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Cell Injury I – Cell Injury and
Cell Death
Dept. of Pathology
Key Concepts
• Normal cells have a fairly narrow range
of function or steady state:
Homeostasis
• Excess physiologic or pa...
Downloaded from: StudentConsult (on 8 September 2010 02:58 PM) © 2005 Elsevier
Key Concepts (cont’d)
• Cell injury can be reversible or
irreversible
• Reversibility depends on the type,
severity and du...
Cell Injury – General Mechanisms
• Four very interrelated cell systems are
particularly vulnerable to injury:
– Membranes ...
Cell Injury – General Mechanisms
• Loss of calcium homeostasis
• Defects in membrane permeability
• ATP depletion
• Oxygen...
Downloaded from: StudentConsult (on 8 September 2010 02:58 PM) © 2005 Elsevier
Causes of Cell Injury and Necrosis
• Hypoxia
– Ischemia
– Hypoxemia
– Loss of oxygen carrying capacity
• Free radical dama...
Reversible Injury
• Mitochondrial oxidative phosphorylation is
disrupted first  Decreased ATP 
– Decreased Na/K ATPase ...
Irreversible Injury
• Mitochondrial swelling with formation of
large amorphous densities in matrix
• Lysosomal membrane da...
Downloaded from: StudentConsult (on 8 September 2010 02:58 PM) © 2005 Elsevier
Funky mitochondria
Cell Injury
• Membrane damage and loss of calcium
homeostasis are most crucial
• Some models of cell death suggest that
a ...
Downloaded from: StudentConsult (on 8 September 2010 02:58 PM) © 2005 Elsevier
Downloaded from: StudentConsult (on 8 September 2010 02:58 PM) © 2005 Elsevier
Downloaded from: StudentConsult (on 8 September 2010 02:58 PM) © 2005 Elsevier
Clinical Correlation
• Injured membranes are leaky
• Enzymes and other proteins that escape
through the leaky membranes ma...
Free Radicals
• Free radicals have an unpaired electron
in their outer orbit
• Free radicals cause chain reactions
• Gener...
Examples of Free Radical Injury
• Chemical (e.g., CCl4, acetaminophen)
• Inflammation / Microbial killing
• Irradiation (e...
Mechanism of Free Radical Injury
• Lipid peroxidation  damage to cellular
and organellar membranes
• Protein cross-linkin...
Downloaded from: StudentConsult (on 8 September 2010 02:58 PM) © 2005 Elsevier
Morphology of Cell Injury –
Key Concept
• Morphologic changes follow functional
changes
© 2005 Elsevier Downloaded from: StudentConsult (on 8 September 2010 02:58 PM)
Reversible Injury -- Morphology
• Light microscopic changes
– Cell swelling (a/k/a hydropic change)
– Fatty change
• Ultra...
Irreversible Injury -- Morphology
• Light microscopic changes
– Increased cytoplasmic eosinophilia (loss of
RNA, which is ...
Irreversible Injury – Nuclear Changes
• Pyknosis
– Nuclear shrinkage and increased basophilia
• Karyorrhexis
– Fragmentati...
Karyolysis & karyorrhexis --
micro
Types of Cell Death
• Apoptosis
– Usually a regulated, controlled process
– Plays a role in embryogenesis
• Necrosis
– Alw...
Apoptosis
• Involved in many processes, some
physiologic, some pathologic
– Programmed cell death during
embryogenesis
– H...
Apoptosis – Morphologic Features
• Cell shrinkage with increased
cytoplasmic density
• Chromatin condensation
• Formation ...
Downloaded from: StudentConsult (on 8 September 2010 02:59 PM) © 2005 Elsevier
Downloaded from: StudentConsult (on 8 September 2010 02:58 PM) © 2005 Elsevier
Downloaded from: StudentConsult (on 8 September 2010 02:59 PM) © 2005 Elsevier
Apoptosis – Micro
Types of Necrosis
• Coagulative (most common)
• Liquefactive
• Caseous
• Fat necrosis
• Gangrenous necrosis
Coagulative Necrosis
• Cell’s basic outline is preserved
• Homogeneous, glassy eosinophilic
appearance due to loss of cyto...
Downloaded from: StudentConsult (on 8 September 2010 02:58 PM) © 2005 Elsevier
Splenic infarcts -- gross
Infarcted bowel -- gross
Myocardium photomic
Adrenal infarct -- Micro
3 stages of coagulative
necrosis (L to R) -- micro
Liquefactive Necrosis
• Usually due to enzymatic dissolution of
necrotic cells (usually due to release of
proteolytic enzy...
Lung abscesses (liquefactive
necrosis) -- gross
Liver abscess -- micro
Liquefactive necrosis -- gross
Liquefactive necrosis of brain
-- micro
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Macrophages cleaning
liquefactive necrosis -- micro
Caseous Necrosis
• Gross: Resembles cheese
• Micro: Amorphous, granular eosinophilc
material surrounded by a rim of
inflam...
Caseous necrosis -- gross
Downloaded from: StudentConsult (on 8 September 2010 02:58 PM) © 2005 Elsevier
Extensive caseous necrosis
-- gross
Caseous necrosis -- micro
Enzymatic Fat Necrosis
• Results from hydrolytic action of lipases
on fat
• Most often seen in and around the
pancreas; ca...
Enzymatic fat necrosis of
pancreas -- gross
Downloaded from: StudentConsult (on 8 September 2010 02:58 PM) © 2005 Elsevier
Fat necrosis -- micro
Gangrenous Necrosis
• Most often seen on extremities, usually
due to trauma or physical injury
• “Dry” gangrene – no bacte...
Gangrene -- gross
Wet gangrene -- gross
Gangrenous necrosis -- micro
Fibrinoid Necrosis
• Usually seen in the walls of blood
vessels (e.g., in vasculitides)
• Glassy, eosinophilic fibrin-like...
Downloaded from: StudentConsult (on 8 September 2010 02:58 PM) © 2005 Elsevier
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Pathology cellinjuryi

