ROLE OF SELECTINS IN LEUKOCYTE RECRUITMENT TO INFLAMED AIRWAYS IN ASTHMA

哮喘的一个特征是大气道炎。 嗜酸性粒细胞受到了特别的关注，因为它 哮喘患者发炎呼吸道的流行率，因为其产品 与支气管收缩、支气管高反应性和 呼吸道上皮损伤。 白细胞招募是一个多步骤的过程，被认为涉及到 选择素、激活信号和白细胞的顺序作用 整合素。选择素启动和维持白细胞在 内皮细胞。选择素的反向受体是碳水化合物- 将配体建立在相对的细胞上。特定的可溶性或内皮细胞- 相关信号导致白细胞整合素的激活，导致 白细胞被牢牢控制住。白血球渗入血管 组织部位是最后一步。就哮喘而言，信息是 在选择素的参与和性质方面明显缺乏 白血球激活信号。以下具体目标将 关注选择素在哮喘病理生理学中的作用 强调嗜酸性粒细胞招募： 1)使用急性哮喘的小鼠模型，我们将确定 单独使用抗三种选择素抗体的动物的治疗 两者结合在一起，将限制白细胞的募集和发育 支气管高反应性的症状。 2)我们将通过以下方法鉴定细胞因子诱导的L-选择素的内皮配体 以重组L-选择素分子为亲和探针。这些 配体可能与体内小静脉内皮细胞上的配体相关， 支持L-选择素依赖的白细胞滚动。 3)使用激活依赖的单抗和功能黏附试验，我们将 确定已知的哪种化学引诱剂和引发因素 嗜酸性粒细胞迅速增加其β1亲和力和 β2整合素。我们还将确定L-选择素作为信号的作用 整合素亲和力调节中的转导分子 嗜酸性粒细胞。 这些研究有望增加我们对白细胞的了解 哮喘的招募机制并可能导致新的治疗方法 治疗这种疾病的方法。

A characteristic feature of asthma is inflammation of large airways. Particular attention has been given to the eosinophil, because of its prevalence in inflamed airways of asthmatics and because its products are associated with bronchoconstriction, bronchial hyperresponsiveness, and respiratory epithelial damage. Leukocyte recruitment is multistep process thought to involve the sequential action of selectins, activating signals, and leukocyte integrins. The selectins initiate and sustain the rolling of leukocytes on the endothelium. The counter-receptors for the selectins are carbohydrate- based ligands on the opposed cells. Specific soluble or endothelial- associated signals cause activation of leukocyte integrins, leading to firm arrest of the leukocyte. Extravasation of the leukocyte into the tissue site is the final step. In the case of asthma, information is significantly lacking with respect to selectin involvement and the nature of the leukocyte activation signals. The following specific aims will focus on the role of selectins in the pathophysiology of asthma with emphasis on eosinophil recruitment: 1) Using a mouse model of acute asthma, we will determine whether treatment of animals with antibodies to the three selectins, used singly and in combination, will limit leukocyte recruitment and the development of bronchial hyperreactivity. 2) We will identify cytokine-induced endothelial ligands for L-selectin by using a recombinant L-selectin molecule as an affinity probe. These ligands may have relevance to the ligands on venular endothelium in vivo, which support L-selectin dependent rolling of leukocytes. 3) Using activation-dependent mAbs and functional adhesion assays, we will determine which of the known chemoattractants and priming factors for eosinophils produce a rapid increase in the avidity of their Beta1 and Beta2 integrins. We will also determine the role of L-selectin as a signal transduction molecule in the regulation of integrin avidity on the eosinophil. These studies are anticipated to increase our knowledge of leukocyte recruitment mechanisms in asthma and potentially lead to new therapeutic approaches for the treatment of this disease.