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 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 on treatment with corticosteroids. Moreover, PGE2 has been shown to have not only immunomodulatory actions, but bronchodilatory effects as well. 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 tranduction 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. The overall aim of this proposal is to evaluate the contribution of PGE2, through each of these the receptors, to the pathogenesis of allergic airway disease and to determine the potential of both PGE2 and the four EP receptors as therapeutic targets for the treatment of asthma.
