ROLE OF SELECTINS IN LEUKOCYTE RECRUITMENT TO INFLAMED AIRWAYS IN ASTHMA

哮喘的一个典型特征是大气道的炎症。 特别注意的是嗜酸性粒细胞，因为它 在哮喘患者的发炎气道中的患病率，并且因为其产品 与支气管收缩、支气管高反应性和 呼吸道上皮损伤 白细胞募集是一个多步骤的过程， 选择素、激活信号和白细胞的顺序作用 整合素选择素启动并维持白细胞在 内皮细胞选择素的反受体是碳水化合物- 基于对立细胞上的配体。 特异性可溶性或内皮- 相关信号引起白细胞整联蛋白的活化，导致 对白细胞的有效抑制。白细胞外渗到 组织部位是最后一步在哮喘的情况下， 在选择参与和性质方面明显缺乏 白细胞激活信号的一部分以下具体目标将 关注选择素在哮喘病理生理学中的作用， 强调嗜酸性粒细胞募集： 1)使用急性哮喘小鼠模型，我们将确定是否 用三种选择素的抗体治疗动物，单独使用 结合起来，将限制白细胞的募集和 支气管高反应性 2)我们将通过以下方法鉴定精氨酸诱导的L-选择素内皮配体： 使用重组L-选择素分子作为亲和探针。这些 配体可能与体内小静脉内皮上的配体相关， 其支持白细胞的L-选择素依赖性滚动。 3)使用激活依赖性单克隆抗体和功能性粘附试验，我们将 确定哪些已知的化学引诱剂和引发因子 嗜酸性粒细胞产生其β 1的亲合力的快速增加， β 2整合素。我们还将确定L-选择素作为信号的作用， 转导分子在调节整合素亲合力中的作用 嗜酸性粒细胞 这些研究有望增加我们对白细胞的认识 招募机制，并可能导致新的治疗 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.