Cell Injury

Overview

• Reversible - homeostasis is restored once the stress is removed
• Irreversible - leading to cell death (necrosis or apoptosis)

1. Causes of Cell Injury

2. Cellular Responses: The Spectrum

• Adaptation (new steady state preserved): hypertrophy, hyperplasia, atrophy, metaplasia
• Reversible injury: cell swelling, fatty change - cell recovers if stress removed
• Irreversible injury/cell death: necrosis or apoptosis

3. Reversible Cell Injury - Morphology

• Cell swelling (cytoplasmic vacuolation / "hydropic change") - from failure of Na+/K+-ATPase
• Dilation of the endoplasmic reticulum (ER)
• Detachment of ribosomes from rough ER
• Fatty change (lipid vacuoles) - especially in liver, heart, kidney cells dependent on fat metabolism

4. Irreversible Injury and Cell Death

Necrosis

• Characterized by cell swelling, membrane rupture, and release of cellular contents, triggering inflammation
• Morphologically: eosinophilic cytoplasm, nuclear changes (pyknosis, karyorrhexis, karyolysis)

Apoptosis

• Programmed cell death - cell shrinks, chromatin condenses, cell fragments into apoptotic bodies
• No inflammation (bodies are phagocytosed cleanly)
• Mediated by caspases (executioner proteases)
• Two main pathways:
  • Intrinsic (mitochondrial): triggered by DNA damage, ER stress, growth factor withdrawal - regulated by BCL-2 family proteins (pro-apoptotic: BAX, BAK; anti-apoptotic: BCL-2, BCL-XL); releases cytochrome c → activates caspase-9 → caspase-3
  • Extrinsic (death receptor): Fas-L binds Fas (CD95) or TNF binds TNFR → FADD → caspase-8 → caspase-3

5. Mechanisms of Cell Injury

A. Mitochondrial Dysfunction (→ Necrosis)

• Hypoxia, toxins, radiation damage mitochondria → ↓ ATP
• Consequences of ATP depletion:
  1. Failure of Na+/K+-ATPase → Na+ and water influx → cell swelling
  2. Anaerobic glycolysis → lactic acid accumulation → ↓ intracellular pH → enzyme inhibition
  3. Detachment of ribosomes from rough ER → ↓ protein synthesis
  4. Ultimately: membrane rupture → necrosis
• Mitochondria also generate a permeability transition pore (mPTP) under injury, releasing cytochrome c (triggers apoptosis)

B. Oxidative Stress / Reactive Oxygen Species (ROS)

• ROS sources: mitochondrial leakage, activated phagocytes (respiratory burst), reperfusion after ischemia, radiation
• ROS species: superoxide (O₂⁻), hydrogen peroxide (H₂O₂), hydroxyl radical (·OH)
• Damage caused: lipid peroxidation of membranes, protein oxidation/cross-linking, DNA strand breaks
• Cellular defenses: superoxide dismutase (SOD), catalase, glutathione peroxidase, vitamins E/C

C. Membrane Damage (→ Necrosis)

• Plasma membrane damage: loss of osmotic balance, leakage of cellular contents (enzymes detected in serum: troponin, CK-MB, LDH, AST)
• Lysosomal membrane damage: release of digestive enzymes → autodigestion of cell (endonucleases, proteases, phospholipases)
• Mechanisms: direct toxins, ROS-mediated lipid peroxidation, decreased phospholipid synthesis, loss of membrane phospholipids

D. Calcium Homeostasis Disturbance

• Normally, intracellular Ca²+ is very low (0.1 μM) vs. extracellular (1.3 mM)
• Ischemia and toxins → cytosolic Ca²+ rises → activates:
  • Phospholipases (membrane damage)
  • Proteases (cytoskeletal/membrane breakdown)
  • ATPases (↓ ATP)
  • Endonucleases (DNA fragmentation)

E. Endoplasmic Reticulum (ER) Stress (→ Apoptosis)

• Accumulation of misfolded proteins → unfolded protein response (UPR)
• If UPR cannot restore normal ER function → activates apoptosis
• Relevant in: diabetes (β-cell loss), neurodegeneration (Alzheimer's, Parkinson's), atherosclerosis

F. DNA Damage (→ Apoptosis)

• Caused by radiation, ROS, chemotherapy drugs
• Activates p53 → either cell cycle arrest (to allow DNA repair) or apoptosis if damage is irreparable
• Activates BH3-only sensors → triggers intrinsic apoptosis pathway

6. Clinicopathologic Examples

Hypoxia/Ischemia

• Sequence: ↓O₂ → ↓ATP → cell swelling (reversible) → membrane failure → necrosis (irreversible)
• Point of no return: mitochondrial membrane permeability transition; lysosomal rupture

Ischemia-Reperfusion Injury

• Paradoxically, restoring blood flow can worsen injury
• Mechanisms: burst of ROS on reoxygenation, Ca²+ overload, inflammatory cell recruitment, complement activation
• Clinically important in: MI reperfusion therapy, stroke thrombolysis, organ transplantation

Toxic Cell Injury

• Direct toxicity: e.g., HgCl₂ binds sulfhydryl groups on membrane proteins → membrane injury
• Bioactivation: e.g., CCl₄ → CCl₃ radical (by P-450) → lipid peroxidation → fatty liver → necrosis
• Acetaminophen overdose: hepatotoxic NAPQI metabolite accumulates when glucuronidation is saturated

7. Autophagy

• A survival mechanism under nutrient deprivation - cellular components are sequestered in autophagosomes, fused with lysosomes, and digested to provide nutrients
• Can paradoxically trigger apoptosis if excessive
• Regulated by ATG (autophagy) genes

Summary Table: Reversible vs. Irreversible Injury