Causes, morphology and mechanism of cell necrosis

1. Definition

• Necrosis (壊死) = circumscribed, unregulated death of cells/tissues/organs in a living body, followed by acute inflammation.
• Cellular membranes fall apart and cellular enzymes leak out → inflammatory response.
• Generally pathological (contrast: apoptosis is often physiological), but not always undesired (e.g. necrosis of tumour cells is desirable).

2. Causes (Etiology)

• Oxygen deprivation
  • Hypoxia = reduced O₂ supply (impaired gas exchange e.g. pneumonia, or ↓carrying capacity e.g. anaemia, CO poisoning). Rarely causes necrosis (spreads homogeneously).
  • Ischemia = obstruction/shortage of blood supply to an area; more dangerous — sudden, no supply of O₂ or nutrients, no time to adapt.
• Chemical agents: osmotically active particles (glucose, salt), high-pressure O₂, membrane-permeability disruptors, drugs.
• Infectious agents: fungi, viruses, bacteria and their toxins.
• Genetic defects: deficient functional proteins, accumulation of DNA/misfolded proteins.
• Nutritional imbalance: vitamin deficiency; excess (obesity → adipocyte rupture).
• Physical agents: trauma, temperature extremes, radiation, pressure changes.
• Immunological reactions: autoimmune/allergic.
• Aging: progressive telomere shortening.

3. Morphology

Changes result from enzymatic digestion — heterolytic (leukocyte enzymes) or autolytic (cell’s own lysosomal enzymes).

Nuclear changes

• Pyknosis (核濃縮) → chromatin condensation, shrunken basophilic nucleus.
• Karyorrhexis (核崩壊) → nuclear fragmentation.
• Karyolysis (核融解) → chromatin dissolution by DNase, fading basophilia.

Cytoplasmic changes

• Increased eosinophilia (denatured proteins bind eosin; ↓basophilic RNA).
• Glassy/homogeneous appearance (↓ATP → ↓glycogen granules).
• Vacuolation (digestion of organelles).
• Myelin figures (phospholipid remnants; calcification → calcium soaps).
• Membrane fragmentation.

4. Mechanisms of Cell Injury

Main targets: mitochondria, membranes, protein synthesis, cytoskeleton, genetic apparatus.

1. ATP depletion (hypoxia/ischemia → ↓oxidative phosphorylation):
   • Failure of Na⁺ pump → Na⁺ + H₂O influx → cellular swelling.
   • ↑Anaerobic glycolysis → ↓glycogen, ↑lactic acid → ↓pH → chromatin clumping.
   • Ribosome detachment from rER → ↓protein synthesis (→ hepatocyte lipidosis).
2. Mitochondrial damage (by ROS, Ca²⁺, hypoxia, toxins) → permeability transition pores, loss of membrane potential, leakage of cytochrome c → apoptosis.
3. Ca²⁺ influx — “point of no return”: ↑cytosolic Ca²⁺ activates phospholipases (membrane damage), proteases (cytoskeleton), endonucleases (DNA), ATPases (↓ATP).
4. ROS / free radicals → lipid peroxidation, protein cross-linking, DNA fragmentation.
5. Toxins: direct-acting (e.g. mercuric chloride, most chemotherapeutics) or latent (converted by cytochrome P450, e.g. acetaminophen).

5. Types of Necrosis

Type	Key feature	Typical sites
Coagulative (凝固壊死)	Protein denaturation; tissue outline preserved, firm	Heart, kidney, spleen (ischemic infarcts)
Liquefactive (融解壊死)	Enzymatic digestion → liquid/pus; outlines lost	Brain infarct, abscesses
Caseous (乾酪壊死)	Coagulative + liquefactive; cheesy; caseating granuloma (Langhans giant cells)	TB (lung, kidney)
Fat (脂肪壊死)	Lipase → free fatty acids + Ca²⁺ → chalky saponification	Pancreatitis, breast trauma
Fibrinoid (フィブリノイド壊死)	Immune-complex + fibrin in vessel walls; bright pink	Vasculitis, malignant HTN, pre-eclampsia
Gangrenous	Dry (coagulative, ischemic limb) vs wet (superimposed infection → liquefactive)	Lower limbs, bowel

💡 High-yield: Coagulative necrosis preserves tissue architecture (ghost cells) and occurs in ischemic infarcts of solid organs; the brain is the exception — it undergoes liquefactive necrosis.