Eicosanoid receptors as therapeutic targets for asthma.

Abstract

Eicosanoids comprise a group of oxidation products of arachidonic and 5,8,11,14,17-eicosapentaenoic acids formed by oxygenases and downstream enzymes. The two major pathways for eicosanoid formation are initiated by the actions of 5-lipoxygenase (5-LO), leading to leukotrienes (LTs) and 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE), and cyclooxygenase (COX), leading to prostaglandins (PGs) and thromboxane (TX). A third group (specialized pro-resolving mediators; SPMs), including lipoxin A4 (LXA4) and resolvins (Rvs), are formed by the combined actions of different oxygenases. The actions of the above eicosanoids are mediated by approximately 20 G protein-coupled receptors, resulting in a variety of both detrimental and beneficial effects on airway smooth muscle and inflammatory cells that are strongly implicated in asthma pathophysiology. Drugs targeting proinflammatory eicosanoid receptors, including CysLT1, the receptor for LTD4 (montelukast) and TP, the receptor for TXA2 (seratrodast) are currently in use, whereas antagonists of a number of other receptors, including DP2 (PGD2), BLT1 (LTB4), and OXE (5-oxo-ETE) are under investigation. Agonists targeting anti-inflammatory/pro-resolving eicosanoid receptors such as EP2/4 (PGE2), IP (PGI2), ALX/FPR2 (LXA4), and Chemerin1 (RvE1/2) are also being examined. This review summarizes the contributions of eicosanoid receptors to the pathophysiology of asthma and the potential therapeutic benefits of drugs that target these receptors. Because of the multifactorial nature of asthma and the diverse pathways affected by eicosanoid receptors, it will be important to identify subgroups of asthmatics that are likely to respond to any given therapy.