Reversible cell injury mechanisms

Hallmarks of Reversible Injury - The Cell's First SOS

• Cellular Swelling: First manifestation; due to ion pump failure & Na⁺ influx. Grossly, leads to pallor and ↑ turgor.
• Fatty Change (Steatosis): Lipid vacuoles in cytoplasm; often in hepatocytes and myocardial cells.
• Ultrastructural Changes:
  • Membrane blebbing
  • Ribosomal detachment (↓ protein synthesis)
  • Mitochondrial swelling
  • Myelin figures (damaged membranes)

⭐ Cellular swelling (hydropic change or vacuolar degeneration) is the first manifestation of almost all forms of injury to cells.

ATP Depletion - The Energy Crisis

• Central Role: The most common cause of cell injury, triggered by ischemia, hypoxia, or mitochondrial damage.
• Mechanism: Reduced ATP production below ~5-10% of normal levels initiates a cascade of events.

⭐ The failure of the Na⁺/K⁺-ATPase pump is a critical early event, leading to an influx of sodium and water, causing acute cellular swelling-a hallmark of reversible injury.

Calcium Influx - The Trouble Unleashed

• Ischemia & toxins → membrane damage → ↑ cytosolic $Ca^{2+}$ influx.
• $Ca^{2+}$ also released from mitochondrial & ER stores.
• This ↑ $Ca^{2+}$ activates downstream enzymes, amplifying damage:
  • Phospholipases: ↓ phospholipids → membrane injury.
  • Proteases: Disrupt membrane & cytoskeletal proteins.
  • ATPases: Hasten ATP depletion.
  • Endonucleases: Nuclear chromatin damage.

⭐ Increased cytosolic $Ca^{2+}$ is a crucial driver of the transition from reversible to irreversible injury, particularly by inducing mitochondrial permeability.

Oxidative Stress - The Radical Attack

• Cell injury from increased Reactive Oxygen Species (ROS) that overwhelm antioxidant defenses. Key ROS include superoxide ($O_2^•$), hydrogen peroxide ($H_2O_2$), and the hydroxyl radical ($•OH$).

• Cellular Defenses:
  • Enzymes: Catalase, Superoxide Dismutase (SOD), and Glutathione Peroxidase convert ROS to harmless substances.
  • Vitamins: A, C, and E directly scavenge free radicals.

⭐ The Fenton reaction ($Fe^{2+} + H_2O_2 \rightarrow Fe^{3+} + •OH + OH^−$) uses iron to create the highly destructive hydroxyl radical, linking iron overload states (e.g., hemochromatosis) to severe free radical injury.

Membrane & Protein Damage - The Crumbling Fortress

• Membrane Damage:
  • ↑ Cytosolic $Ca^{2+}$ activates key enzymes, leading to:
    • Phospholipase activation: ↓ phospholipid synthesis & ↑ breakdown.
    • Protease activation: Disrupts cytoskeleton, causing surface blebs.
• Protein Misfolding & Damage:
  • Caused by ↑ ROS and ↓ ATP-dependent chaperone activity.
  • Triggers the Unfolded Protein Response (UPR) in the ER.

⭐ Membrane blebbing is a classic, reversible sign of hypoxic injury, caused by protease-mediated cytoskeletal damage. It's a key feature to spot on histology.

High‑Yield Points - ⚡ Biggest Takeaways

• ATP depletion is the central event, crippling key cellular functions like ion pumps.
• Failure of the Na+/K+ pump causes a massive influx of Na+ and water, leading to cellular swelling.
• Increased intracellular Ca2+ activates damaging enzymes.
• Mitochondrial swelling and the appearance of amorphous densities are key ultrastructural signs.
• Ribosomal detachment from the RER impairs protein synthesis.
• Reversibility hinges on restoring mitochondrial function and ATP levels after the stimulus is removed.