Eicosanoids, products of arachidonic acid (AA) metabolism, are potent modulators of the inflammatory response. A significant role for these lipid mediators in the pathogenesis of asthma has been demonstrated, and drugs targeting one branch of this pathway, the leukotriene pathway, have recently been developed and added to our therapeutic armamentarium against asthma. A number of studies have suggested that prostanoids, cyclooxygenase (COX) metabolites of AA, have a significant impact on inflammation in asthmatic patients. The most extensively studied of these is prostaglandin E2 (PGE2). A number of lines of evidence suggests that PGE2 plays a significant anti-inflammatory role in asthma, and might produce many of the same beneficial effects observed after treatment with corticosteroids. Moreover, PGE2 has been shown to have not only immunomodulatory actions, but also to oppose antigen induced bronchoconstriction. While all other prostanoids are thought to act through a single cell surface receptor specific for that prostanoid, four receptors for PGE2 have been identified and cloned, and have been termed EP1-EP4. Each receptor subtype binds PGE2 with equal affinity, but these receptors can trigger unique signal transduction pathways, which in turn can evoke opposing physiologic actions. Most cells express a unique combination of EP receptor subtypes, and the physiologic response of that cell to PGE2 is determined by the subset of receptors expressed. The therapeutic potential of PGE2 has not yet been exploited in part due to this complex physiology. We hypothesize that PGE2 plays a key role in shaping the pathogenesis of allergic airway disease and that its role in asthma is complex due to the diverse and sometimes opposing actions of the different EP receptor isoforms. As increased intracellular cAMP levels cause relaxation of smooth muscle cells and inhibition of inflammatory responses, we posit that stimulation of the Gs-coupled EP2 and EP4 receptors will attenuate disease. Conversely, stimulation of the PLC-coupled EP1 receptor might cause bronchoconstriction and our preliminary studies have identified potent pro-inflammatory actions of the EP3 receptor. Therefore, we suggest that stimulation of EP1 and EP3 receptors might promote allergic airway disease. By defining the precise role of each EP receptor along with maneuvers designed to enhance or reduce PGE2 production in the lung, we will determine the potential of PGE2 and its receptors as therapeutic targets in asthma.
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