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、有害刺激和过敏原导致气道中激肽的快速产生。激肽介导过敏性气道炎症的发生和传播的重要功能。虽然激肽受体拮抗剂在实验动物和人类哮喘受试者中均表现出有效的抗哮喘作用，但缺乏缓激肽B2受体（B2 R）的小鼠在过敏性气道炎症的OVA模型中表现出增强的支气管高反应性、炎症和气道重塑。因此，B2 R似乎能够介导对过敏性气道炎症的促炎和抗炎作用。该项目的总体假设是B2 R以时空方式介导不同的和相反的作用;具体地说，B2 R通过对淋巴细胞和/或树突状细胞的作用在免疫诱导阶段介导对无害抗原的耐受，但随后通过对气道上皮细胞的作用在炎症的效应阶段介导促炎作用。本申请将解决以下关键问题：1）B2 R敲除小鼠中增强的过敏性气道炎症的机制是什么？2)是否有可能以时空方式分离B2 R抑制的促炎和抗炎作用; 3）从回答上述问题中获得的信息是否允许以优化其治疗益处的方式使用B2 R作用药物？提出了两个目标。目的1将分析在B2 R基因敲除小鼠中观察到的Th 2极化增强的潜在机制，并评估其对过敏性气道炎症的影响。首先，将阐明基因敲除小鼠和正常小鼠中的抗原特异性T细胞应答。接下来，将在野生型和基因敲除小鼠中分析特定树突状细胞亚群向肺的分化和迁移。第三，将评估B2 R敲除对吸入耐受性发展的影响。最后，将树突状细胞从野生型小鼠过继转移到B2 R敲除小鼠中，以显示这是否可以纠正异常T细胞极化。目的2将分析缓激肽信号传导的时空模式的改变如何影响该模型中最终的气道过敏性炎症表型。首先，将解构B1 R在介导表型中的作用。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，将探讨影响缓激肽系统的药物给药时间和途径的变化的影响，以更好地理解小鼠基因敲除模型中结果的临床相关性。 公共卫生相关性： 7.本项目的总体目标是确定缓激肽B2受体在过敏性气道炎症中介导促炎或抗炎后果的机制。通过阐明这些机制，我们期望更多地了解气道先天免疫系统如何与适应性免疫系统相互作用，并利用这一机制， 信息，以帮助最大限度地发挥新的缓激肽B2受体作用的药物，接近临床部署的临床效益。哮喘是退伍军人和普通人群中的常见疾病，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.