This document discusses cell injury and cell death. It notes that cells have a normal steady state of homeostasis but stress can force adaptation or injury. Cell injury can be reversible or irreversible, depending on the severity and duration of the stress. Irreversible injury leads to cell death. Mechanisms of injury include damage to membranes, respiration, protein synthesis, and DNA. Causes include hypoxia, free radicals, chemicals, infections, and physical or immunological stresses. Reversible injury disrupts mitochondria and ATP production, while irreversible injury severely damages membranes and organelles. The morphology of injury progresses from reversible changes like swelling to irreversible changes like membrane breaks and nuclear fragmentation. Types of cell death include apoptosis and various forms

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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