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Cell Injury — Study Notes

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Overview

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1. Causes of Cell Injury

Key principle: Low doses / brief duration → reversible injury; large doses / prolonged duration → irreversible injury and necrosis.

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2. Reversible Cell Injury

Morphologic Features

• Cellular swelling (hydropic change / vacuolar degeneration) — earliest sign; small clear vacuoles in cytoplasm (distended ER segments); organ shows pallor, increased turgor and weight
• Fatty change — lipid vacuoles accumulate in organs active in lipid metabolism (e.g., liver)
• Cytoplasmic eosinophilia — loss of RNA (which binds the blue hematoxylin dye) makes cytoplasm appear redder

Ultrastructural Features (EM)

1. Plasma membrane blebbing, blunting/loss of microvilli
2. Mitochondrial swelling + small amorphous densities
3. ER dilation with detachment of ribosomes and dissociation of polysomes
4. Nuclear chromatin clumping
5. Myelin figures — collections of phospholipids from damaged membranes

Mechanism

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3. Irreversible Injury ("Point of No Return")

1. Inability to restore mitochondrial function (oxidative phosphorylation and ATP generation)
2. Membrane damage — loss of structural integrity of plasma and intracellular membranes
3. Loss of DNA/chromatin structural integrity

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4. Cell Death

A. Necrosis

• Pyknosis — nuclear shrinkage and condensation
• Karyorrhexis — nuclear fragmentation
• Karyolysis — nuclear dissolution

Clinical use: Tissue-specific proteins leak from necrotic cells into blood — troponin (cardiac), transaminases (liver), alkaline phosphatase (bile duct).

B. Apoptosis

• Cell shrinkage, chromatin condensation at periphery
• Cellular fragmentation into apoptotic bodies (membrane-bound)
• Plasma membrane remains intact — no leakage of contents
• Phosphatidylserine flips to outer leaflet → "eat me" signal for phagocytes → efferocytosis
• No inflammation (contrast with necrosis)

1. Intrinsic (mitochondrial) pathway — triggered by DNA damage, loss of growth factors, ER stress → BCL-2 family proteins regulate mitochondrial membrane permeability → cytochrome c release → caspase activation → cell death. Anti-apoptotic BCL-2 and BCL-XL keep this in check; pro-apoptotic BAX/BAK promote it.
2. Extrinsic (death receptor) pathway — ligands (e.g., FasL, TNF) bind death receptors (Fas/CD95, TNFR1) → FADD recruitment → caspase-8 activation → execution caspases. Used by cytotoxic T lymphocytes; eliminates self-reactive lymphocytes.

Necrosis vs. Apoptosis — Quick Comparison

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5. Other Forms of Cell Death

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6. Mechanisms of Cell Injury

Mitochondrial Damage

• ATP depletion → Na⁺/K⁺-ATPase failure → cell swelling
• Anaerobic glycolysis → lactic acidosis
• Ribosome detachment → reduced protein synthesis
• Release of pro-apoptotic proteins (cytochrome c) → apoptosis
• Ultimately → irreversible membrane damage → necrosis

Oxidative Stress (ROS)

• Membrane lipids (lipid peroxidation)
• Proteins (cross-linking, fragmentation)
• DNA (strand breaks → apoptosis)

Membrane Damage

• Loss of selective permeability → cellular swelling
• Lysosomal membrane rupture → enzymatic digestion of cell contents
• Plasma membrane disruption → protein leakage into blood (biomarkers)

DNA Damage

• Radiation or chemical damage → if unrepaired → p53 activation → apoptosis

Calcium Homeostasis Disturbance

• Ischemia/toxins → intracellular Ca²⁺↑ → activates phospholipases (membrane damage), proteases (protein breakdown), ATPases (↓ ATP), endonucleases (DNA fragmentation) → cell death

ER Stress

• Misfolded proteins accumulate in ER → unfolded protein response (UPR) → if unresolved → apoptosis

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7. Ischemia–Reperfusion Injury

• Sudden oxygen reintroduction generates a burst of ROS
• Influx of Ca²⁺
• Neutrophil activation and inflammation
• Mitochondrial permeability transition pore (MPTP) opening → cell death

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8. Cellular Adaptations to Sublethal Stress

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9. Summary Flowchart

INJURIOUS STIMULUS
        ↓
  REVERSIBLE INJURY
  • Cell swelling (hydropic change)
  • Fatty change
  • Cytoplasmic eosinophilia
  • Mitochondrial swelling
        ↓ (stimulus persists/worsens)
  IRREVERSIBLE INJURY
        ↓              ↓
   NECROSIS        APOPTOSIS
 (pathologic)    (programmed)
 • Inflammation   • No inflammation
 • Membrane       • Apoptotic bodies
   rupture        • Phagocytosis

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