LTB4-BLT1 Interactions in the Pathogenesis of Allergic Airway Disease

哮喘的病理生理学机制是复杂的，有几条通路能够调节呼吸道。 高反应性(AHR)、呼吸道炎症和杯状细胞化生。此外，该项目的贡献者 疾病的起始/敏感化阶段可能与导致 挑战/维护/进展阶段。由于在研究和剖析这些方面存在困难 哮喘患者的时相及其潜在的病理生理学，动物模型在这方面已被证明是非常有价值的。 敬重。尽管有一些局限性，但小鼠模型已经为病理生理学提供了重要的见解。 (人类)哮喘，特别是当不同的过敏原暴露方法被用于识别 特定的肥大细胞-LGE依赖和肥大细胞非依赖的通路，引起相似的表型。这个 该项目的中心假设是，一个新的和独特的CD8+T细胞亚群在 与IL-13有关的呼吸道功能改变、肺部炎症和杯状细胞化生的发展 这些反应的关键调解人。我们假设CD8+T细胞的这一亚群是必不可少的，因为它们 产生IL-13的能力。它们在肺中招募(和激活)的关键特征是它们表达 BLT1，白三烯B4(LTB4)的高亲和力受体。假定LTB4从激活状态释放 过敏原暴露的过敏性宿主中的肥大细胞和巨噬细胞。基于广泛的初步数据，我们 将这种独特的CD8+BLT1+IL-13+T细胞亚群置于肺部过敏反应的核心。 使用分子、细胞和生物工具的组合，我们将定义分布和调节 BLT1在变态反应性肺组织免疫/炎症细胞上的表达及LTB4结扎对其影响 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 在过敏原暴露的小鼠中，对炎症以及确定LTB4的来源进行了研究。在最后一个具体目标中， 我们将把过敏小鼠的这些发现转化为哮喘患者的临床研究，确定这一点的作用 CD8+BLT1+IL-13+T细胞的独特致病亚群，我们在BAL和肺组织中证明了这一点， 确定激素抵抗型哮喘患者中它们的数量是否增加，以及 抑制LTB4的产生导致呼吸道中这些细胞的数量减少，并改善肺功能 在这一亚群哮喘患者中。这一项目将对发病机制和异质性提供新的见解。 并提供了与该计划赠款中的另外两个项目的关键联系。

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.