6th semester pathology

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
– 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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