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Pathology cell injury i Presentation Transcript

  • 1. Cell Injury I – Cell Injury and Cell Death Dept. of Pathology
  • 2. Key Concepts
    • Normal cells have a fairly narrow range of function or steady state: Homeostasis
    • Excess physiologic or pathologic stress may force the cell to a new steady state: Adaptation
    • Too much stress exceeds the cell’s adaptive capacity: Injury
  • 3. Downloaded from: StudentConsult (on 8 September 2010 02:58 PM) © 2005 Elsevier
  • 4. Key Concepts (cont’d)
    • Cell injury can be reversible or irreversible
    • Reversibility depends on the type, severity and duration of injury
    • Cell death is the result of irreversible injury
  • 5. Cell Injury – General Mechanisms
    • Four very interrelated cell systems are particularly vulnerable to injury:
      • Membranes (cellular and organellar)
      • Aerobic respiration
      • Protein synthesis (enzymes, structural proteins, etc)
      • Genetic apparatus (e.g., DNA, RNA)
  • 6. Cell Injury – General Mechanisms
    • Loss of calcium homeostasis
    • Defects in membrane permeability
    • ATP depletion
    • Oxygen and oxygen-derived free radicals
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  • 8. Causes of Cell Injury and Necrosis
    • Hypoxia
      • Ischemia
      • Hypoxemia
      • Loss of oxygen carrying capacity
    • Free radical damage
    • Chemicals, drugs, toxins
    • Infections
    • Physical agents
    • Immunologic reactions
    • Genetic abnormalities
    • Nutritional imbalance
  • 9. Reversible Injury
    • Mitochondrial oxidative phosphorylation is disrupted first  Decreased ATP 
      • Decreased Na/K ATPase  gain of intracellular Na  cell swelling
      • Decreased ATP-dependent Ca pumps  increased cytoplasmic Ca concentration
      • Altered metabolism  depletion of glycogen
      • Lactic acid accumulation  decreased pH
      • Detachment of ribosomes from RER  decreased protein synthesis
    • End result is cytoskeletal disruption with loss of microvilli, bleb formation, etc
  • 10. Irreversible Injury
    • Mitochondrial swelling with formation of large amorphous densities in matrix
    • Lysosomal membrane damage  leakage of proteolytic enzymes into cytoplasm
    • Mechanisms include:
      • Irreversible mitochondrial dysfunction  markedly decreased ATP
      • Severe impairment of cellular and organellar membranes
  • 11. Downloaded from: StudentConsult (on 8 September 2010 02:58 PM) © 2005 Elsevier
  • 12. Funky mitochondria
  • 13. Cell Injury
    • Membrane damage and loss of calcium homeostasis are most crucial
    • Some models of cell death suggest that a massive influx of calcium “causes” cell death
    • Too much cytoplasmic calcium:
      • Denatures proteins
      • Poisons mitochondria
      • Inhibits cellular enzymes
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  • 17. Clinical Correlation
    • Injured membranes are leaky
    • Enzymes and other proteins that escape through the leaky membranes make their way to the bloodstream, where they can be measured in the serum
  • 18. Free Radicals
    • Free radicals have an unpaired electron in their outer orbit
    • Free radicals cause chain reactions
    • Generated by:
      • Absorption of radiant energy
      • Oxidation of endogenous constituents
      • Oxidation of exogenous compounds
  • 19. Examples of Free Radical Injury
    • Chemical (e.g., CCl 4 , acetaminophen)
    • Inflammation / Microbial killing
    • Irradiation (e.g., UV rays  skin cancer)
    • Oxygen (e.g., exposure to very high oxygen tension on ventilator)
    • Age-related changes
  • 20. Mechanism of Free Radical Injury
    • Lipid peroxidation  damage to cellular and organellar membranes
    • Protein cross-linking and fragmentation due to oxidative modification of amino acids and proteins
    • DNA damage due to reactions of free radicals with thymine
  • 21. Downloaded from: StudentConsult (on 8 September 2010 02:58 PM) © 2005 Elsevier
  • 22. Morphology of Cell Injury – Key Concept
    • Morphologic changes follow functional changes
  • 23. © 2005 Elsevier Downloaded from: StudentConsult (on 8 September 2010 02:58 PM)
  • 24. Reversible Injury -- Morphology
    • Light microscopic changes
      • Cell swelling (a/k/a hydropic change)
      • Fatty change
    • Ultrastructural changes
      • Alterations of cell membrane
