EICOSANOIDS IN THE REGULATION OF ALLERGIC AND INFLAMMATORY RESPONSES

该提案的总体目标是勾勒出潜在的机制。 参与细胞活化的调节和二十烷类介体 放手。一个主要的焦点将是定义监管的角色 前列腺素类药物在哮喘和过敏性疾病中的作用 环氧合酶抑制。阿司匹林诱导的全身肥大细胞激活 会导致面色发红，偶尔会出现低血压等症状 肥大细胞介质系统性释放的后果，而 阿司匹林诱发的哮喘通常与严重的支气管痉挛和 鼻炎。在阿司匹林诱导的系统性肥大细胞激活的患者中， 初步观察表明，前列腺素E 受体激动剂对细胞有很强的抑制作用 导致肥大细胞介体释放的事件。建议数 调查将进一步评估这一假说及其治疗方法。 这意味着什么。对阿司匹林诱发的哮喘的研究将表征 中介人随后被释放到上呼吸道和下呼吸道 环氧合酶抑制。血管内皮细胞的生化和组织学反应 对环氧合酶抑制的气道反应将根据以下方面进行评估 定义可能参与这一反应的细胞-细胞相互作用。 阿司匹林致分散鼻息肉患者鼻息肉的培养 哮喘/鼻炎将被用来确定阿司匹林引起的 炎性细胞的激活可以在体外模拟。假说 一种环氧合酶产物，特别是PGE2，抑制激活 阿司匹林诱导的患者靶细胞释放介质的研究 哮喘将在细胞和临床层面上进行测试。这个 米索前列醇的治疗效果，一种代谢稳定的类似物 在这些患者中，PGE1将在一项对照研究中进行评估。这 生化、组织学功能和组织化学的综合评价 阿司匹林在体内和体外激发时的药理学反应 应该为这些综合征的病理生理学提供新的见解。 前列腺素E_2抑制肥大细胞活化的机制 将在细胞内水平上通过研究其对 肥大细胞的信号机制。最后，我们将继续我们的 黄曲霉毒素对前列腺素产物形成调控的研究 通过探索人肺泡巨噬细胞是否具有新的 可被糖皮质激素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.