Role of the Leukotriene B4 Receptors in Asthma

描述（由申请人提供）：哮喘现在被认为是一种 呼吸道的炎症性疾病。嗜酸性粒细胞、中性粒细胞、巨噬细胞和 淋巴细胞也被募集到气道中。花生四烯酸 衍生物白三烯B4（LTB 4）及其受体是重要的介导剂， 白细胞趋化性LTB 4信号转导与肺结核的发病机制有关， 哮喘和这种疾病的小鼠模型。然而， LTB 4受体，BLTR 1和BLTR 2，在哮喘的病理生物学是不完全的 知道的我们的实验室最近培育了一种小鼠品系， 编码BLTR 1的基因缺失（BLTR 1-/-）。初步实验 在哮喘的鼠模型中使用该小鼠品系显示出 嗜酸性粒细胞聚集到气道中。我们的假设是LTB 4是一种 哮喘模型中白细胞重要化学引诱物及其 作用主要通过BLTR 1受体介导。我们亦建议 LTB 4信号传导在气道重塑的发展中是重要的。 具体地，我们寻求确定以下内容：1）如果BLTR 1信号传导是 对嗜酸性粒细胞、中性粒细胞和巨噬细胞的募集很重要， 2）如果BLTR 1影响T细胞的募集和分布， 3）如果BLTR 1信号传导 在气道高反应性和粘液产生中是重要的; 4）如果BLTR 1 在慢性哮喘模型中信号传导影响气道重塑; 5）如果新的 所描述的受体BLTR 2在该鼠模型中具有任何功能作用， 哮喘使用BLTR 1-/-小鼠的哮喘模型，我们希望精确地定义 BLTR 1在哮喘发病机制中的作用。在存在以下物质的情况下重复实验 BLTR 2拮抗剂也将允许表征这种作用， 哮喘中的受体

DESCRIPTION (provided by the applicant): Asthma is now recognized as an inflammatory disease of the airways. Eosinophils, neutrophils, macrophages and lymphocytes, are also recruited into the airways. The arachidonic acid derivative leukotriene B4 (LTB4) and its receptors are important mediators of leukocyte chemotaxis. LTB4 signaling has been implicated in the pathogenesis of asthma and in a murine model of this disorder. However, the precise role of the LTB4 receptors, BLTR1 and BLTR2, in the pathobiology of asthma is incompletely known. Our laboratory has recently generated a mouse strain with a targeted deletion in the gene that codes for BLTR1 (BLTR1-/-). Preliminary experiments using this mouse strain in a murine model of asthma have shown a reduction in eosinophils recruited into the airways. Our hypothesis is that LTB4 is an important chemoattractant for leukocytes in this model of asthma and that its actions are mediated primarily through the BLTR1 receptor. We also propose that LTB4 signaling is important in the development of airway remodeling. Specifically we seek to determine the following: 1) if BLTR1 signaling is important for the recruitment of eosinophils, neutrophils, and macrophages in this model of asthma; 2) if BLTR1 effects the recruitment and profile of T lymphocytes in the airways and lymph nodes in this model; 3) if BLTR1 signaling is important in airways hyperreactivity and mucous production; 4) if BLTR1 signaling effects airway remodeling in a chronic asthma model; 5) if the newly described receptor BLTR2 has any functional role in this murine model of asthma. Using a model of asthma in BLTR1-/- mice we hope to precisely define the role of BLTR1 in asthma pathogenesis. Repeat experiments in the presence of a BLTR2 antagonist will also allow characterization of the role of this receptor in asthma.