The organization and consequences of eicosanoid signaling

Organization of leukotriene and prostaglandin synthesisAs described in the introduction to this Perspective series (1), signaling by arachidonic acid represents a paradigm for the use of oxygen in the transmission of information.At the same time, arachidonic acid signaling can also contribute to the propagation of cellular damage.This duality is typified by a signaling cascade that (a) prevents the activation of 5-lipoxygenase (5-LO) in resting cells and (b) results in the formation and release of leukotrienes (LTs), which requires the sequential activation and interaction of at least eight different proteins.In fact, all lipoxygenases require membrane translocation to exert activity.In the case of the formation of COX products, particularly prostaglandin E 2 (PGE 2 ) and PGD 2 , humans have evolved two sets of biosynthetic enzymes that differ not only in their cell-and tissue-specific localization, but also in their subcellular localization and requirement for reduced glutathione, a cellular defense against oxidative damage.This review will focus on three aspects of arachidonic acid biology.First, the compartmentalization and organization of eicosanoid synthesis, specifically LTs and PGs, will be discussed.This will illustrate the elaborate mechanisms that keep unwanted lipoxygenation at arm's length and also show that the enzymes such as glutathione-Stransferases, epoxide hydrolases, and carrier proteins that are commonly thought of as biosynthetic also belong to families that are generally considered to play a role in detoxification.Second, the potential cellular oxidative damage that is produced as a by-product of the use of oxygen and lipid substrates is examined.Finally, mechanisms that are used to amplify signaling diversity from a core of LTs and PGs are discussed. The role of leukotrienes C 4 and D 4 in diseaseLTs are the products of the 5-LO pathway of arachidonic acid metabolism (Figure 1).The initial interest in LTs followed largely from their association with the pathogenesis of asthma (2).LTC 4 , identified as the parent molecule of the sulfidopeptide LTs, is generated from eosinophils and mast cells in large amounts, and also from monocytes and macrophages (2-7).However, it is not formed by polymorphonuclear leukocytes (2-5).When released from cells, LTC 4 is converted to LTD 4 (2-7), and both exert their biological effects via G protein-coupled receptors (8, 9).LTD 4 and LTC 4 cause the constriction of smooth muscle, and the clinical correlate is bronchial smooth muscle constriction in asthma (2,10,11).The role of LTD 4 as a major contributor to asthmatic bronchospasm has been firmly established, and aerosolized LTD 4 and LTC 4 cause bronchospasm when taken by inhaler (10,11).The metabolic product of LTD 4 , 5(S)-hydroxy,6(R)-cysteinyl-7,9,11-trans,14-cis-eicosatetraenoic acid, (LTE 4 ), has been found at high levels in the serum and urine of patients with asthma and allergic rhinitis (12).When cold-induced bronchoconstriction, allergen-induced asthma, and exercise-induced asthma were analyzed, antagonists of the 5-LO pathway were able to alleviate bronchospasm (13-17).Pretreatment with the LTD 4 receptor antagonist MK-0476 has been shown to block the bronchoconstrictive response to all forms of challenge and alleviate ongoing brochoconstriction ( 16).The use of LTD 4 receptor and 5-LO antagonists has also blocked the severity and occurrence of asthmatic attacks in clinical trials, and these agents are particularly effective in chronic mild asthma, for which they are recommended for clinical use (18)(19)(20)(21)(22)(23).LTs are also considered to be central to the pathogenesis of allergic rhinitis, in which cells expressing the cysteinyl LT1 receptor are highly expressed in CD45 + nasal leukocytes, and recent studies have shown that cysteinyl LTs regulate the trafficking of T cells in vivo (24, 25).Subsequently, LTD 4 receptor antagonists have proved to constitute an effective therapeutic modality for this disorder.Knockout animals that lack LTC 4 synthase have markedly attenuated vascular responses that are dependent on IgE-mediated LTC 4 release (26).As described above, LTD 4 and LTC 4 have been shown to function via both high-and low-affinity G protein-coupled receptors (8,9,27,28), and these receptors are present on human eosinophils and monocytes,