Cell Injury and Death Mechanisms

Cell Injury

• Cells strive to maintain a stable internal environment.
• When cells encounter stress, they adapt to preserve survival.
• If adaption fails, cell injury results.

Cell Death Mechanisms

• Necrosis: Occurs due to harmful conditions, characterized by:
  • Cell swelling
  • Protein denaturation
  • Organelle breakdown
• Apoptosis: Programmed cell death, happens normally for cell turnover or during physiological processes.

Causes of Cell Injury

• Hypoxia: Insufficient oxygen, impacting aerobic respiration.
  • Differs from ischemia, which also causes hypoxic injury but involves reduced blood flow.
• Physical Agents: Trauma, extreme temperatures, radiation, electric shock, pressure changes
• Chemicals & Drugs: Can disrupt cell membranes, osmotic balance, enzymes, etc.
• Microbiologic Agents: Viruses, bacteria, parasites.
• Immunologic Reactions: Immune responses can cause cell damage (e.g. anaphylaxis).
• Genetic Defects: Lead to abnormal cellular processes (e.g. Down's syndrome, sickle cell).
• Nutritional Imbalances: Protein-calorie deficiency, vitamin deficiencies, diets high in animal fats contribute to diseases like atherosclerosis.
• Aging: Natural decline in cellular function over time.

Mechanisms of Cell Injury

• Cell response to damage depends on the type, duration, and severity of injury.
• The cell type, health, and adaptability also influence the outcome.
• Four key cellular systems vulnerable to injury:
  • Cell membrane integrity: Maintains ion and osmotic balance.
  • Aerobic respiration: Essential for energy production.
  • Protein synthesis: Creates essential proteins.
  • Genetic apparatus: Contains and protects DNA.

Calcium's Role in Cell Injury

• Cytosolic calcium is kept low by ATP-dependent pumps.
• Increased extracellular calcium or release from mitochondria activates enzymes like:
  • Phospholipases: Degrade cell membranes.
  • Proteases: Catabolize structural proteins.
  • ATPases: Deplete ATP levels.
  • Endonucleases: Fragment DNA.

Oxygen Free Radicals

• Important mediators of cell death.
• Generated during:
  • Ischemia
  • Reperfusion
  • Chemical injury
  • Radiation exposure
  • Normal metabolism

Ischemic and Hypoxic Injury

• Reversible Injury:

  • First effect: Hypoxia reduces ATP production, leading to:
    • Calcium influx into the cell.
    • Impaired sodium pump function.
    • Sodium accumulation, potassium loss, and water influx, causing cell swelling.
    • Accumulation of other metabolites like inorganic phosphates, lactate, and purines.
  • Further consequences:
    • Increased anaerobic glycolysis depletes glycogen, acidifies the cell, and leads to eosinophilia (pink staining) in cell cytoplasm.
    • Ribosomes detach from ER, inhibiting protein synthesis.
    • Cytoskeleton disappears, affecting cell shape and function.

• Irreversible Injury:

  • Hallmarks:
    • Severe mitochondrial vacuolization and calcium accumulation.
    • Plasma membrane damage.
    • Lysosome swelling.
  • Effects of reperfusion:
    • Additional calcium-mediated injury.
    • Loss of cellular components due to membrane permeability.
    • Lysosomal enzymes degrade cell components.
  • Final outcome:
    • Myelin figure formations (whorled masses of phospholipids).

Mechanisms of Irreversible Injury

• Progressive loss of membrane phospholipids.
• Cytoskeletal abnormalities: Proteases and calcium can disrupt the cytoskeleton, leading to cell membrane detachment.
• Toxic oxygen radicals: Released during reperfusion by neutrophils, damage cell structures.
• Lipid breakdown products: Have detergent-like effects on membranes.

Free Radical Mediation of Cell Injury

• Implicated in:
  • Chemical injury
  • Radiation injury
  • Oxygen toxicity
  • Cellular aging
  • Microbial killing
  • Inflammatory damage
  • Tumor killing

Free Radical Generation Within Cells

• Absorption of Radiant Energy: Hydrolyzes water to form hydroxyl (OH-) and hydrogen (H.) radicals.
• Reduction-Oxidation Reactions:
  • Normal metabolism produces small amounts of reactive oxygen species (ROS):
    • Superoxide radicals (O2.-)
    • Hydrogen peroxide (H2O2)
    • Hydroxyl radicals (OH.-)
  • Some enzymes, like xanthine oxidase, produce superoxide radicals.
  • Metals like copper and iron participate in redox reactions that generate free radicals.
• Enzymatic Catabolism of Oxygenous Chemicals:
  • Example: Carbon tetrachloride (CCl4) is converted to a toxic free radical (CCl3.) in the liver, causing membrane lipid peroxidation.

