40. LIPID DERIVED AUTACOIDS AND PLATELET ACTIVATING FACTOR

Introduction

Lipid-derived autacoids are chemical mediators formed from membrane phospholipids. They include prostaglandins, thromboxanes, leukotrienes and platelet activating factor (PAF). These substances are produced on demand and play major roles in inflammation, allergy, smooth muscle activity, platelet function and cardiovascular responses.

Eicosanoids

Eicosanoids are derived from arachidonic acid, a 20-carbon polyunsaturated fatty acid stored in cell membrane phospholipids. They are not stored in advance; instead, they are synthesized when cells are stimulated by injury, immune reactions, trauma or chemical signals.

Release of Arachidonic Acid

The key enzyme releasing arachidonic acid is phospholipase A2 (PLA2). It is activated by phosphorylation and rises in response to inflammatory mediators such as thrombin, complement C5a, bradykinin and antigen–antibody reactions.

Metabolic Pathways

  • Cyclooxygenase (COX-1 and COX-2) pathway: Produces prostaglandins and thromboxanes.
  • Lipoxygenase pathway: Produces leukotrienes, lipoxins and related compounds.

Prostanoids

Prostanoids include prostaglandins (PGs) and thromboxanes (TXs). They are produced from arachidonic acid through COX enzymes.

COX Isoenzymes

  • COX-1: Constitutive; responsible for physiological, protective prostaglandins.
  • COX-2: Induced during inflammation; produces inflammatory prostanoids.

Major Prostanoids and Their Actions

  • PGE2: Vasodilation, fever, pain sensitization, gastric protection.
  • PGI2 (prostacyclin): Vasodilation, inhibits platelet aggregation, increases renal blood flow.
  • PGD2: Vasodilation, inhibits platelet aggregation and relaxes GI and uterine muscles.
  • PGF2α: Uterine contraction, luteolysis.
  • TXA2: Vasoconstriction, bronchoconstriction and strong platelet aggregation.

Role in Inflammation

  • Increase blood flow (vasodilation)
  • Potentiate vascular permeability caused by histamine and bradykinin
  • Sensitize nerve endings → pain
  • PGE2 in hypothalamus → fever

Therapeutic Uses of Prostanoids

  • PGE2 / PGF2α: Induction of labour, cervical ripening
  • PGI2 analogues: Pulmonary hypertension
  • PGE1: Erectile dysfunction, maintaining ductus arteriosus in infants

Leukotrienes

Leukotrienes (LTs) are produced by the 5-lipoxygenase pathway, mainly in inflammatory cells like mast cells, eosinophils, basophils and macrophages.

Major Leukotrienes

  • LTB4: Potent chemotactic agent for neutrophils and macrophages.
  • LTC4, LTD4, LTE4: Cysteinyl leukotrienes that cause bronchoconstriction, mucus secretion and increased vascular permeability.

Actions

  • Respiratory system: Strong, long-lasting bronchoconstriction (more powerful than histamine); key mediators in asthma.
  • Cardiovascular system: Cause fall in blood pressure and constrict small arteries.
  • Inflammatory response: Recruit neutrophils, enhance cytokine release, and promote oxidative burst.

Receptors

  • BLT receptors (for LTB4): Mediate chemotaxis and inflammatory cell activation.
  • CysLT receptors (for LTC4, LTD4, LTE4): Mainly in bronchial and intestinal smooth muscle; responsible for bronchoconstriction.

Platelet Activating Factor (PAF)

PAF is a potent phospholipid mediator produced by platelets, neutrophils, monocytes, macrophages and endothelial cells. It is active even in very small concentrations.

Synthesis

PAF is synthesized from membrane phospholipids through the lyso-PAF pathway. PLA2 forms lyso-PAF, which is then acetylated into active PAF.

Major Actions of PAF

  • Platelets: Aggregation, degranulation and thromboxane release.
  • Blood vessels: Vasodilation, increased permeability → edema.
  • Lungs: Bronchoconstriction (important in asthma).
  • Leukocytes: Chemotaxis, increased adhesion, inflammatory mediator release.

Role in Inflammation

  • Enhances arachidonic acid metabolism
  • Triggers oxidative burst in neutrophils
  • Increases vascular permeability → swelling and redness
  • Contributes to anaphylaxis

Clinical Significance

Conditions Involving Eicosanoids and PAF

  • Asthma and allergic reactions
  • Rheumatoid arthritis
  • Inflammatory bowel disease
  • Cardiovascular diseases
  • Anaphylaxis and severe inflammation

Therapeutic Targets

  • COX inhibitors (NSAIDs): Block prostaglandin synthesis.
  • Leukotriene inhibitors: Zileuton (5-LOX inhibitor), Montelukast and Zafirlukast (CysLT receptor blockers).
  • PAF antagonists: Still under research; limited clinical use.

Detailed Notes:

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