      • Swelling of and small amorphous deposits in mitochondria
      • Swelling of RER and detachment of ribosomes
  • 25. Irreversible Injury -- Morphology
    • Light microscopic changes
      • Increased cytoplasmic eosinophilia (loss of RNA, which is more basophilic)
      • Cytoplasmic vacuolization
      • Nuclear chromatin clumping
    • Ultrastructural changes
      • Breaks in cellular and organellar membranes
      • Larger amorphous densities in mitochondria
      • Nuclear changes
  • 26. Irreversible Injury – Nuclear Changes
    • Pyknosis
      • Nuclear shrinkage and increased basophilia
    • Karyorrhexis
      • Fragmentation of the pyknotic nucleus
    • Karyolysis
      • Fading of basophilia of chromatin
  • 27. Karyolysis & karyorrhexis -- micro
  • 28. Types of Cell Death
    • Apoptosis
      • Usually a regulated, controlled process
      • Plays a role in embryogenesis
    • Necrosis
      • Always pathologic – the result of irreversible injury
      • Numerous causes
  • 29. Apoptosis
    • Involved in many processes, some physiologic, some pathologic
      • Programmed cell death during embryogenesis
      • Hormone-dependent involution of organs in the adult (e.g., thymus)
      • Cell deletion in proliferating cell populations
      • Cell death in tumors
      • Cell injury in some viral diseases (e.g., hepatitis)
  • 30. Apoptosis – Morphologic Features
    • Cell shrinkage with increased cytoplasmic density
    • Chromatin condensation
    • Formation of cytoplasmic blebs and apoptotic bodies
    • Phagocytosis of apoptotic cells by adjacent healthy cells
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  • 34. Apoptosis – Micro
  • 35. Types of Necrosis
    • Coagulative (most common)
    • Liquefactive
    • Caseous
    • Fat necrosis
    • Gangrenous necrosis
  • 36. Coagulative Necrosis
    • Cell’s basic outline is preserved
    • Homogeneous, glassy eosinophilic appearance due to loss of cytoplasmic RNA (basophilic) and glycogen (granular)
    • Nucleus may show pyknosis, karyolysis or karyorrhexis
  • 37. Downloaded from: StudentConsult (on 8 September 2010 02:58 PM) © 2005 Elsevier
  • 38. Splenic infarcts -- gross
  • 39. Infarcted bowel -- gross
  • 40. Myocardium photomic
  • 41. Adrenal infarct -- Micro
  • 42. 3 stages of coagulative necrosis (L to R) -- micro
  • 43. Liquefactive Necrosis
    • Usually due to enzymatic dissolution of necrotic cells (usually due to release of proteolytic enzymes from neutrophils)
    • Most often seen in CNS and in abscesses
  • 44. Lung abscesses (liquefactive necrosis) -- gross
  • 45. Liver abscess -- micro
  • 46. Liquefactive necrosis -- gross
  • 47. Liquefactive necrosis of brain -- micro
  • 48. Downloaded from: StudentConsult (on 8 September 2010 02:58 PM) © 2005 Elsevier
  • 49. Macrophages cleaning liquefactive necrosis -- micro
  • 50. Caseous Necrosis
    • Gross: Resembles cheese
    • Micro: Amorphous, granular eosinophilc material surrounded by a rim of inflammatory cells
      • No visible cell outlines – tissue architecture is obliterated
    • Usually seen in infections (esp. mycobacterial and fungal infections)
  • 51. Caseous necrosis -- gross
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  • 53. Extensive caseous necrosis -- gross
  • 54. Caseous necrosis -- micro
  • 55. Enzymatic Fat Necrosis
    • Results from hydrolytic action of lipases on fat
    • Most often seen in and around the pancreas; can also be seen in other fatty areas of the body, usually due to trauma
    • Fatty acids released via hydrolysis react with calcium to form chalky white areas  “saponification”
  • 56. Enzymatic fat necrosis of pancreas -- gross
  • 57. Downloaded from: StudentConsult (on 8 September 2010 02:58 PM) © 2005 Elsevier
  • 58. Fat necrosis -- micro
  • 59. Gangrenous Necrosis
    • Most often seen on extremities, usually due to trauma or physical injury
    • “ Dry” gangrene – no bacterial superinfection; tissue appears dry
    • “ Wet” gangrene – bacterial superinfection has occurred; tissue looks wet and liquefactive
  • 60. Gangrene -- gross
  • 61. Wet gangrene -- gross
  • 62. Gangrenous necrosis -- micro
  • 63. Fibrinoid Necrosis
    • Usually seen in the walls of blood vessels (e.g., in vasculitides)
    • Glassy, eosinophilic fibrin-like material is deposited within the vascular walls
  • 64. Downloaded from: StudentConsult (on 8 September 2010 02:58 PM) © 2005 Elsevier