ROLE OF SELECTINS IN LEUKOCYTE RECRUITMENT TO INFLAMED AIRWAYS IN ASTHMA

选择素在哮喘炎症气道白细胞募集中的作用

• 批准号: 6355581
• 负责人: STEVEN D ROSEN
• 金额: $ 13.95万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6355581
• 关键词: asthma; cell migration; chemoattractants; eosinophil; human subject; immunologic assay /test; inflammation; integrins; laboratory mouse; leukocyte activation /transformation; receptor binding; respiratory hypersensitivity; selectins

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.

哮喘的一个特征是大气道炎症。 嗜酸性粒细胞受到特别关注，因为它 哮喘患者气道发炎的患病率，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。 白细胞募集是一个多步骤过程，被认为涉及 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的滚动 内皮细胞。选择素的反受体是碳水化合物- 基于相对细胞的配体。 特定可溶性或内皮- 相关信号引起白细胞整合素的激活，从而导致 白细胞的牢固停滞。白细胞外渗到 组织部位是最后一步。就哮喘而言，信息是 在选择参与和性质方面严重缺乏 白细胞激活信号。将实现以下具体目标 重点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单独使用来治疗动物 结合起来，将限制白细胞的招募和发育 支气管高反应性。 2) 我们将通过以下方式鉴定细胞因子诱导的 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， 它支持白细胞的 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测定，我们将 确定哪些已知的化学引诱剂和启动因子 嗜酸性粒细胞的 Beta1 亲和力迅速增加， Beta2 整合素。我们还将确定 L-选择素作为信号的作用 转导分子对整合素亲和力的调节 嗜酸性粒细胞。 这些研究预计将增加我们对白细胞的了解 哮喘的募集机制并可能导致新的治疗方法 治疗这种疾病的方法。