Arachidonic acid metabolism: role in inflammation.

Arachidonic acid is oxygenated and further transformed into a variety of products which mediate or modulate inflammatory reactions. The cyclo-oxygenase pathway, which is inhibited by nonsteroidal anti-inflammatory drugs, produces vasodilator prostaglandins such as PGE2 and prostacyclin (PGI2) and also thromboxane A4, a potent platelet aggregating agent. Recent work has demonstrated the importance of products formed via various lipoxygenase-catalyzed reactions. Leukotrienes are formed by initial oxygenation at C-5 followed by further transformation to an unstable epoxide intermediate, leukotriene A4 (LTA4). The intermediate can be converted into LTB4 by hydrolysis and into LTC4 by conjugation with glutathione. The formation of the leukotriene, LTA4, is catalyzed by a 5-lipoxygenase possessing both lipoxygenase and LTA4-synthase activities. Unlike other lipoxygenases, this enzyme requires multiple stimulatory factors for maximal activity. These include Ca2+, ATP, and three non-dialyzable cellular components. The cDNAs for human 5-lipoxygenase and LTA4-hydrolase have recently been cloned and the amino acid sequences for the enzymes have been deduced. LTC4 and its metabolites, LTD4 and LTE4, increase vascular permeability and contract airway smooth muscle. Leukotriene B4 causes adherence of neutrophils to endothelial cells and is a potent chemotactic agent. It also stimulates release of lysosomal enzymes and generation of superoxide anion in neutrophils. Oxygenation of arachidonic acid at C-12 and C-15 generates products (5S, 12S-DHETE and 14,15-DHETE) which can modulate various neutrophil functions. A new group of arachidonic acid-derived products was recently discovered. These compounds (lipoxins), formed by oxygenation at C-5 and C-15 and additional reactions, contain a conjugated tetraene structure and three alcohol groups.(ABSTRACT TRUNCATED AT 250 WORDS)