Overview
Cell injury and death occur when cells are exposed to stress beyond their adaptive capacity.
The outcome depends on:
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Type, duration, and severity of the injury.
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Cell type, metabolic state, adaptability, and genetics.
Major Mechanisms of Cell Injury
1. Mitochondrial Dysfunction
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Causes: Hypoxia, toxins, radiation.
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Effects:
○ ↓ ATP → failure of ion pumps, cell swelling, and metabolic disruption.
○ Abnormal oxidative phosphorylation → ROS generation.
○ Mitochondrial permeability transition → loss of membrane potential → necrosis.
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2. Oxidative Stress (Reactive Oxygen Species – ROS)
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Sources:
○ Byproduct of normal metabolism (redox reactions).
○ Generated by phagocytes during in ammation (respiratory burst).
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Damage mechanisms:
○ Lipid peroxidation → membrane damage.
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○ Protein crosslinking → loss of function, misfolding.
○ DNA damage → mutations, apoptosis, cancer.
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Defense: Antioxidants (vitamins E, C, A), enzymes (SOD, catalase, glutathione
peroxidase).
3. Membrane Damage
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Causes: ROS, phospholipid degradation, cytoskeletal abnormalities.
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Consequences:
○ Mitochondrial damage → ATP loss.
○ Plasma membrane damage → ion imbalance, cell lysis.
○ Lysosomal leakage → enzymatic digestion of cell components.
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4. Calcium Homeostasis Disturbance
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Normal: Low cytosolic Ca²⁺, high in ER and mitochondria.
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Injury: Increased cytosolic Ca²⁺ → activates phospholipases, proteases, endonucleases
→ membrane and DNA damage.
5. Endoplasmic Reticulum (ER) Stress
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Cause: Accumulation of misfolded proteins (due to mutations, aging, viral infections,
ischemia).
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Response: Unfolded Protein Response (UPR)
○ Increases chaperones, decreases protein synthesis.
○ If stress persists → apoptosis (mitochondrial pathway).
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6. DNA Damage and p53 Role
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Causes: Radiation, chemotherapy, ROS, mutations.
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Response:
○ p53 arrests cell cycle for repair.
○ If irreparable → triggers apoptosis.
○ p53 loss → survival of mutated cells → cancer risk.
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Clinicopathologic Examples
Hypoxia vs. Ischemia
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Hypoxia: O₂ de ciency, but blood ow preserved → anaerobic glycolysis continues.
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Ischemia: Reduced blood ow → depletion of both oxygen and nutrients → faster, more
severe injury.
Ischemia-Reperfusion Injury
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Paradox: Reperfusion may worsen injury due to:
○ ↑ ROS, ↑ Ca²⁺ in ux, leukocyte activation, complement activation.
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Toxin-Induced Injury
Direct-Acting Toxins
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Mercury, chemotherapy, bacterial toxins → directly damage membranes or DNA.
Latent (Indirect) Toxins
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Require metabolic activation (via cytochrome P-450):
○ CCl₄: Forms CCl₃• radical → lipid peroxidation → liver damage.
○ Acetaminophen (high dose): Toxic metabolites → hepatocyte injury.
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Key Reference
Robbins and Kumar Basic Pathology, 11th Edition, Chapter 1 (pp. 10–15).