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

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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

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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., 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. 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

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22. Morphology of Cell Injury – Key Concept
Morphologic changes follow functional changes

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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 Necrosis
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

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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

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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

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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

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