REGULATION AND MEDIATION OF THE IMMUNE RESPONSE BY EICOSANOIDS

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The specific aims for this Project are focused on a single overarching hypothesis that PGE2 inhibits infiltration of the airway with the inflammatory cells which cause bronchoconstriction in atopic asthmatics. The hypothesis is based on evidence that inhaled PGE2 completely prevents acute and late allergic bronchoconstriction. The experiments in this Project I have been planned in concert with those of Breyer's Project where the role of EP2 receptors in airway constriction and inflammation also will be examined. The overall hypothesis will be addressed by three specific aims. The hypothesis that inhaled PGE2 inhibits the mast cell activation associated with acute allergic bronchoconstriction will be tested in patients with asthma, examining mast cell degranulation, lipid mediator release and cytokine formation. In purified human lung mast cells, the effects of PGE2 on activation-induced cytokine formation will be examined further and the EP receptor subtype responsible for inhibiting activation will be characterized. The second specific aim examines the hypothesis that PGE2 inhibits late allergic bronchoconstriction by inhibiting the cytokine signaling system that leads to eosinophil infiltration in the airway, and that the predominant effect of PGE2 on this signaling system is through cells other than the mast cell. The effect of PGE2 on the IL-5 signaling cascade and inflammation associated with late allergic bronchoconstriction will specifically be examined. To provide evidence the inhibition of the late phase by PGE2 is not mediated by its effect on the mast cell, studies with a beta-adrenergic agonist, which also blocks mast cell activation through a G coupled receptor in vitro will be employed as an investigational tool. It is hypothesized that the beta-agonist will inhibit mast cell activation but will not prevent athe late phase airway infiltration and bronchoconstriction. The EP receptor subtypes on the cells of the asthmatic airway will be characterized to further elucidate the cellular mechanism for inhibition of late bronchoconstriction by PGE2. In addition to the mast cell, EP receptor subtypes will be examined on the alveolar macrophage, dendritic cells and T-lymphocytes. Because athe antigen presenting dendritic cell activates T-lymphocytes to produce Il-4 and Il-5, the effects of PGE2 on this function of the dendritic cell will be investigated. As a late allergic bronchoconstriction is considered to be a model for the airway dysfunction in chronic asthma, the effect of continuing administration of PGE2 on the airway inflammatory infiltrate and hyperreactivity in patients with asthma will be examined.