Arachidonic Acid Metabolism

Arachidonic Acid Metabolites

• Arachidonic acid is a fatty acid present in the cell membrane
• Metabolized by two pathways: Cyclooxygenase (COX) and Lipoxygenase
• COX pathway produces:
  • Prostaglandins (promote bronchoconstriction and vasodilation)
  • Thromboxane (promotes platelet aggregation)
  • Aspirin/NSAIDs block COX pathway
• Lipoxygenase pathway produces:
  • Leukotrienes (promote bronchoconstriction and increase capillary permeability)

Chemical Mediators of Inflammation

• Interleukins (IL) and Tumor Necrosis Factor (TNF):
  • Proteins produced by lymphocytes and macrophages
  • Many kinds, some pro-inflammatory (IL-1β, IL-6), some anti-inflammatory (IL-4, IL-10)
  • Many overlapping functions, including:
    • Recruitment and activation of leukocytes
    • Induction of acute-phase responses
• Interferons:
  • Produced by virus-infected cells and lymphocytes
  • Enhance defense against viruses by inhibiting DNA/RNA synthesis
  • Some activate macrophages to destroy viruses
• Nitric oxide:
  • Produced by endothelial cells
  • Promotes smooth muscle relaxation and vasodilation

Types of Inflammation

• Acute inflammation:
  • Early, short-term, and self-limiting
  • Occurs before adaptive immunity can exert its effect
  • Designed to remove injurious agent and limit extent of damage
  • Neutrophils predominate in first 24 hours
• Chronic inflammation:
  • Late, long-term, and self-perpetuating
  • Usually the result of recurrent inflammation/irritation or slow processes that fail to induce an acute response
  • Macrophages and lymphocytes are more common

Acute Inflammation: Vascular Response

• Following tissue injury:
  • Clear pathogens and debris from injured tissue/wounds
  • Coordinate vascular and cellular aspects of inflammation
  • Tightly regulated with lots of checks and balances

Chemical Mediators of Inflammation

• Histamine:
  • First inflammatory mediator released
  • Produced by mast cells
  • Responsible for:
    • Vasodilation
    • Increased vascular permeability
    • Bronchoconstriction
  • Temporary, with leukotrienes taking over once synthesized
• Bradykinin:
  • Initiated by activation of Hageman factor (factor XII)
  • Responsible for:
    • Vasodilation
    • Increased vascular permeability
    • Bronchoconstriction
    • Pain
• Clotting factors:
  • Produced by liver
  • Induce the clotting cascade
  • Lead to production of fibrin clot
• Complement proteins:
  • Plasma proteins
  • Present in inactive form
  • As part of inflammation:
    • Increase vascular permeability
    • Promote chemotaxis
  • As part of immune system:
    • Act as opsonins and facilitate phagocytosis
    • Create holes in cell membrane of pathogens (membrane attack complex - MAC)

Innate Immunity: The Gastrointestinal Tract

• Gastrointestinal tract:
  • Most pathogens are transported via food contaminated with fecal material
  • Gastric acid destroys pathogens in stomach
  • Viscous mucous layer coats gut and entraps microbes
  • Pancreatic enzymes and bile detergents destroy organisms
  • IgA secreted by mucous membranes in gut
  • Normal bacterial flora compete with pathogens for nutrients

Inflammation

• SECOND LINE OF DEFENSE
• Programmed response to tissue injury
• Integrated system of humoral and cellular responses designed to:
  • Limit tissue damage
  • Destroy pathogens
  • Initiate adaptive immune system
  • Begin healing
• Rapid response in vascularized tissue (begins in seconds)

Cells of Inflammation

• Endothelial cells:
  • Layer of cells lining blood vessels
  • Release nitric oxide (NO) to promote vasodilation
  • Release inflammatory mediators (interleukins, prostaglandins, etc.) to regulate cellular changes during inflammation
  • Control movement of cells through endothelial layer
  • Release tissue factor in response to injury (activates extrinsic pathway of clotting cascade)
• Mast cells:
  • Cells that lie in connective tissue near blood vessels
  • When activated, mast cells:
    • Degranulate (release inflammatory mediators stored in cellular granules)
    • Immediate response, primarily histamine