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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)

Transcript

  • 1. Overview + Stress Normal Adapted cell - Stress Cell ess Injury + Str es sReversibly - Strinjured cell ApoptosisIrreversibly Dead cell Injured cell Necrosis
  • 2. Causes of Cell Injury• Oxygen Deprivation• Physical Agents• Chemical Agents and Drugs• Infectious Agents• Immunologic Reactions• Genetic Derangements• Nutritional Imbalances
  • 3. Oxygen Deprivation• Hypoxia – deficiency of oxygen• Ischemia – loss of blood supply (arterial flow or reduced venous drainage)
  • 4. Physical Agents• Mechanical trauma• Extremes of temperature – burns, deep cold• Radiation• Electric shock
  • 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. Infectious Agents• Parasites• Fungi• Bacteria• Rickettsiae• Viruses
  • 7. Immunologic Reactions• Anaphylactic reaction to foreign protein or drug• Reactions to endogenous self-antigens – autoimmune diseases
  • 8. Genetics Derangements• Congenital malformation – Down syndrome• Decreased life of red blood cell – Thalassemia, Sickle cell anemia• Inborn errors of metabolism
  • 9. Nutritional Imbalances• Protein-calorie deficiencies• Vitamin deficiencies• Anorexia nervosa• Excesses of lipids – Obesity, Atherosclerosis• Metabolic diseases – Diabetes
  • 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. Depletion of ATPCauses Hypoxia, Ischemia Chemical Injury Membrane transportATP Na+K+ATPase (Na-pump), Ca2+Mg2+ATPases (Ca-pump) Protein synthesis, Lipogenesis etc
  • 12. Depletion of ATP Na+ K+ Ca2+
  • 13. Mitochondrial DamageCauses Hypoxia, Toxins Cytosolic Ca2+ Oxidative stress Lipid breakdown product
  • 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. Mitochondrial Damage
  • 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. Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)• Absorption of radiant energy (ultraviolet light: UV, X-ray) Ionizing radiation H20 OH H
  • 18. Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)• Transition Metals – iron, copper “Fenton reaction” H202 Fe2+ Fe3+ OH OH-
  • 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. 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. 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. Superoxide dismutase(SOD)
  • 23. Defects in Membrane PermeabilityMechanism of Membrane damage in Cell Injury• Mitochondrial Dysfunction -Decreased phospholipid synthesis -Phospholipase activation• Loss of Membrane phospholipid
  • 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. Cellular and biochemical sites of damage in cell injury