The eicosanoids, so called because of their derivation from a 20-carbon unsaturated fatty acid, arachidonic acid (eicosatetraenoic acid), are obtained from membrane phospholipids and synthesized de novo at the time of cellular stimulation. Arachidonic acid is cleaved from membrane-bound phosphatidylcholine by the enzyme phospholipase A2. Alternatively, arachidonic acid may be derived by the sequential actions of phospholi-pase C and diacylglyceryl lipase. Arachidonic acid can then follow either of two enzymatic pathways that result in the production of inflammatory mediators. The pathway initiated by cyclooxygenase (COX) produces prostaglandins; the lipoxygenase pathway generates leukotrienes (Fig. 36.2).
The COX enzyme exists in at least two isoforms. COX-1 is a constitutive or "housekeeping" isoform that is responsible for the basal production of prosta-glandins, prostacyclins, and thromboxanes. COX-2 is inducible by cytokines and other inflammatory stimuli and is believed to predominate during chronic inflammation. The final product of the COX pathway is tissue specific. For example, platelets produce thromboxane A2 (TxA2); vascular endothelial cells produce prostacyclin (PGI2); mast cells produce prostaglandin D2 (PGD2);
and the vasculature, gastrointestinal (GI) tract, lung, and other tissues produce prostaglandin E2 (PGE2).
The biological effects of the more important eicosanoids are listed in Table 36.1. The production of inflammatory eicosanoids is an important target of many anti-inflammatory drugs. In addition, the side effects of these drugs frequently result from their inhibition of eicosanoid production.
A number of eicosanoids are used as therapeutic agents. In infants with congenital heart anomalies, a patent ductus arteriosus can be temporarily maintained by the PGE1 analogue alprostadil (Prostin VR Pediatric) until surgical correction can be performed. In patients undergoing treatment with nonsteroidal anti-inflammatory drugs, the PGE1 analogue misoprostol (Cytotec) is often used to decrease gastric acid secretion, thereby inhibiting the ulceration caused by these agents. Misoprostol is also used in several non-FDA-approved applications, including the induction of labor by enhancing cervical ripening, and the induction of abortion in combination with mifepristone (RU-486). These uses of misoprostol are associated with an increased risk of uterine rupture or perforation. Dinoprostone (Prostin E2), a synthetic PGE2, causes uterine contraction and is used clinically to induce abortion during the second trimester and to empty the
Glucocorticoids —C^^*" Annexins (Lipocortins)
Cell Membrane Phospholipid
Phospholipase A 2
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