Dual role of the bradykinin B2 receptor during inflammation

缓激肽 B2 受体在炎症过程中的双重作用

• 批准号: 8391112
• 负责人: Bruce L. Zuraw
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8391112
• 关键词: Acute; Address; Adoptive Transfer; Adverse effects; Affect; Agonist; Allergens; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antigens; Antiinflammatory Effect; Asthma; Bradykinin; Bradykinin B1 Receptor; Bradykinin B2 Receptor; Breathing; Clinical; Complement 5a; Dendritic Cells; Development; Disease; Environmental Exposure; Epithelial Cells; Exhibits; Exposure to; General Population; Generations; Goals; Human; Immune; Immune response; Immune system; Immunologics; Inflammation; Inflammatory; Injury; Kallidin; Kinins; Knock-out; Knockout Mice; Learning; Lung; Lymphocyte; Mediating; Mediator of activation protein; Modeling; Mus; Normal tissue morphology; Patients; Pattern; Pharmaceutical Preparations; Phase; Phenotype; Population; Population Study; Receptor Inhibition; Receptor Signaling; Research; Role; Route; Sentinel; Signal Transduction; Staging; Stimulus; System; T cell response; T-Lymphocyte; Testing; Therapeutic; Time; Veterans; Virus; Wild Type Mouse; Work; abstracting; airway hyperresponsiveness; airway inflammation; airway remodeling; allergic airway inflammation; clinically relevant; migration; novel; public health relevance; receptor

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.

描述（由申请人提供）： 6。项目摘要/抽象环境暴露于病毒，有害刺激和过敏原导致气道中快速产生的基因蛋白。然后，动力素在过敏性气道炎症的启动和传播中介导了重要的功能。虽然动力蛋白受体拮抗剂在实验动物和人哮喘受试者中都表现出有效的抗哮喘作用，但缺乏心动激肽B2受体（B2R）的小鼠在Arnegregic Airway炎症的OVA模型中均表现出增强的支气管性高反应，炎症，炎症和气道重塑。因此，B2R似乎能够介导对过敏气道炎症的促炎和抗炎作用。该项目的总体假设是，B2R以时间空间方式介导了不同的相反作用。具体而言，在免疫诱导阶段，B2R通过对淋巴细胞和/或树突状细胞的作用介导了对无害抗原的耐受性，但随后通过在炎症的炎症阶段中介导了促炎的作用，通过在炎症的效应阶段中通过呼吸道上皮细胞的作用进行介导。该应用程序将解决以下关键问题：1）B2R敲除小鼠中增强过敏性气道炎症的基础的机制是什么？ 2）是否有可能以时间空间方式将B2R抑制的促和抗炎作用分开； 3）从回答上述问题中获得的信息是否可以允许以优化其治疗益处的方式使用B2R代理药物？提出了两个目标。 AIM 1将分析在B2R敲除小鼠中观察到的增强的Th2极化的潜在机制，并评估其对过敏气道炎症的影响。首先，将阐明敲除和正常小鼠中的抗原特异性T细胞反应。接下来，将在野生型和基因敲除小鼠中分析特定的树突状细胞亚群的分化和迁移。第三，将评估B2R敲除对吸入耐受性发展的影响。最后，将进行野生型小鼠的树突状细胞转移到B2R敲除小鼠中，以表明这是否可以纠正异常的T细胞极化。然后，AIM 2将分析缓激肽信号传导的时间空间模式的变化如何影响该模型中最终气道过敏性炎症表型。首先，B1R在介导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，将探讨影响激发素系统的药物制剂的时间和给药途径的影响，以更好地了解鼠敲除模型中发现的临床相关性。