LTB4-BLT1 Interactions in the Pathogenesis of Allergic Airway Disease

哮喘的病理生理学是复杂的，有几种途径能够介导气道 高反应性（AHR）、气道炎症和杯状细胞化生。此外， 疾病的起始/致敏阶段可能与引起疾病的因素有很大不同。 激发/维持/进展阶段。由于研究和剖析这些困难， 在哮喘的发病阶段及其潜在的病理生理学方面，动物模型已经证明在这方面是非常宝贵的。 请注意。尽管有一些局限性，小鼠模型提供了重要的见解的病理生理学 （人类）哮喘，特别是当不同的方法来过敏原暴露已被用来确定 特异性肥大细胞IgE依赖性和肥大细胞非依赖性途径，其引起相似的表型。的 该项目的中心假设是，一种新的和独特的CD8 + T细胞亚群在 气道功能改变、肺部炎症和杯状细胞化生的发展，IL-13 这些反应的关键媒介。我们认为，这一亚群的CD8 + T细胞是必不可少的，因为他们的免疫功能。 产生IL-13的能力。它们在肺中的募集（和激活）的关键特征是它们表达 BLT 1是白三烯B4（LTB 4）的高亲和力受体。LTB4被假定为从激活的 肥大细胞和巨噬细胞在过敏原暴露的过敏性宿主。根据大量的初步数据，我们 已经将这种独特的CD8 + BLT 1 + IL-13 + T细胞亚群置于肺中过敏反应的核心。 使用分子、细胞和生物学工具的组合，我们将定义 过敏性肺中免疫/炎症细胞上的BLT1表达，LTB4连接的结果， BLT1、BLT1对T细胞亚群的特异性作用及其在AHR和肺发育中的相互作用 炎症以及识别过敏原暴露小鼠中LTB4的来源。在最后一个具体目标中， 我们将把这些在过敏小鼠中的发现转化为哮喘的临床研究， 我们在BAL和肺组织中证实了CD8 + BLT 1 + IL-13 + T细胞的独特致病性亚群， 确定它们在皮质类固醇抵抗性哮喘患者中的数量是否增加， 抑制LTB4的产生导致气道中这些细胞的数量减少并改善肺功能 在这个哮喘患者的亚群中。该项目将提供新的见解的发病机制和异质性 并提供了一个关键的链接到其他两个项目在这个计划的赠款。

The pathophysiology of asthma is complex with several pathways capable of mediating airway hyperresponsiveness (AHR), airway inflammation, and goblet cell metaplasia. Moreover, the contributors to the initiation/sensitization phase of the disease may differ considerably from the factors responsible for the challenge/maintenance/progression phase. Because of the difficulties in studying and dissecting these phases and their underlying pathophysiology in asthmatics, animal models have proven invaluable in this regard. Despite some limitations, mouse models have provided important insights into the pathophysiology of (human) asthma, especially when different approaches to allergen exposure have been used to identify specific mast cell-lgE-dependent and mast cell-independent pathways which elicit similar phenotypes. The central hypothesis of this project is that a novel and unique subset of CD8+ T cells plays an important role in the development of altered airway function, lung inflammation, and goblet cell metaplasia, with IL-13 being the critical mediator of these responses. We posit that this subset of CD8+ T cells is essential due to their ability to produce IL-13. The key feature in their recruitment (andactivation) in the lung is their expression of BLT1, a high affinity receptor for leukotriene B4 (LTB4). LTB4 is postulated to be released from activated mast cells and macrophages in allergen-exposed allergic hosts. Based on extensive preliminary data, we have placed this unique subset of CD8+BLT1+IL-13+ T cells at the core of allergic responses in the lung. Using combinations of molecular, cellular, and biologic tools we will define the distribution and regulation of BLT1 expression on immune/inflammatory cells in the allergic lung, the consequences of LTB4 ligation of BLT1, the specific role of BLT1on T cell subsets, and their interactions in the development of AHR and lung inflammation as well as identifying the sources of LTB4 in allergen-exposed mice. In the last specific aim, we will translate these findings in allergic mice to clinical studies of asthmatics, defining the role of this unique, pathogenic subset of CD8+BLT1+IL-13+ T cells, which we demonstrated in BAL and lung tissue, determining whether they are increased in numbers in corticosteroid-resistant asthmatics and whether inhibition of LTB4 production leads to lower numbers of these cells in the airways and improved lung function in this subset of asthmatics. This project will provide novel insights into the pathogenesis and heterogeneity of asthma and provides a critical link to the two other projects in this program grant.