AIRWAY BIOLOGY OF ASTHMA

哮喘的气道生物学

• 批准号: 2069704
• 负责人: ALAN Richard LEFF
• 金额: $ 66.77万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-08-01 至 1998-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2069704
• 关键词: asthma; cooperative study; eosinophil; inflammation

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.

该 AAIDCRC 应用的重点是炎症 人类气道高反应性的发病机制 哮喘。将特别强调发病机制 细胞粘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 重点关注 l) 分泌、2) 神经体液和 3) 造血 嗜酸性粒细胞在气道反应性中的功能。第四个 项目是一个示范和教育项目（D&E） 旨在安装和评估教育计划的有效性 芝加哥市中心的一个哮喘治疗中心。 项目 1 旨在评估特定内皮细胞和 基质蛋白粘附反应对刺激上调 免疫磁性分离的人血液嗜酸性粒细胞的分泌物。 这些调查的第二个方面决定了 配体/基质粘附增强了嗜酸性粒细胞的分泌 诱导人体气道体外收缩过度。项目2 评估感觉 c 纤维之间的双向相互作用 嗜酸性粒细胞，增强细胞募集和激活。这 这些因素与气道高反应性的生理相关性 还在两种豚鼠模型中评估了体外相互作用 体内炎症。项目 3 详细研究了分子和 使用最近开发的方法研究嗜红细胞生成的细胞方面 用于从脐带血中体外培养嗜酸性粒细胞 新生儿。由于嗜红细胞生成是细胞生成的第一步 这些炎症细胞易位至传导 气道，建议进行研究以评估 GM-的重要作用 CSF、白细胞介素 (IL)-3 和 IL-5 在体外分化中的作用 具有生物活性的嗜酸性粒细胞。第二系列研究旨在确定 细胞外基质因子与嗜酸性粒细胞之间的相互作用 影响细胞因子指导的嗜酸性粒细胞生成。项目4是D 和E项目测试自我管理的假设 社区卫生工作者的指导意义重大 降低内城区儿童的发病率和死亡率 医疗保健资源有限。该计划通过 儿科和拉比达儿童医院， 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帮助改善哮喘 通过改变患者行为进行治疗。数据来源于基础数据 这些调查的科学部分将提供 协调的方法来了解嗜酸性粒细胞的作用 关心气道高反应性。 D&E 项目利用 经验丰富的临床教师应用药理学概念 对面临医疗保健减少的人群进行哮喘治疗 资源。预计这些研究中提出的研究 项目将有助于机械地理解 转化正常反应性组织的细胞机制 进入哮喘气道并应用现有疗法 有效地。

项目成果

Association of granular exocytosis with Ca(2+)-activated K+ channels in human eosinophils.

颗粒胞吐作用与人嗜酸性粒细胞中 Ca(2) 激活的 K 通道的关联。

• DOI: 10.1152/ajplung.1997.273.1.l16
• 发表时间: 1997
• 期刊: The American journal of physiology.
• 作者: Saito,M;Sato,R;Munoz,NM;Herrnreiter,A;Oyaizu,M;Kasugai,H;Narahashi,T;Leff,AR
• 通讯作者: Leff,AR

Differential effects of cyclosporine A after acute antigen challenge in sensitized cats in vivo and ex vivo.

环孢素 A 对致敏猫体内和离体急性抗原攻击后的不同作用。

• DOI: 10.1038/sj.bjp.0701716
• 发表时间: 1998
• 期刊: British journal of pharmacology
• 影响因子: 7.3
• 作者: Mitchell,RW;Cozzi,P;Ndukwu,IM;Spaethe,S;Leff,AR;Padrid,PA
• 通讯作者: Padrid,PA

Assessment of agonist- and cell-mediated responses in airway microsections by computerized videomicrometry.

通过计算机视频显微测量法评估气道显微切片中激动剂和细胞介导的反应。

• DOI: 10.1152/ajplung.1995.268.3.l519
• 发表时间: 1995
• 期刊: The American journal of physiology.
• 作者: Galens,S;Munoz,NM;Rabe,KF;Herrnreiter,A;Mayer,D;Morton,B;McAllister,K;Leff,AR
• 通讯作者: Leff,AR

Intracellular expression of Fc gamma RIII (CD16) and its mobilization by chemoattractants in human eosinophils.

• DOI: 10.4049/jimmunol.161.5.2574
• 发表时间: 1998-09
• 期刊: Journal of immunology
• 影响因子: 4.4
• 作者: X. Zhu;K. Hamann;N. Muñoz;N. Rubio;D. Mayer;A. Hernrreiter;A. Leff

Airway reopening pressure in isolated rat lungs.

离体大鼠肺部气道重新开放压力。

• DOI: 10.1152/jappl.1994.76.3.1372
• 发表时间: 1994
• 期刊: Journal of applied physiology (Bethesda, Md. : 1985)
• 作者: Naureckas,ET;Dawson,CA;Gerber,BS;Gaver3rd,DP;Gerber,HL;Linehan,JH;Solway,J;Samsel,RW
• 通讯作者: Samsel,RW