LTB4-BLT1 Interactions in the Pathogenesis of Allergic Airway Disease

哮喘的病理生理是复杂的，有几种途径能够介导气道

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.