Pathology cell injury i

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Pathology cell injury i

  1. 1. Cell Injury I – Cell Injury and Cell Death Dept. of Pathology
  2. 2. Key Concepts <ul><li>Normal cells have a fairly narrow range of function or steady state: Homeostasis </li></ul><ul><li>Excess physiologic or pathologic stress may force the cell to a new steady state: Adaptation </li></ul><ul><li>Too much stress exceeds the cell’s adaptive capacity: Injury </li></ul>
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  4. 4. Key Concepts (cont’d) <ul><li>Cell injury can be reversible or irreversible </li></ul><ul><li>Reversibility depends on the type, severity and duration of injury </li></ul><ul><li>Cell death is the result of irreversible injury </li></ul>
  5. 5. Cell Injury – General Mechanisms <ul><li>Four very interrelated cell systems are particularly vulnerable to injury: </li></ul><ul><ul><li>Membranes (cellular and organellar) </li></ul></ul><ul><ul><li>Aerobic respiration </li></ul></ul><ul><ul><li>Protein synthesis (enzymes, structural proteins, etc) </li></ul></ul><ul><ul><li>Genetic apparatus (e.g., DNA, RNA) </li></ul></ul>
  6. 6. Cell Injury – General Mechanisms <ul><li>Loss of calcium homeostasis </li></ul><ul><li>Defects in membrane permeability </li></ul><ul><li>ATP depletion </li></ul><ul><li>Oxygen and oxygen-derived free radicals </li></ul>
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  8. 8. Causes of Cell Injury and Necrosis <ul><li>Hypoxia </li></ul><ul><ul><li>Ischemia </li></ul></ul><ul><ul><li>Hypoxemia </li></ul></ul><ul><ul><li>Loss of oxygen carrying capacity </li></ul></ul><ul><li>Free radical damage </li></ul><ul><li>Chemicals, drugs, toxins </li></ul><ul><li>Infections </li></ul><ul><li>Physical agents </li></ul><ul><li>Immunologic reactions </li></ul><ul><li>Genetic abnormalities </li></ul><ul><li>Nutritional imbalance </li></ul>
  9. 9. Reversible Injury <ul><li>Mitochondrial oxidative phosphorylation is disrupted first  Decreased ATP  </li></ul><ul><ul><li>Decreased Na/K ATPase  gain of intracellular Na  cell swelling </li></ul></ul><ul><ul><li>Decreased ATP-dependent Ca pumps  increased cytoplasmic Ca concentration </li></ul></ul><ul><ul><li>Altered metabolism  depletion of glycogen </li></ul></ul><ul><ul><li>Lactic acid accumulation  decreased pH </li></ul></ul><ul><ul><li>Detachment of ribosomes from RER  decreased protein synthesis </li></ul></ul><ul><li>End result is cytoskeletal disruption with loss of microvilli, bleb formation, etc </li></ul>
  10. 10. Irreversible Injury <ul><li>Mitochondrial swelling with formation of large amorphous densities in matrix </li></ul><ul><li>Lysosomal membrane damage  leakage of proteolytic enzymes into cytoplasm </li></ul><ul><li>Mechanisms include: </li></ul><ul><ul><li>Irreversible mitochondrial dysfunction  markedly decreased ATP </li></ul></ul><ul><ul><li>Severe impairment of cellular and organellar membranes </li></ul></ul>
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  12. 12. Funky mitochondria
  13. 13. Cell Injury <ul><li>Membrane damage and loss of calcium homeostasis are most crucial </li></ul><ul><li>Some models of cell death suggest that a massive influx of calcium “causes” cell death </li></ul><ul><li>Too much cytoplasmic calcium: </li></ul><ul><ul><li>Denatures proteins </li></ul></ul><ul><ul><li>Poisons mitochondria </li></ul></ul><ul><ul><li>Inhibits cellular enzymes </li></ul></ul>
