Cell Injury and Death Overview

Cell Injury and Death

• Adaptation: Cells respond to stressors by adapting, undergoing injury, or death.
• Reversible injury: Characterized by generalized cellular swelling (hydropic change) and fatty change, but fully reversible if stressor removed.
• Irreversible injury:
  • Inability to recover from mitochondrial dysfunction (lack of oxidative phosphorylation + ATP production) and profound membrane disturbances.
  • Occurs after ischemic insult in most organs except the brain.
• Types of Necrosis:
  • Coagulative necrosis: Architecture preserved for a while, firm texture. Occurs in most organs (except brain) after ischemia.
  • Liquefactive necrosis: Digestion of dead cells, creamy yellow appearance. Seen in brain ischemia and focal bacterial/fungal infections.
  • Caseous necrosis: Granulomatous appearance under microscope, fragmented cells enclosed in inflammation border.
  • Fat necrosis: Chalky white areas (saponification) due to pancreatic enzymes. Occurs in acute pancreatitis.
  • Fibrinoid necrosis: Complexes of antigens and antibodies in vessel walls; bright pink and amorphous on H&E stains.
• Apoptosis: Programmed cell death, tightly regulated, no inflammation.
  • Physiologic: removal of excess cells in development, involution of hormone-dependent tissues, elimination of self-reactive lymphocytes.
  • Pathologic: DNA damage, accumulation of misfolded proteins, viral infections.
  • Morphology: Cell shrinkage, chromatin condensation, cytoplasmic blebs, apoptotic bodies (phagocytosed).
  • Pathways: Mitochondrial (intrinsic) and death receptor (extrinsic); both converge on caspase activation.
• Necroptosis: Necrosis-like cell death, triggered by excess iron or reactive oxygen species (ROS), looks like necrosis but regulated. Involves kinases RIPK1 and RIPK3.

Cellular Aging

• Cells have a limited capacity for replication, leading to cellular senescence.
• Telomere shortening, DNA damage, defective protein homeostasis, nutrient sensing, and insulin/IGF signaling contribute to cellular aging.
• Cellular senescent cells produce factors that induce inflammation and contribute to tissue dysfunction.

Pathologic Calcification

• Dystrophic calcification: Deposition of calcium salts in dying tissue despite normal serum calcium levels.
• Metastatic calcification: Deposition of calcium salts in normal tissues due to hypercalcemia (elevated blood calcium).
  • Causes: parathyroid hormone (PTH) overactivity, vitamin D-related disorders, renal failure, hemochromatosis.

Other Cellular Damage

• Hypoxia/ischemia: Inadequate oxygenation of blood; often worse than hypoxia due to metabolite buildup. Key factor is hypoxia-inducible factor 1 (HIF-1) activation.
• Chemical injury: Direct binding to important molecules or conversion to toxic metabolites.
• Oxidative stress: ROS's (oxygen-derived free radicals) damage lipids, proteins, and nucleic acids that leads to cell injury.
• Calcium homeostasis disturbances: Excessive intracellular calcium activates enzymes that damage cellular components.
• Endoplasmic reticulum stress: Accumulation of misfolded proteins triggers apoptosis or cellular dysfunction.

Adaptations

• Hypertrophy: Increase in cell size (physiological or pathological, e.g., cardiac hypertrophy).
• Hyperplasia: Increase in cell number (physiological or pathological, e.g., benign prostatic hyperplasia).
• Atrophy: Decrease in cell size and number (e.g., reduced blood supply, inadequate nutrition, loss of endocrine stimulation).
• Metaplasia: Change in cell type, sometimes associated with increased cancer risk.
• Intracellular accumulations: Abnormal accumulation of substances like lipids, proteins, or pigments, e.g., fatty change.