What are eicosanoids?

What Are Eicosanoids?

Eicosanoids are a family of biologically active lipid signaling molecules derived from 20-carbon polyunsaturated fatty acids—primarily arachidonic acid—that regulate inflammation, vascular function, immunity, and numerous physiological processes throughout the body. 1, 2

Biochemical Origin and Structure

• Eicosanoids are synthesized from arachidonic acid (a 20-carbon omega-6 polyunsaturated fatty acid) that is stored in cell membrane phospholipids and released upon cellular activation. 2, 3

• The term "eicosanoid" derives from the Greek word "eicosa" meaning twenty, reflecting the 20-carbon backbone of their precursor fatty acids. 3

• Arachidonic acid can also be obtained from dietary linoleic acid or directly from the diet, serving as the primary substrate for eicosanoid synthesis in most mammalian cells. 4

Major Classes and Enzymatic Pathways

Eicosanoids are produced through three distinct enzymatic pathways, each generating different classes of mediators:

Cyclooxygenase (COX) Pathway

• The COX pathway produces prostaglandins (PGE₂, PGD₂, PGF₂α), prostacyclin (PGI₂), and thromboxane A₂ (TXA₂) through two isoforms: COX-1 (constitutively expressed) and COX-2 (induced by inflammation). 5, 1

• Prostaglandins mediate pain, fever, inflammation, gastric mucosal protection, renal perfusion, and platelet function. 5

• Thromboxane A₂ acts as a potent platelet activator and vasoconstrictor, while prostacyclin (PGI₂) produces opposing effects—vasodilation and platelet inhibition. 5

Lipoxygenase (LOX) Pathway

• The LOX pathway generates leukotrienes (including LTB₄ and cysteinyl leukotrienes LTC₄, LTD₄, LTE₄) and hydroxyeicosatetraenoic acids (HETEs). 1, 3

• Leukotrienes are powerful mediators of bronchoconstriction, vascular permeability, and leukocyte chemotaxis, playing central roles in asthma and allergic responses. 4, 3

• Cysteinyl leukotrienes are increased in induced sputum and exhaled breath condensate of patients with exercise-induced bronchoconstriction, correlating with severity. 4

Cytochrome P450 Pathway

• This pathway produces epoxyeicosatrienoic acids (EETs) and additional HETEs with roles in vascular tone regulation and renal function. 2

Specialized Pro-Resolving Mediators (SPMs)

• SPMs represent a distinct subfamily of eicosanoids derived from omega-3 polyunsaturated fatty acids (EPA and DHA) that actively promote resolution of inflammation without suppressing host defenses. 4, 1

• SPM families include lipoxins (from arachidonic acid), resolvins, protectins, and maresins (from EPA and DHA), each with distinct anti-inflammatory and tissue-repair functions. 4

• Unlike traditional anti-inflammatory drugs, SPMs actively disrupt inflammatory pathways and shift immune responses toward resolution and homeostasis while preserving antimicrobial defenses. 4

Receptor-Mediated Signaling

• Eicosanoids exert their biological effects by binding to specific G-protein-coupled receptors (GPCRs) on target cells, triggering diverse intracellular signaling cascades. 1, 2

• Examples include EP receptors (EP1-EP4) for PGE₂, DP receptors for PGD₂, BLT receptors for LTB₄, and CysLT receptors for cysteinyl leukotrienes. 1

• Some eicosanoid receptors display remarkably high binding affinity, such as GPR32 binding resolvin D1 with picomolar potency (EC₅₀ = 4 pM). 1

Physiological and Pathological Roles

Normal Physiological Functions

• Eicosanoids regulate vascular homeostasis, gastric mucosal protection, platelet aggregation, renal blood flow, uterine contractions during labor, and immune cell trafficking. 2, 6

• PGF₂α serves as the universal final common pathway for parturition across all mammalian species, coordinating uterine contractions at term. 5

Pathological Involvement

• Dysregulated eicosanoid production contributes to chronic inflammatory diseases (rheumatoid arthritis, inflammatory bowel disease), asthma, cardiovascular disease, cancer progression, and autoimmune disorders. 2, 6

• In exercise-induced bronchoconstriction, mast cells and eosinophils release pro-inflammatory eicosanoids (cysteinyl leukotrienes, PGD₂) while protective eicosanoids like PGE₂ and lipoxin A₄ are reduced. 4

• COX-2 expression in premalignant and malignant cells correlates with poor prognosis in non-small cell lung cancer. 1

Clinical Significance

• Nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin exert their therapeutic effects by inhibiting COX enzymes, thereby blocking prostaglandin and thromboxane synthesis. 5, 3

• Selective COX-2 inhibitors were developed to preserve anti-inflammatory efficacy while theoretically sparing COX-1-mediated gastric protection, though subsequent evidence showed both isoforms must be inhibited to produce gastric ulceration. 5

• Omega-3 fatty acid supplementation (EPA and DHA) can reduce inflammation in cancer patients by decreasing inflammatory markers and shifting eicosanoid production toward less inflammatory mediators. 4

• The omega-6 to omega-3 fatty acid ratio in the diet profoundly influences eicosanoid profiles: high omega-6 intake promotes pro-inflammatory eicosanoid production, while omega-3 supplementation generates anti-inflammatory and pro-resolving mediators. 4