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  17. 17. Clinical Correlation <ul><li>Injured membranes are leaky </li></ul><ul><li>Enzymes and other proteins that escape through the leaky membranes make their way to the bloodstream, where they can be measured in the serum </li></ul>
  18. 18. Free Radicals <ul><li>Free radicals have an unpaired electron in their outer orbit </li></ul><ul><li>Free radicals cause chain reactions </li></ul><ul><li>Generated by: </li></ul><ul><ul><li>Absorption of radiant energy </li></ul></ul><ul><ul><li>Oxidation of endogenous constituents </li></ul></ul><ul><ul><li>Oxidation of exogenous compounds </li></ul></ul>
  19. 19. Examples of Free Radical Injury <ul><li>Chemical (e.g., CCl 4 , acetaminophen) </li></ul><ul><li>Inflammation / Microbial killing </li></ul><ul><li>Irradiation (e.g., UV rays  skin cancer) </li></ul><ul><li>Oxygen (e.g., exposure to very high oxygen tension on ventilator) </li></ul><ul><li>Age-related changes </li></ul>
  20. 20. Mechanism of Free Radical Injury <ul><li>Lipid peroxidation  damage to cellular and organellar membranes </li></ul><ul><li>Protein cross-linking and fragmentation due to oxidative modification of amino acids and proteins </li></ul><ul><li>DNA damage due to reactions of free radicals with thymine </li></ul>
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  22. 22. Morphology of Cell Injury – Key Concept <ul><li>Morphologic changes follow functional changes </li></ul>
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  24. 24. Reversible Injury -- Morphology <ul><li>Light microscopic changes </li></ul><ul><ul><li>Cell swelling (a/k/a hydropic change) </li></ul></ul><ul><ul><li>Fatty change </li></ul></ul><ul><li>Ultrastructural changes </li></ul><ul><ul><li>Alterations of cell membrane </li></ul></ul><ul><ul><li>Swelling of and small amorphous deposits in mitochondria </li></ul></ul><ul><ul><li>Swelling of RER and detachment of ribosomes </li></ul></ul>
  25. 25. Irreversible Injury -- Morphology <ul><li>Light microscopic changes </li></ul><ul><ul><li>Increased cytoplasmic eosinophilia (loss of RNA, which is more basophilic) </li></ul></ul><ul><ul><li>Cytoplasmic vacuolization </li></ul></ul><ul><ul><li>Nuclear chromatin clumping </li></ul></ul><ul><li>Ultrastructural changes </li></ul><ul><ul><li>Breaks in cellular and organellar membranes </li></ul></ul><ul><ul><li>Larger amorphous densities in mitochondria </li></ul></ul><ul><ul><li>Nuclear changes </li></ul></ul>
  26. 26. Irreversible Injury – Nuclear Changes <ul><li>Pyknosis </li></ul><ul><ul><li>Nuclear shrinkage and increased basophilia </li></ul></ul><ul><li>Karyorrhexis </li></ul><ul><ul><li>Fragmentation of the pyknotic nucleus </li></ul></ul><ul><li>Karyolysis </li></ul><ul><ul><li>Fading of basophilia of chromatin </li></ul></ul>
  27. 27. Karyolysis & karyorrhexis -- micro
  28. 28. Types of Cell Death <ul><li>Apoptosis </li></ul><ul><ul><li>Usually a regulated, controlled process </li></ul></ul><ul><ul><li>Plays a role in embryogenesis </li></ul></ul><ul><li>Necrosis </li></ul><ul><ul><li>Always pathologic – the result of irreversible injury </li></ul></ul><ul><ul><li>Numerous causes </li></ul></ul>
  29. 29. Apoptosis <ul><li>Involved in many processes, some physiologic, some pathologic </li></ul><ul><ul><li>Programmed cell death during embryogenesis </li></ul></ul><ul><ul><li>Hormone-dependent involution of organs in the adult (e.g., thymus) </li></ul></ul><ul><ul><li>Cell deletion in proliferating cell populations </li></ul></ul><ul><ul><li>Cell death in tumors </li></ul></ul><ul><ul><li>Cell injury in some viral diseases (e.g., hepatitis) </li></ul></ul>
