Eicosanoids are signaling molecules derived from arachidonic acid, a 20-carbon polyunsaturated fatty acid. They act locally in paracrine and autocrine signaling and are involved in inflammation, fever, pain, blood clotting, smooth muscle contraction, and immune regulation.
Arachidonic Acid Release
Arachidonic acid is esterified in membrane phospholipids and must be released to serve as a substrate for eicosanoid synthesis. Phospholipase A2 cleaves arachidonic acid from the sn-2 position of membrane glycerophospholipids, a process detailed in phospholipid and sphingolipid metabolism. This is the rate-limiting step in eicosanoid production and is activated by mechanical trauma, cytokines, growth factors, and other inflammatory stimuli. Glucocorticoids inhibit phospholipase A2, partly explaining their anti-inflammatory effects.
The Cyclooxygenase Pathway
Cyclooxygenase enzymes convert arachidonic acid into prostaglandin H2, the precursor for all prostaglandins and thromboxanes. There are two cyclooxygenase isoforms. COX-1 is constitutively expressed in most tissues and produces prostaglandins involved in gastric protection, platelet function, and renal homeostasis. COX-2 is induced by inflammatory stimuli and produces prostaglandins that mediate inflammation and pain.
Prostaglandin H2 is converted by specific synthases into a variety of bioactive eicosanoids. Prostaglandin E2 is a major mediator of inflammation, fever, and pain. Prostaglandin I2, also called prostacyclin, is a vasodilator and inhibits platelet aggregation. Thromboxane A2 is produced by platelets and promotes platelet aggregation and vasoconstriction. The balance between prostacyclin and thromboxane A2 is critical for vascular homeostasis.
The Lipoxygenase Pathway
Lipoxygenases incorporate molecular oxygen into arachidonic acid to produce hydroperoxyeicosatetraenoic acids. 5-Lipoxygenase generates leukotrienes, which are potent mediators of inflammation and allergic responses. Leukotriene B4 is a powerful chemoattractant for neutrophils. The cysteinyl leukotrienes, LTC4, LTD4, and LTE4, cause bronchoconstriction and are important in asthma. 12-Lipoxygenase and 15-lipoxygenase produce other classes of bioactive lipids with roles in inflammation resolution and platelet function.
Cytochrome P450 Pathway
Cytochrome P450 epoxygenases convert arachidonic acid to epoxyeicosatrienoic acids, which have vasodilatory and anti-inflammatory effects. P450 hydroxylases produce hydroxyeicosatetraenoic acids involved in vascular tone and inflammation.
Lipoxins and Specialized Pro-Resolving Mediators
Lipoxins, resolvins, and protectins are eicosanoids that actively promote the resolution of inflammation. They are synthesized during the later stages of inflammation from arachidonic acid and omega-3 fatty acids. These specialized pro-resolving mediators inhibit neutrophil recruitment, stimulate macrophage clearance of apoptotic cells, and reduce pain. They represent a shift in understanding inflammation from a passive process to an actively regulated one.
Pharmacology of Eicosanoids
The eicosanoid pathway is a major target for pharmaceutical drugs. Nonsteroidal anti-inflammatory drugs such as aspirin, ibuprofen, and naproxen inhibit cyclooxygenases, reducing prostaglandin synthesis. Aspirin irreversibly acetylates both COX-1 and COX-2, while ibuprofen is a reversible inhibitor. Selective COX-2 inhibitors such as celecoxib were developed to spare gastric prostaglandin production but were found to increase cardiovascular risk. Corticosteroids inhibit phospholipase A2 and reduce the release of arachidonic acid. Leukotriene receptor antagonists such as montelukast are used in asthma management.
