Cell Injury and Its Causes

Cell Injury

• Cells maintain a narrow range of physiological activities within their intracellular milieu
• Cell injury occurs when the adaptive capability of a cell is exceeded
• There are two principal patterns of cell death: necrosis and apoptosis
• Necrosis occurs after exposure to noxious conditions and is characterized by cell swelling, protein denaturation and organellar breakdown
• Apoptosis is programmed cell death occurring in normal or physiological conditions

Causes Of Cell Injury

• Hypoxia: Impedes aerobic oxidative respiration; should be distinguished from ischemia, which also results in hypoxic cell injury
• Physical agents: Trauma, temperature extremes, radiation, electric shock, sudden atmospheric pressure changes
• Chemicals and drugs: May alter membrane permeability, osmotic homeostasis, or enzyme cofactor integrity
• Microbiologic agents: Range from viruses to tapeworms
• Immunologic reactions: Body's immune system can cause cell injury, e.g., anaphylactic reaction
• Genetic defects: E.g., Down syndrome, sickle cell anemia
• Nutritional imbalances: Protein-calorie insufficiency, vitamin deficiencies; diets rich in animal fat are implicated in atherosclerosis pathogenesis
• Aging:

Mechanisms Of Cell Injury

• Cell response to injuries depends on the type of injury, duration, and severity
• Consequences of injury depend on the type of cell, current health status, and adaptability
• Four intracellular systems are vulnerable to injury:
  • Cell membrane integrity (altering ionic and osmotic homeostasis)
  • Aerobic respiration
  • Protein synthesis
  • Genetic apparatus
• Calcium influx:
  • Cytosolic free calcium is maintained at low levels by ATP-dependent calcium transporters
  • Ischemia or toxins allow calcium influx from the extracellular space, with mitochondrial calcium release
  • Activates enzymes like phospholipases, proteases, ATPases, and endonucleases
• Oxygen free radicals: Important mediators of cell death

Ischemic And Hypoxic Injury

• Reversible Injury:
  • First effect of hypoxia is on aerobic respiration, reducing intracellular ATP
  • Reduced ATP leads to:
    • Influx of extracellular calcium
    • Reduced plasma membrane sodium pump activity
    • Intracellular sodium accumulation
    • Potassium diffusion out of the cell
    • Isosmotic water gain, resulting in acute cellular swelling
  • Accumulation of metabolites: inorganic phosphates, lactic acid, purine nucleotides
  • Increased anaerobic glycolysis due to decreased ATP and AMP, leading to glycogen depletion, lactic acid and inorganic phosphate accumulation, and reduced intracellular pH
  • Detachment of ribosomes from the endoplasmic reticulum, reducing protein synthesis
  • If hypoxia continues, the cytoskeleton disappears, resulting in loss of ultrastructural features (microvilli) and cell surface blebs
• Irreversible Injury:
  • Severe vacuolization of mitochondria and calcium particle accumulation
  • Extensive plasma membrane damage
  • Swelling of lysosomes
  • Calcium-mediated injury upon reperfusion of oxygen
  • Continued loss of proteins, coenzymes, and RNA from hyperpermeable membranes
  • Leakage of lysosomal enzymes into the cytoplasm, degrading cytoplasmic components
  • Dead cells may be replaced by whorled masses of phospholipids (myelin figures)

Mechanisms Of Irreversible Injury

• Progressive loss of membrane phospholipids
• Cytoskeletal abnormalities: Protease activation and increased calcium can detach the cell membrane
• Toxic oxygen radicals: Generated after reperfusion of the ischemic area, released by neutrophils
• Lipid breakdown products: Have detergent effects

Cellular Accumulations

• Cells may accumulate abnormal substances transiently or permanently, harmful or injurious, located in the cytoplasm or nucleus
• Substances may be synthesized by the cell or produced elsewhere
• Accumulations categorized into three types:
  • Normal endogenous substance produced at normal or increased rate, with inadequate metabolism (e.g., fatty change of the liver)
  • Normal or abnormal endogenous substance that can't be metabolized due to genetic enzymatic defect (storage diseases)
  • Deposition in dead or dying tissues (dystrophic calcification)

Dystrophic Calcification

• Deposition occurs despite normal serum calcium levels and absence of calcium metabolic derangement
• Encountered in areas of necrosis, seen in atheromas of advanced atherosclerosis, intimal injuries of large arteries, aging, aortic valves
• Appears as intracellular or extracellular basophilic deposits; sometimes heterotopic bone may be formed

Metastatic Calcification

• Occurs in normal tissues when hypercalcemia exists
• Causes of hypercalcemia include:
  • Primary endocrine dysfunction (hyperparathyroidism)
  • Tumors associated with increased bone catabolism (multiple myeloma, metastatic cancer, leukemia)
  • Ingested exogenous substances causing vitamin D intoxication or milk alkali syndrome
  • Sarcoidosis
  • Advanced renal failure (secondary hyperparathyroidism due to phosphate retention)
• Metastatic calcification may occur widely in tissues, primarily in the interstitial tissues, kidneys, lungs, and gastric mucosa
• Usually does not significantly impair organ function, but extensive nephrocalcinosis can cause impairment

Cellular Adaptations Of Growth And Differentiation

• Physiologic adaptations are responses to normal stimulation by hormones or endogenous chemicals (e.g., breast growth and lactation)
• Pathologic adaptations often share the same underlying mechanisms, allowing cells to modulate their environment and avoid injury

Atrophy

• Shrinkage in cell size due to loss of cell substance; may involve the entire organ
• Atrophied cells have diminished function but are not dead
• Apoptotic death can be induced by the same signals causing atrophy
• Causes:
  • Decreased workload
  • Loss of innervation
  • Diminished blood supply
  • Inadequate nutrition
  • Loss of endocrine stimulation
  • Aging
• Cells become smaller, reaching an equilibrium with reduced blood supply, nutrition, or trophic stimulation
• Biochemically: Decreased synthesis, increased catabolism, or both

Hypertrophy

• Increase in cell size due to increased synthesis of structural proteins and organelles, resulting in an enlarged organ
• Examples:
  • Increased muscle mass due to exercise (physiological hypertrophy)
  • Enlargement of the heart in hypertension (pathological hypertrophy)

This quiz explores the concepts of cell injury, including the mechanisms behind necrosis and apoptosis. Additionally, it covers various causes of cell injury such as hypoxia, physical agents, chemicals, and immunologic reactions. Test your understanding of cellular responses to harmful conditions.