REGULATION AND MEDIATION OF THE IMMUNE RESPONSE BY EICOSANOIDS

该项目的具体目标集中在一个单一的总体目标上 假设前列腺素E_2抑制呼吸道的渗透 引起特应性哮喘患者支气管收缩的炎性细胞。 这一假说是基于吸入前列腺素E_2完全阻止 急性和晚期过敏性支气管收缩。这里面的实验 项目I与布雷耶项目的计划是一致的，其中 EP2受体在呼吸道收缩和炎症中的作用也将 接受检查。总体假设将通过三个具体的 目标。吸入前列腺素E_2抑制肥大细胞活化的假说 与急性过敏性支气管收缩相关的将在 哮喘患者，检查肥大细胞脱颗粒、脂质介质 释放和细胞因子的形成。在纯化的人肺肥大细胞中， PGE2对激活诱导的细胞因子形成的影响将被检测 进一步和负责抑制激活的EP受体亚型 将被描述为。第二个具体目标是检验假设 前列腺素E_2抑制晚期变态反应性支气管收缩 细胞因子信号转导系统导致嗜酸性粒细胞在 PGE2对该信号系统的主要作用是 通过除肥大单元之外的单元。前列腺素E_2对白介素5的影响 与晚期过敏相关的信号级联和炎症 将对支气管收缩进行专门检查。为了提供证据， PGE2对晚期细胞的抑制不是通过其对细胞周期的影响来实现的 肥大细胞，研究一种β-肾上腺素能激动剂，它也能阻断肥大 在体外通过G偶联受体激活细胞将被用作 一种调查工具。据推测，β-激动剂将 抑制肥大细胞激活，但不能阻止晚期呼吸道 浸润性和支气管收缩。脑脊液中EP受体亚型 哮喘呼吸道细胞的特征将进一步阐明 前列腺素E_2抑制晚期支气管收缩的细胞机制。 除肥大细胞外，EP受体亚型还将在 肺泡巨噬细胞、树突状细胞和T淋巴细胞。因为阿瑟 抗原提呈树突状细胞激活T淋巴细胞产生IL-4 和IL-5，PGE2对树突状细胞这一功能的影响将 被调查。作为一种晚期过敏性支气管收缩，被认为 作为慢性哮喘气道功能障碍的模型，其作用 持续应用前列腺素E_2对气道炎性浸润性病变的影响 哮喘患者的高反应性将被检查。

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.