Lecture on Cellular Injury and Free Radicals

Overview of Cellular Injury

• Discussion is centered on cellular injury with particular focus on free radicals as a significant cause of injury.
  • Free radicals will be explored in detail as a separate subsection due to their importance.

Definition of Free Radicals

• Free Radical:
  • A chemical species characterized by an unpaired electron in its outer orbit.
  • The presence of this unpaired electron enables the free radical to induce cellular damage.
• Free radicals can occur both physiologically and pathologically.

Physiological Generation of Free Radicals

• Free radicals are generated through oxidative phosphorylation, a fundamental process in normal human physiology.
  • Oxidative Phosphorylation:
  • Involves the enzyme cytochrome c oxidase.
  • Electrons are transferred to oxygen, which acts as the final electron acceptor.
  • Resulting reactions produce a proton gradient used in ATP synthesis.
  • Oxygen typically accepts four electrons entirely leading to water formation:
  • If oxygen accepts:
    1. One electron → Superoxide (O2•−)
    2. Two electrons → Hydrogen peroxide (H2O2)
    3. Three electrons → Hydroxyl ion (•OH)
    4. Four electrons → Water (H2O)
  • Partial reduction of oxygen (accepting less than four electrons) generates free radicals physiologically.

Pathological Generation of Free Radicals

1. Ionizing Radiation:
   • Can produce free radicals, particularly hydroxyl ions (•OH).
   • Mechanism:
     • Ionizing radiation interacts with water molecules in tissues, leading to free radical formation.
   • Hydroxyl free radical is identified as the most damaging free radical.
2. Inflammation:
   • Neutrophils utilize oxygen-dependent mechanisms for microbial killing, generating free radicals.
   • NADPH Oxidase: An enzyme that converts oxygen to superoxide.
     • Superoxide rapidly converts to hydrogen peroxide via superoxide dismutase.
     • Hydrogen peroxide is then converted by myeloperoxidase, further producing reactive substances.
3. Interaction with Metals (Iron and Copper):
   • Free radicals can form through interactions with metals like copper and iron due to free metal ions.
   • Fenton Reaction:
     • Important reaction showing how free iron can generate free radicals.
     • Emphasizes importance of metal-binding proteins in preventing free radical formation.

Implications of Free Radical Damage

• Free radicals can:
  1. Peroxidize lipids, damaging cell membranes.
  2. Oxidize proteins, potentially leading to diseases.
  3. Damage DNA, elevating cancer risk.

Biological Defense Mechanisms Against Free Radicals

1. Metal Carrier Proteins:
   • Transferrin: In blood, binds iron for safe transport.
   • Ferritin: Binds iron within macrophages/liver, preventing free radical generation.
2. Enzymatic Elimination of Free Radicals:
   • Superoxide Dismutase: Converts superoxide to hydrogen peroxide.
   • Catalase: Converts hydrogen peroxide to water.
   • Glutathione Peroxidase: Utilizes glutathione to remove hydroxyl free radicals.

High-Yield Examples of Free Radical Injury

1. Carbon Tetrachloride Toxicity:
   • Historically linked to dry cleaning; leads to decreased protein synthesis.
   • Liver function deteriorates due to damage, primarily affecting apolipoprotein synthesis.
   • Resulting histological finding: Fatty Change in the Liver.
2. Reperfusion Injury:
   • Occurs when blood flow is restored to an organ post-ischemia.
   • Introduction of oxygen and inflammatory cells to dead tissue generates more free radicals.
   • Persistent elevation of cardiac enzymes post-reperfusion indicates ongoing myocardial damage due to free radical generation.