  30. 30. Apoptosis – Morphologic Features <ul><li>Cell shrinkage with increased cytoplasmic density </li></ul><ul><li>Chromatin condensation </li></ul><ul><li>Formation of cytoplasmic blebs and apoptotic bodies </li></ul><ul><li>Phagocytosis of apoptotic cells by adjacent healthy cells </li></ul>
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  34. 34. Apoptosis – Micro
  35. 35. Types of Necrosis <ul><li>Coagulative (most common) </li></ul><ul><li>Liquefactive </li></ul><ul><li>Caseous </li></ul><ul><li>Fat necrosis </li></ul><ul><li>Gangrenous necrosis </li></ul>
  36. 36. Coagulative Necrosis <ul><li>Cell’s basic outline is preserved </li></ul><ul><li>Homogeneous, glassy eosinophilic appearance due to loss of cytoplasmic RNA (basophilic) and glycogen (granular) </li></ul><ul><li>Nucleus may show pyknosis, karyolysis or karyorrhexis </li></ul>
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  38. 38. Splenic infarcts -- gross
  39. 39. Infarcted bowel -- gross
  40. 40. Myocardium photomic
  41. 41. Adrenal infarct -- Micro
  42. 42. 3 stages of coagulative necrosis (L to R) -- micro
  43. 43. Liquefactive Necrosis <ul><li>Usually due to enzymatic dissolution of necrotic cells (usually due to release of proteolytic enzymes from neutrophils) </li></ul><ul><li>Most often seen in CNS and in abscesses </li></ul>
  44. 44. Lung abscesses (liquefactive necrosis) -- gross
  45. 45. Liver abscess -- micro
  46. 46. Liquefactive necrosis -- gross
  47. 47. Liquefactive necrosis of brain -- micro
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  49. 49. Macrophages cleaning liquefactive necrosis -- micro
  50. 50. Caseous Necrosis <ul><li>Gross: Resembles cheese </li></ul><ul><li>Micro: Amorphous, granular eosinophilc material surrounded by a rim of inflammatory cells </li></ul><ul><ul><li>No visible cell outlines – tissue architecture is obliterated </li></ul></ul><ul><li>Usually seen in infections (esp. mycobacterial and fungal infections) </li></ul>
  51. 51. Caseous necrosis -- gross
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  53. 53. Extensive caseous necrosis -- gross
  54. 54. Caseous necrosis -- micro
  55. 55. Enzymatic Fat Necrosis <ul><li>Results from hydrolytic action of lipases on fat </li></ul><ul><li>Most often seen in and around the pancreas; can also be seen in other fatty areas of the body, usually due to trauma </li></ul><ul><li>Fatty acids released via hydrolysis react with calcium to form chalky white areas  “saponification” </li></ul>
  56. 56. Enzymatic fat necrosis of pancreas -- gross
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  58. 58. Fat necrosis -- micro
  59. 59. Gangrenous Necrosis <ul><li>Most often seen on extremities, usually due to trauma or physical injury </li></ul><ul><li>“ Dry” gangrene – no bacterial superinfection; tissue appears dry </li></ul><ul><li>“ Wet” gangrene – bacterial superinfection has occurred; tissue looks wet and liquefactive </li></ul>
  60. 60. Gangrene -- gross
  61. 61. Wet gangrene -- gross
  62. 62. Gangrenous necrosis -- micro
  63. 63. Fibrinoid Necrosis <ul><li>Usually seen in the walls of blood vessels (e.g., in vasculitides) </li></ul><ul><li>Glassy, eosinophilic fibrin-like material is deposited within the vascular walls </li></ul>
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