AIRWAY BIOLOGY OF ASTHMA

本AAIDCRC应用程序的重点是炎症性 人类呼吸道高反应性的发病机制 哮喘。我们将特别强调它的发病机制。 细胞黏附和激活引起的气道高反应性 嗜酸性粒细胞。该计划由3个相关项目组成， 关注L的分泌性，2)神经体液和3)造血 嗜酸性粒细胞功能在呼吸道反应性中的作用。第四个 项目是示范和教育项目(D&E)，即 旨在安装和评估教育项目的效果 在芝加哥市中心的一家哮喘治疗中心。 项目1旨在评估特定的内皮细胞和 基质蛋白黏附反应对受刺激细胞上调的影响 免疫磁性分离的人血嗜酸性粒细胞的分泌物。 这些调查的第二个方面决定了 嗜酸性粒细胞分泌被配体/基质黏附所增强 在体外诱导人呼吸道的过度收缩。项目2 评估感觉神经c-纤维和 嗜酸性粒细胞，它放大细胞的募集和激活。这个 这些细胞与呼吸道高反应性的生理学相关性 在两种豚鼠模型中也评估了体外相互作用。 体内炎症。项目3详细研究了分子和 使用一种新开发的方法研究嗜酸性粒细胞生成的细胞方面 脐带血中嗜酸性粒细胞的体外培养 新生儿。因为嗜酸性粒细胞的生成是 这些炎性细胞移位到传导 航空公司，建议进行研究，以评估转基因的基本作用- 脑脊液、白介素3和白介素5在人骨肉瘤细胞体外分化中的作用 生物活性嗜酸性粒细胞。第二系列研究试图找出 细胞外基质因子与嗜酸性粒细胞的相互作用 影响细胞因子引导的嗜酸性粒细胞生成。项目4是一个D 和E项目，测试自我管理的假设 通过社区卫生工作者的指导 降低市中心儿童的发病率和死亡率 有限的卫生保健资源。这项计划是通过 儿科和拉拉比达儿童医院， 评估有针对性的共同管理方法的有效性 医生和社区卫生工作者在改善哮喘方面的作用 通过改变病人的行为来治疗。从基本数据派生的数据 这些调查的科学部分将提供 协调一致的方法来理解嗜酸性粒细胞在 关心呼吸道高反应性。D&E项目利用一个 经验丰富的临床教师将药理学概念应用于 对面临医疗保健减少的人群的哮喘治疗 资源。预计这些建议中提出的研究 项目将有助于从机械的角度理解 转化正常反应性组织的细胞机制 进入哮喘的呼吸道，并应用当前的治疗方法 有效地。

The focus of this AAIDCRC application is on the inflammatory pathogenesis of airway hyperresponsiveness that characterizes human asthma. Particular emphasis will be placed upon the pathogenesis of airway hyperreactivity caused by cellular adhesion and activation of eosinophils. The program consists of 3 related projects that focus upon the l) secretory, 2) neurohumoral and 3) hematopoietic aspects of eosinophil function in airway responsiveness. A fourth project is a Demonstration and Education Project (D&E) that is designed to install and assess the efficacy of an education program for an asthma treatment center in the inner city of Chicago. Project 1 aims to assess the role of specific endothelial and matrix protein adhesion reactions on the upregulation of stimulated secretion from immunomagnetically isolated human blood eosinophils. A second aspect of these investigations determines the role of eosinophil secretion that is augmented by ligand/matrix adhesion in inducing in vitro hypercontractility in human airways. Project 2 assesses bidirectional interactions between sensory c-fibers and eosinophils, which amplify cell recruitment and activation. The physiological relevance to airway hyperresponsiveness of these in vitro interactions is evaluated also in two models of guinea pig inflammation m vivo. Project 3 examines in detail the molecular and cellular aspects of eosinopoiesis using a recently developed method for culturing eosinophils in vitro from the umbilical cord blood of neonates. Since eosinopoiesis is the first step in the translocation of these inflammatory cells to the conducting airways, studies are proposed to assess the essential roles of GM- CSF, interleukin (IL)-3 and IL-5 in the in vitro differentiation of bioactive eosinophils. A second series of studies seeks to identify interactions between extracellular matrix factors and eosinophils that influence cytokine-directed eosinopoiesis. Project 4 is a D and E project that tests the hypothesis that self-management instruction through community health workers significantly decreases morbidity and mortality among inner city children with limited health care resources. This program, conducted through the Department of Pediatrics and the La Rabida Children's Hospital, assesses the efficacy of a targeted co-management approach between physician and community health worker in achieving better asthma treatment by altering patient behavior. Data derived from the basic science component of these investigations will provide a coordinated approach to understanding the role of the eosinophil in caring airway hyperresponsiveness. The D & E project utilizes an experienced clinical teacher to apply pharmacological concepts of asthma therapy to a population facing diminishing health care resources. It is anticipated that the studies proposed in these projects will contribute to a mechanistic understanding of the cellular mechanisms that convert normally responsiveness tissues into asthmatic airways and of applying current therapies effectively.