Cell Injury and Types of Necrosis — Reversible vs Irreversible Injury, Necrosis Patterns and Apoptosis

A stressed cell has three possible outcomes: it can adapt by reversibly changing its function and structure, it can suffer injury that is still reversible, or it can die by necrosis or apoptosis. Cell injury is reversible until a threshold is reached, after which it progresses to cell death. That threshold — the 'point of no return' — is the core idea examiners test.

• Model injury: hypoxia/ischaemia — the best-studied sequence, used below to explain each microscopic change.
• Key targets: mitochondrial ATP production, membrane pumps, the plasma membrane and the nucleus.
• Necrosis vs apoptosis: necrosis follows extensive membrane and organelle damage; apoptosis is a regulated programme the cell runs itself.

Ischaemic injury is the model sequence. Each step explains a microscopic finding.

1. Less oxygen → less oxidative phosphorylation → less ATP in the cytoplasm.
2. Na+/K+ ATPase fails → sodium accumulates inside the cell and pulls water in → cellular swelling, surface blebs and loss of microvilli. If ATP is restored in time, these changes reverse.
3. Calcium pump fails → calcium floods the cytoplasm and activates enzymes: phospholipase (membrane damage; phospholipid breakdown forms whorled myelin figures), protease (breaks down cell proteins), endonuclease (clumps and cleaves chromatin) and ATPase (burns the remaining ATP).
4. Mitochondrial damage: calcium opens the mitochondrial permeability transition pore; cytochrome c leaks out and activates caspases.
5. Membrane rupture: the plasma membrane breaks, contents leak out and provoke inflammation; cell-specific proteins appear in blood.

Necrosis sets in when extensive damage to the cell membrane and internal structures pushes the cell past the point of reversible injury. In ischaemia, the decisive step is ATP not being restored before calcium floods in — after that, the cell cannot recover even if blood supply returns.

Coagulative and liquefactive necrosis are the two major patterns. Caseous, fat, fibrinoid and gangrenous necrosis are descriptive patterns with distinctive gross or microscopic looks. The cause of death, the organ and the duration together decide which pattern appears.

In coagulative necrosis, injury denatures structural proteins and the enzymes that would digest the cell, so the dead tissue keeps its shape for days. It is the default pattern of ischaemia in every organ except the brain.

In liquefactive necrosis, hydrolytic enzymes dissolve the dead cells. In infections, the enzymes come from neutrophils and bacteria, producing an abscess. The brain is the classic exception for ischaemia: an infarct in the brain liquefies (the exact reason is not fully understood), leaving a fluid-filled cavity.

• Caseous necrosis: typical of tuberculosis. The lipid-rich mycobacterial cell wall (mycolic acid) gives the 'cheesy' look. The necrotic centre is surrounded by activated macrophages (epithelioid cells), giant cells and lymphocytes — a granuloma.
• Fat necrosis: in tissues rich in fat. In acute pancreatitis, released lipases split fat into free fatty acids that bind calcium to form chalky calcium soaps (saponification). The breast, also rich in fat, is the other classic site.
• Fibrinoid necrosis: a microscopic pattern of vessel-wall damage — immune complexes, autoimmune vasculitis or infections. Plasma proteins, mainly fibrin, leak into the wall, which stains bright pink.
• Gangrene: a clinical term for ischaemic necrosis of a limb or digit. Dry gangrene is coagulative necrosis from slowly progressive ischaemia, mainly in the digits. Wet gangrene adds bacterial infection and liquefaction. Gas gangrene is a life-threatening clostridial myonecrosis, usually due to Clostridium perfringens after deep wounds.

Restoring blood flow is essential, but it can add damage to cells that were injured but still alive. Returning oxygen generates a burst of reactive oxygen species (free radicals), which cause lipid peroxidation and membrane dysfunction, and calcium floods into already weakened cells. This is ischaemia–reperfusion injury.

Neutrophils arrive within hours, guided by chemokines and damage signals. They clear debris but their proteolytic enzymes and free radicals can also amplify the damage — one reason necrosis, unlike apoptosis, injures neighbouring tissue.

Apoptosis is genetically programmed, ATP-dependent, enzyme-driven cell death that removes cells without provoking inflammation. Necrosis is accidental, unregulated and inflammatory.

Apoptosis is carried out by caspases — cysteine proteases. Two upstream routes activate initiator caspases, and both converge on the executioner caspases 3 and 7.

• p53 (the TP53 tumour suppressor) arrests the cycle in G1 after DNA damage to allow repair; if repair fails, it pushes the cell into apoptosis.
• BCL-2 genes on chromosome 18 encode the anti-apoptotic BCL-2 protein, balanced against pro-apoptotic BAX; tipping this balance decides whether a stressed cell lives or dies.
• Annexin V binds exposed phosphatidylserine and is used in the lab to detect early apoptosis.