EICOSANOIDS IN THE REGULATION OF ALLERGIC AND INFLAMMATORY RESPONSES

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The overall goal of this proposal is to delineate potential mechanisms involved in the regulation of cell activation and eicosanoid mediator release. A major focus will be to define the regulatory role of prostanoids in syndromes of asthma and anaphylaxis precipitated by cyclooxygenase inhibition. Aspirin-evoked systemic mastocyte activation produces a syndrome of flushing, occasionally hypotension, and other consequences of the systemic release of mast cell mediators, whereas aspirin-evoked asthma is often associated with severe bronchospasm and rhinitis. In patients with aspirin-evoked systemic mastocyte activation, the initial observations suggest the hypothesis that prostaglandin E receptor agonists exert a potent restraining effect on the cellular events that lead to mast cell mediator release. The proposed investigations will further evaluate this hypothesis and its therapeutic implications. The studies on aspirin-evoked asthma will characterize the mediators released into both the upper and lower airways following cyclooxygenase inhibition. The biochemical and histologic responses of the airway to cyclooxygenase inhibition will be evaluated in terms of defining cell-cell interactions that could participate in this reaction. Cultures of dispersed nasal polyps from patients with aspirin-induced asthma/rhinitis will be developed to determine if aspirin-induced inflammatory cell activation can be mimicked ex vivo. The hypothesis that a cyclooxygenase product, specifically PGE2, restrains activation and mediator release from target cells in patients with aspirin-induced asthma will be tested both at a cellular and clinical level. The efficacy of treatment with misoprostol, a metabolically stable analog of PGE1, in these patients will be evaluated in a controlled study. This integrated assessment of the biochemical, histological functional and pharmacologic responses during aspirin challenges in vivo and ex vivo should provide new insights into the pathophysiology of these syndromes. The mechanism by which prostaglandin E2 inhibits mast cell activation will be pursued at the intracellular level by examining its effects on mastocyte signalling mechanisms. Finally, we will pursue our investigations of the regulation of prostanoid product formation from human alveolar macrophages by exploring whether these cells have a novel cyclooxygenase activity that is suppressible by glucocorticoids.