons – arsenic, cyanide, or mercuric salts• Insecticides and Herbicides• Air pollutant – carbon monoxide• Occupational hazard – asbestos• Alcohol and Narcotic drugs
    6. 6. Infectious Agents• Parasites• Fungi• Bacteria• Rickettsiae• Viruses
    7. 7. Immunologic Reactions• Anaphylactic reaction to foreign protein or drug• Reactions to endogenous self-antigens – autoimmune diseases
    8. 8. Genetics Derangements• Congenital malformation – Down syndrome• Decreased life of red blood cell – Thalassemia, Sickle cell anemia• Inborn errors of metabolism
    9. 9. Nutritional Imbalances• Protein-calorie deficiencies• Vitamin deficiencies• Anorexia nervosa• Excesses of lipids – Obesity, Atherosclerosis• Metabolic diseases – Diabetes
    10. 10. Mechanisms of Cell Injury• Depletion of ATP• Mitochondrial Damage• Influx of Intracellular Calcium and Loss of Calcium Homeostasis• Accumulation of Oxygen-Derived free radical (Oxidative stress)• Defects in Membrane Permeability
    11. 11. Depletion of ATPCauses Hypoxia, Ischemia Chemical Injury Membrane transportATP Na+K+ATPase (Na-pump), Ca2+Mg2+ATPases (Ca-pump) Protein synthesis, Lipogenesis etc
    12. 12. Depletion of ATP Na+ K+ Ca2+
    13. 13. Mitochondrial DamageCauses Hypoxia, Toxins Cytosolic Ca2+ Oxidative stress Lipid breakdown product
    14. 14. Mitochondrial Damage• Mitochondrial permeability transition of innermembrane (formation of high-conductancechannel)channel Mitochondrial Oxidative Phosphorylation ATP production• Leakage of Cytochrome c into cytosol
    15. 15. Mitochondrial Damage
    16. 16. Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)• The Oxidation-Reduction reaction (normal metabolic processes) -superoxide anion (O2-) -hydrogen peroxide (H2O2) -hydroxyl ion (OH )
    17. 17. Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)• Absorption of radiant energy (ultraviolet light: UV, X-ray) Ionizing radiation H20 OH H
    18. 18. Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)• Transition Metals – iron, copper “Fenton reaction” H202 Fe2+ Fe3+ OH OH-
    19. 19. Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress) Effects of the free radicals on cell injury• Lipid peroxidation of Membranes - Plasma membrane - Organellar membrane Double bonds in unsaturated fatty acids membrane damage
    20. 20. Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress) Effects of the free radicals• Oxidative modification of proteins -Oxidation of amino acid side chains Protein-protein cross-linkages -Oxidation of the protein backbone Protein fragmentation
    21. 21. Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress) Effects of the free radicals• Lesions in DNA Reaction with Thymine DNA single-stranded break DNA fragmentation
    22. 22. Superoxide dismutase(SOD)
    23. 23. Defects in Membrane PermeabilityMechanism of Membrane damage in Cell Injury• Mitochondrial Dysfunction -Decreased phospholipid synthesis -Phospholipase activation• Loss of Membrane phospholipid
    24. 24. Defects in Membrane PermeabilityMechanism of Membrane damage in Cell Injury • Cytoskeletal Abnormality Cytosolic Ca+ protease • Reactive Oxygen species • Lipid breakdown products (detergen effect on membrane)
    25. 25. Cellular and biochemical sites of damage in cell injury

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