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Pathology cellinjuryi

  1. 1. Cell Injury I – Cell Injury and Cell Death Dept. of Pathology
  2. 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. 3. Downloaded from: StudentConsult (on 8 September 2010 02:58 PM) © 2005 Elsevier
  4. 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. 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. 6. Cell Injury – General Mechanisms • Loss of calcium homeostasis • Defects in membrane permeability • ATP depletion • Oxygen and oxygen-derived free radicals
  7. 7. Downloaded from: StudentConsult (on 8 September 2010 02:58 PM) © 2005 Elsevier
  8. 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. 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. 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. 11. Downloaded from: StudentConsult (on 8 September 2010 02:58 PM) © 2005 Elsevier
  12. 12. Funky mitochondria
  13. 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
  14. 14. Downloaded from: StudentConsult (on 8 September 2010 02:58 PM) © 2005 Elsevier
  15. 15. Downloaded from: StudentConsult (on 8 September 2010 02:58 PM) © 2005 Elsevier
  16. 16. Downloaded from: StudentConsult (on 8 September 2010 02:58 PM) © 2005 Elsevier
  17. 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. 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. 19. Examples of Free Radical Injury • Chemical (e.g., CCl4, 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. 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. 21. Downloaded from: StudentConsult (on 8 September 2010 02:58 PM) © 2005 Elsevier
  22. 22. Morphology of Cell Injury – Key Concept • Morphologic changes follow functional changes
  23. 23. © 2005 Elsevier Downloaded from: StudentConsult (on 8 September 2010 02:58 PM)
  24. 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. 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. 26. Irreversible Injury – Nuclear Changes • Pyknosis – Nuclear shrinkage and increased basophilia • Karyorrhexis – Fragmentation of the pyknotic nucleus • Karyolysis – Fading of basophilia of chromatin
  27. 27. Karyolysis & karyorrhexis -- micro
  28. 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. 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. 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
  31. 31. Downloaded from: StudentConsult (on 8 September 2010 02:59 PM) © 2005 Elsevier
  32. 32. Downloaded from: StudentConsult (on 8 September 2010 02:58 PM) © 2005 Elsevier
  33. 33. Downloaded from: StudentConsult (on 8 September 2010 02:59 PM) © 2005 Elsevier
  34. 34. Apoptosis – Micro
  35. 35. Types of Necrosis • Coagulative (most common) • Liquefactive • Caseous • Fat necrosis • Gangrenous necrosis
  36. 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. 37. Downloaded from: StudentConsult (on 8 September 2010 02:58 PM) © 2005 Elsevier
  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 • 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. 44. Lung abscesses (liquefactive necrosis) -- gross
  45. 45. Liver abscess -- micro
  46. 46. Liquefactive necrosis -- gross
  47. 47. Liquefactive necrosis of brain -- micro
  48. 48. Downloaded from: StudentConsult (on 8 September 2010 02:58 PM)© 2005 Elsevier
  49. 49. Macrophages cleaning liquefactive necrosis -- micro
  50. 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. 51. Caseous necrosis -- gross
  52. 52. Downloaded from: StudentConsult (on 8 September 2010 02:58 PM) © 2005 Elsevier
  53. 53. Extensive caseous necrosis -- gross
  54. 54. Caseous necrosis -- micro
  55. 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. 56. Enzymatic fat necrosis of pancreas -- gross
  57. 57. Downloaded from: StudentConsult (on 8 September 2010 02:58 PM) © 2005 Elsevier
  58. 58. Fat necrosis -- micro
  59. 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. 60. Gangrene -- gross
  61. 61. Wet gangrene -- gross
  62. 62. Gangrenous necrosis -- micro
  63. 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. 64. Downloaded from: StudentConsult (on 8 September 2010 02:58 PM) © 2005 Elsevier

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