Cell injury can range from reversible to irreversible and can lead to cell death. The main mechanisms of cell injury involve damage to cell membranes, mitochondria, protein synthesis machinery, and DNA. Injury can be caused by factors like hypoxia, free radicals, toxins, infections, and physical or immunological stresses. Depending on the severity and duration of injury, cells may adapt and recover or die through necrosis or apoptosis. Necrosis is always pathological and results in irreversible damage, while apoptosis is a regulated form of cell death.

1. Cell Injury I –
Cell Injury and
Cell Death

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. 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

4. 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)

5. Cell Injury – General
Mechanisms
• Loss of calcium homeostasis
• Defects in membrane permeability
• ATP depletion
• Oxygen and oxygen-derived free radicals

6. Causes of Cell Injury and
Necrosis1. Hypoxia/Hypoxic Injury
– Ischemia
– Hypoxemia
– Loss of oxygen carrying capacity
2. Free radical damage
3. Chemicals, drugs, toxins
4. Infections
5. Physical agents
6. Immunologic reactions
7. Genetic abnormalities
8. Nutritional imbalance

7. Cell injury
See also Chap. 1,
p. 14, Fig. 1-17

8. Mechanisms of injury
See Ch. 1, p. 17, Fig. 1-21

9. Ischemic injury
See also Ch. 1, p. 14,
Fig. 1-17

10. 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

11. Calcium in cell injury
See Ch. 1, p. 15, Fig. 1-19Effect of Increased Calcium

12. Reversible and
irreversible injury
See Ch. 1, p. 9,
Fig. 1-9

13. 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

14. 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

15. 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

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

17. 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

18. 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

19. Irreversible Injury –
Nuclear Changes
• Pyknosis
–Nuclear shrinkage and increased basophilia
• Karyorrhexis
–Fragmentation of the pyknotic nucleus
• Karyolysis
–Fading of basophilia of chromatin

20. Karyolysis & karyorrhexis --
micro

21. 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

22. 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)

23. 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

24. Apoptosis Diagram
Ch. 1, p. 6, Fig. 1-6

25. Types of Necrosis
• Coagulative (most common)
• Liquefactive
• Caseous
• Fat necrosis
• Gangrenous necrosis

26. 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

27. Renal infarct -- gross

28. Splenic infarcts -- gross

29. Infarcted bowel -- gross

30. Adrenal infarct -- Micro

31. 3 stages of coagulative
necrosis (L to R) -- micro

32. 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

33. Lung abscesses (liquefactive
necrosis) -- gross

34. Liver abscess -- micro

35. Liquefactive necrosis -- gross

36. Liquefactive necrosis of brain
-- micro

37. Organizing liquefactive
necrosis with cysts -- gross

38. 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)

39. Caseous necrosis -- gross

40. Caseous -- gross

41. Extensive caseous necrosis
-- gross

42. 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”

43. Enzymatic fat necrosis of
pancreas -- gross

44. Fat necrosis -- gross

45. Fat necrosis -- micro

46. 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

47. Gangrene -- gross

48. Wet gangrene -- gross

49. 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