Cell Injury and Cell Death

Cell Injury: Causes & Overview - Hurt Locker Cells

📌 VITAMIN C & D outlines causes:

• Vascular: Hypoxia (most common), Ischemia.
• Infective agents.
• Traumatic/Physical agents.
• Autoimmune reactions.
• Metabolic: Nutritional imbalances, genetic defects.
• Idiopathic/Iatrogenic.
• Neoplastic.
• Chemicals, Toxins, Drugs.
• Degenerative.
• Reversible Injury: Cellular swelling, fatty change; recovery possible if stimulus removed.
• Irreversible Injury: Leads to cell death (necrosis/apoptosis). Point of no return: severe mitochondrial dysfunction, profound membrane damage.

⭐ Hypoxia is the most common cause of cell injury.

Reversible Cell Injury - Cells on Pause

• Key Mechanisms:

  • ↓ATP (hypoxia, toxins): Impairs Na⁺-K⁺ pump, $Ca^{2+}$ homeostasis.
  • Early Mitochondrial Damage: ↓ATP, ↑ROS.
  • Influx of $Ca^{2+}$: Activates deleterious enzymes.
  • Accumulation of Reactive Oxygen Species (ROS): Oxidative stress.
  • Early Membrane Damage: Leakage of contents.

• Morphological Features:

  • Cellular Swelling (Hydropic Change/Vacuolar Degeneration): Due to Na⁺-K⁺ pump failure → water influx.
    • Organs: Kidney, liver, heart, brain.
  • Fatty Change (Steatosis): Abnormal triglyceride accumulation in parenchymal cells.
    • Organs: Liver (classic), heart, muscle, kidney.

• Ultrastructural Changes (EM):

  • ER swelling, detachment of ribosomes (↓protein synthesis).
  • Mitochondrial swelling with small amorphous densities.
  • Plasma membrane blebs, blunting/loss of microvilli.
  • Myelin figures (from damaged membranes).

⭐ Cellular swelling is the first manifestation of almost all forms of injury to cells.

Necrosis & Its Types - Cellular Demolition

• Irreversible cell injury: Point of no return. Severe mitochondrial vacuolization, extensive membrane damage (plasma & lysosomal), lysosomal rupture, nuclear changes (pyknosis → karyorrhexis → karyolysis).
• Necrosis: Spectrum of morphological changes following cell death in living tissue, largely from degradative action of enzymes on lethally injured cells.
• Key Mechanisms: Severe mitochondrial dysfunction (↓ATP, ↑ROS), profound membrane damage, denaturation of intracellular proteins, enzymatic digestion of cell (lysosomal enzymes).

• Morphological Types of Necrosis:

⭐ Coagulative necrosis is the most common type, seen in hypoxic death of cells in all solid organs except the brain (where liquefactive necrosis occurs).

Apoptosis: Mechanisms & Morphology - Programmed Farewell

• Programmed cell death: energy-dependent, no inflammation (vs. necrosis).
• Examples:
  • Physiological: Embryogenesis, endometrial shedding.
  • Pathological: Viral infections (hepatitis), DNA damage, ER stress.
• Mechanisms:
  • Intrinsic (Mitochondrial) Pathway:
    • Triggered by cell stress.
    • Bcl-2 family: Pro (BAX/BAK) vs. Anti (Bcl-2/Bcl-xL). 📌 BAX/BAK = Bad Actors Kill.
    • ↑BAX/BAK → mitochondrial outer membrane permeabilization (MOMP) → Cytochrome c release.
    • Apoptosome (Cyto c + Apaf-1) → Caspase-9 (initiator).
  • Extrinsic (Death Receptor) Pathway:
    • FASL/TNF-α binds FAS/CD95 or TNFR1.
    • → Caspase-8 (initiator).
  • Execution: Both activate Caspases-3, -6, -7 → cell dismantling.
• Morphology: Cell shrinkage; chromatin condensation (pyknosis), fragmentation (karyorrhexis); apoptotic bodies (membrane-bound); phagocytosis by macrophages (no significant inflammation).

⭐ Caspases (Cysteine proteases) are central executioners of apoptosis.

High‑Yield Points - ⚡ Biggest Takeaways

• Reversible injury: cellular swelling, fatty change.
• Irreversible injury: membrane damage, mitochondrial failure, nuclear dissolution (pyknosis, karyorrhexis, karyolysis).
• Apoptosis: programmed cell death, ATP-dependent, caspase-activated (intrinsic/extrinsic pathways), no inflammation.
• Necrosis: uncontrolled cell death, always pathological, triggers inflammation.
• Coagulative necrosis: common in ischemia (e.g., MI, kidney), except brain.
• Liquefactive necrosis: characteristic of brain infarcts and bacterial/fungal infections.
• Free radicals (ROS) cause significant oxidative stress and cell damage.