REGULATION AND MEDIATION OF THE IMMUNE RESPONSE BY EICOSANOIDS

该项目的具体目标集中在一个总体目标上， 假设PGE 2抑制气道的浸润， 炎性细胞引起特应性哮喘患者的支气管收缩。 这一假设是基于吸入PGE 2完全防止 急性和晚期过敏性支气管收缩。 这个实验 我的计划与布雷耶的计划是一致的， EP 2受体在气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PGE 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试验将在 哮喘患者，肥大细胞脱颗粒，脂质介质 释放和细胞因子形成。 在纯化的人肺肥大细胞中， 将检测PGE 2对激活诱导的细胞因子形成的影响 此外，负责抑制激活的EP受体亚型 将被定性。 第二个具体目标是检验假设 PGE 2通过抑制 细胞因子信号系统，导致嗜酸性粒细胞浸润， 气道，并且PGE 2对该信号系统的主要作用是 通过肥大细胞以外的细胞 前列腺素E_2对IL-5的影响 与迟发性变态反应相关的信号级联和炎症 将具体检查支气管收缩。 为了提供证据 PGE 2对晚期相的抑制不是通过其对 肥大细胞，β-肾上腺素能激动剂的研究，也可以阻断肥大细胞 通过G偶联受体的体外细胞活化将被用作 一种研究工具 据推测，β-激动剂将 抑制肥大细胞活化但不阻止晚期气道扩张 浸润和支气管收缩。 EP受体亚型在 哮喘气道的细胞将被表征以进一步阐明 PGE 2抑制晚期支气管收缩的细胞机制。 除了肥大细胞，EP受体亚型将在 肺泡巨噬细胞、树突状细胞和T淋巴细胞。 因为 抗原提呈树突状细胞激活T淋巴细胞产生IL-4 和IL-5，PGE 2对树突状细胞的这种功能的影响将 追究 作为一种晚期过敏性支气管收缩， 作为慢性哮喘气道功能障碍的模型， 持续给予PGE 2治疗气道炎症浸润， 将检查哮喘患者的高反应性。

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.