Free Radical Effects On Cells

• Lipid Peroxidation: Damages cell and organelle membranes.
• DNA Damage: Oxidizes thymines in DNA.
• Protein Cross-Linking: Alters protein structure and function.

Chemical Injury

• Direct Interaction: Chemical binds to a critical cellular component (e.g. mercury binds to sulfhydryl groups, inhibiting ATP-dependent transport).
• Conversion to Toxic Metabolites: Chemical is transformed into a reactive compound by enzymes like P-450 oxidases in the smooth endoplasmic reticulum (SER).
  • Example: CCl4 is converted to CCl3. in the liver, causing lipid peroxidation and damage to the SER.

Patterns of Acute Cell Injury

• Reversible Cell Injury:

  • Light microscopy:
    • Cell swelling (hydropic changes).
    • Cytoplasmic eosinophilia due to acidic pH.
    • Fatty change (accumulation of lipids, often in liver and heart)
  • Electron microscopy:
    • Plasma membrane blebbing, microvilli distortion, loosening of intercellular junctions.
    • Mitochondrial swelling and dense inclusions.
    • ER dilatation, ribosome detachment, and polysome dissociation.
    • Nuclear alterations, like disaggregation of granular elements.

• Necrosis: Irreversible cell death that occurs in living tissue.

  • Morphological features are caused by:
    • Enzymatic digestion of cell components.
    • Protein denaturation.
  • Cytoplasmic changes:
    • Eosinophilia due to loss of glycogen, vacuolation, and calcification.
  • Nuclear changes:
    • Karyolysis: DNA digestion, leading to fading of the nucleus.
    • Pyknosis: Nuclear shrinkage and increased basophilia (dark staining).
    • Karyorrhexis: Fragmentation of the pyknotic nucleus.

Types of Necrosis

• Coagulative Necrosis: Cells maintain structural outline, seen in hypoxic death in most tissues (except brain).
  • Enzymes are denatured, preventing rapid hydrolysis.
  • Affected tissue appears pale and firm.
  • Example: Myocardial infarction.
• Liquefactive Necrosis: Caused by bacterial or fungal infections, or hypoxic death in the central nervous system.
  • Hydrolytic enzymes break down cells, creating a liquid, viscous mass.
  • Affected tissue appears soft and liquefied.
• Gangrenous Necrosis: Not a distinct type of necrosis, but a clinical term:
  • Ischemic coagulative necrosis with superimposed liquefactive necrosis due to infection.
  • "Wet gangrene" refers to infection in ischemic tissue.
• Caseous Necrosis: Characteristic of tuberculosis infection.
  • Cheese-like, white appearance of the necrotic area.
  • Cells are completely destroyed, leaving a granular debris.

Abnormal Cellular Accumulations

• Fatty Change (Steatosis): Abnormal triglyceride buildup within parenchymal cells.
  • Most common in liver (reversible).
  • Also occurs in heart, muscle, kidney, and other organs.
  • Caused by toxins, diabetes, protein malnutrition, obesity, and anoxia.
  • Occurs when there are defects in fatty acid entry, synthesis of lipoproteins, or lipid export.
  • Grossly, the liver enlarges and becomes yellow.
• Cholesterol and Cholesterol Esters:
  • Macrophages ingest lipid debris, forming "foamy cells".
  • In atherosclerosis, smooth muscle cells and macrophages are filled with cholesterol esters.
  • Xanthomas: Fat-filled subcutaneous macrophages, appearing as white nodules.
• Proteins:
  • Less common than lipids, may accumulate in kidneys in certain diseases.
• Glycogen:
  • Accumulates in disorders of glucose or glycogen metabolism appearing as vacuoles.
• Pigments: Colored substances.
  • Melanin: Dark pigment produced by melanocytes, responsible for skin and hair color.
  • Hemosiderin: Golden-brown pigment derived from hemoglobin, accumulates with excess iron.

Pathologic Calcification:

• Abnormal calcium salt deposition with other minerals.

This quiz covers key concepts related to cell injury, including the mechanisms of necrosis and apoptosis. Additionally, it explores various causes of cell injury such as hypoxia, physical agents, and microbiological influences. Understand the physiological challenges cells face and the processes leading to their demise.