Dual role of the bradykinin B2 receptor during inflammation

描述(由申请人提供)： 6.项目摘要/摘要环境暴露于病毒、有害刺激物和过敏原会导致呼吸道中激动素的迅速产生。激肽随后在过敏性呼吸道炎症的启动和传播中起重要作用。虽然激肽受体拮抗剂在实验动物和人类哮喘受试者中都显示了强大的抗哮喘作用，但在过敏性气道炎的OVA模型中，缺乏缓激肽B2受体(B2R)的小鼠表现出增强的支气管高反应性、炎症和气道重塑。因此，B2R似乎能够在过敏性呼吸道炎症中同时介导促炎和抗炎效应。该项目的总体假设是，B2R在时间和空间上调节不同的和相反的效应；具体地说，在免疫诱导阶段，B2R通过作用于淋巴细胞和/或树突状细胞来介导对无害抗原的耐受，但在炎症的效应阶段，B2R通过作用于呼吸道上皮细胞来介导促炎效应。这项应用将解决以下关键问题：1)B2R基因敲除小鼠过敏性呼吸道炎症增强的机制(S)是什么？2)是否有可能以时空方式分离B2R抑制的促炎和抗炎作用；以及3)从回答上述问题中获得的信息是否允许以优化其治疗效果的方式使用B2R作用药物？提出了两个目标。目的1分析在B2R基因敲除小鼠中观察到的Th2极化增强的潜在机制(S)，并评估其对过敏性呼吸道炎症的影响。首先，将阐明基因敲除小鼠和正常小鼠的抗原特异性T细胞反应。接下来，将分析野生型和基因敲除小鼠中特定树突状细胞亚群的分化和向肺的迁移。第三，将评估B2R基因敲除对吸入性耐受性发展的影响。最后，将野生型小鼠的树突状细胞过继转移到B2R基因敲除小鼠中，以表明这是否可以纠正异常的T细胞极化。目的2随后将分析缓激肽信号时空模式的改变如何影响该模型中最终的呼吸道过敏性炎症表型。首先，B1R在调节表型中的作用将被解构。接下来，将测试野生型极化T细胞消除或逆转表型的能力。最后，将探讨不同的给药时间和给药途径对缓激肽系统的影响，以更好地理解在小鼠基因敲除模型中发现的临床相关性。 公共卫生相关性： 7.项目简介本项目的总体目标是确定在过敏性呼吸道炎症过程中，缓激肽B2受体能够调节促炎或抗炎后果的机制。通过阐明这些机制，我们期望了解更多关于呼吸道天然免疫系统如何与适应性免疫系统相互作用的知识，并利用这一点 信息，以帮助最大限度地发挥新型缓激肽B2受体作用药物的临床效益，这些药物已接近临床部署。哮喘是退伍军人和普通人群中的一种常见疾病，这些研究应该有助于开发更有效的哮喘治疗方法。

DESCRIPTION (provided by applicant): 6. Project Summary/Abstract Environmental exposure to viruses, noxious stimuli and allergens leads to the rapid generation of kinins in the airway. Kinins then mediate important functions in the initiation and propagation of allergic airway inflammation. While kinin receptor antagonists have demonstrated potent anti-asthma actions in both experimental animals and human asthmatic subjects, mice lacking the bradykinin B2 receptor (B2R) exhibit enhanced bronchial hyperresponsiveness, inflammation, and airway remodeling in the OVA model of allergic airway inflammation. Thus, the B2R appears to be capable of mediating both pro-inflammatory and anti-inflammatory effects on allergic airway inflammation. The overall hypothesis of this project is that the B2R mediates distinct and opposing effects in a temporal-spatial manner; specifically that B2R mediates tolerance to innocuous antigens during the immunologic induction phase through actions on lymphocytes and/or dendritic cells, but then mediates pro-inflammatory effects during the effector phase of inflammation through actions on airway epithelial cells. This application will address the following key questions: 1) What is/are the mechanism(s) that underlie the enhanced allergic airway inflammation in B2R knockout mice? 2) Is it possible to separate the pro- and anti-inflammatory effects of B2R inhibition in a temporal-spatial manner; and 3) Could the information gained from answering the above questions allow B2R acting drugs to be used in a manner that would optimize their therapeutic benefit? Two aims are proposed. Aim 1 will analyze the underlying mechanism(s) of the enhanced Th2 polarization observed in the B2R knockout mice, and assess the impact of this on allergic airway inflammation. First, the antigen specific T cell responses in knockout and normal mice will be elucidated. Next, the differentiation and migration of specific dendritic cell subpopulations to the lung will be analyzed in wild-type and knockout mice. Third, the impact of B2R knockout on the development of inhalational tolerance will be assessed. Finally, adoptive transfer of dendritic cells from wild-type mice into B2R knockout mice will be performed to show whether this can correct the abnormal T cell polarization. Aim 2 will then analyze how alterations in the temporal-spatial pattern of bradykinin signaling influences the ultimate airway allergic inflammation phenotype in this model. First, the role of the B1R in mediating the phenotype will be deconstructed. Next, the ability of wild-type polarized T cells to abrogate or reverse the phenotype will be tested. Finally, the impact of varying both the timing and route of administration of pharmacologic agents affecting the bradykinin system will be explored to better understand the clinical relevance of the findings in the murine knockout model. PUBLIC HEALTH RELEVANCE: 7. Project Narrative The overall goal of this project is to identify the mechanisms responsible for the ability of bradykinin B2 receptors to mediate either pro-inflammatory or anti-inflammatory consequences during allergic airway inflammation. By elucidating these mechanisms we anticipate learning more about how the airway innate immune system interacts with the adaptive immune system and using this information to help maximize the clinical benefit of novel bradykinin B2 receptor acting drugs that are nearing clinical deployment. Asthma is a common disease both in the Veterans population as well as in the general population, and these studies should help develop more effective asthma treatments.