EICOSANOIDS IN THE REGULATION OF ALLERGIC AND INFLAMMATORY RESPONSES

本提案的总体目标是界定潜在的机制 参与调节细胞活化和类花生酸介质 release. 一个主要的重点将是界定以下机构的监管作用： 前列腺素类在哮喘和过敏反应综合征中的作用 环氧合酶抑制 阿司匹林诱发的系统性肥大细胞激活 产生潮红综合征，偶尔低血压，以及其他 肥大细胞介质的全身释放的后果，而 阿司匹林诱发的哮喘通常伴有严重的支气管痉挛， 鼻炎 在阿司匹林诱发的系统性肥大细胞活化的患者中， 最初的观察表明，前列腺素E 受体激动剂对细胞内的 导致肥大细胞介质释放的事件。 拟议 研究将进一步评估这一假设及其治疗 影响 阿司匹林诱发哮喘的研究将表征 介质释放到上下气道， 环氧合酶抑制 的生化和组织学反应， 将根据以下方面评价气道对环氧合酶抑制 定义了可能参与这个反应的细胞间相互作用。 阿司匹林致鼻息肉患者鼻息肉组织培养 将开发哮喘/鼻炎，以确定阿司匹林诱导的 可以离体模拟炎性细胞活化。 的假设 环氧合酶产物，特别是PGE 2， 和介质释放从靶细胞中的患者阿司匹林诱导 哮喘将在细胞和临床水平上进行测试。 的 米索前列醇代谢稳定类似物治疗的疗效 将在对照研究中评价这些患者中的PGE 1。 这 综合评估的生化，组织学功能和 体内和离体阿司匹林激发期间的药理学反应 应该提供这些综合征的病理生理学的新见解。 前列腺素E2抑制肥大细胞活化的机制 将在细胞内水平上进行研究， 肥大细胞信号机制。 最后，我们将继续努力， 前列腺素类产物形成的调节的研究 人类肺泡巨噬细胞通过探索这些细胞是否有一个新的 糖皮质激素可抑制的环氧合酶活性。

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.