EPITHELIAL MODULATION OF RESPIRATORY SMOOTH MUCSCLE

呼吸平滑肌的上皮调节

• 批准号: 3082911
• 负责人: STEVEN R WHITE
• 金额: $ 7.73万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-09-01 至 1995-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3082911
• 关键词: asthma; bronchoconstrictors; bronchomotion; bronchus; calcium channel blockers; dogs; eicosanoid metabolism; eosinophil; guinea pigs; high performance liquid chromatography; isolation perfusion; membrane potentials; muscle contraction; prostaglandins; respiratory epithelium; respiratory muscles; smooth muscle; tissue /cell culture; trachea

Dr. White has the long term goal of pursuing independent investigation of the mechanism operative in the pathophysiology of asthma. REceipt of a Clinical Investigator Award will facilitate the development of Dr. White's investigative skills and experience by expanding his knowledge of several new cellular techniques as outlined in the propose studies. Dr. White and his sponsor, Dr. Alan Leff, have developed an educational environment which will provide the candidate essential training in emerging areas of airway cell biology and physiology. Sponsors and collaborators have been identified to mentor Dr. White's progression to an independent investigator. The proposed application will permit the candidate to develop a career as an academic physician-scientist committed to basic medical research into the pathophysiology of asthma and obstructive airways diseases. The specific aims in this proposal will extend earlier inquires into epithelial modulation of airway smooth muscle contractility which Dr. White has begun under the guidance of Dr. Leff. Three immediate goals are identified: 1) Determine the role of endothelin on airway smooth muscle contractility. A new in-situ isolated tracheal-epithelial preparation develop in guinea pigs will be used to measure both isometric force of contraction and lower airways resistance after either direct or intravenous stimulation of airways with endothelin-1. These experiments also will test the hypothesis that the airway epithelium modulates the action of a vascular-derived mediator of bronchoconstriction, and further test the hypothesis that the bronchoconstricting effects of endothelin are mediated by metabolites of the cyclooxygenase pathway. 2) Determine the secretion of eicosanoid mediators of airway smooth muscle contraction from airway epithelial cells after stimulation by endothelin or eosinophilic protein mediators. Specifically, changes in bioelectrical potential difference and secretion of eicosanoid mediators will be determined after stimulation of canine tracheal or third-generation bronchial epithelial membranes mounted in perfusion chambers. Mediator secretion will be stimulated by endothelin and the protein mediators eosinophils that have been demonstrated to elicit substantial changes in airway tone. These experiments will test the hypothesis that inflammatory protein mediators elicit important changes in epithelial secretion of important mediators of airway tone. 3) Determine the physiologic response of airway smooth muscle to epithelial ell conditioned medium after stimulation by endothelin or eosinophilic protein mediators. Utilizing the isolated tracheal-epithelial preparation and cultured tracheal epithelial cells, the studies performed in the second specific aim will be extended to test the hypothesis that epithelial cell activation by either endothelin or the protein mediators of eosinophils results in secretion of physiologically important mediators of airway contractile responses. Data derived from these studies should lead to identification of the mechanisms by which epithelium modulates bronchomotor tone. By clarifying the pathophysiology of epithelial modulation of airway contractile responses in animals, these studies should suggest basic physiological and pathophysiologic processes that regulate the tone of airways, and lead to new therapeutic approaches in the management of asthma.

怀特博士的长期目标是对 哮喘病理生理学的机制。 收到 临床调查员奖将促进怀特博士的发展 通过扩展他对几个的知识，调查技能和经验 提出的研究中概述了新的细胞技术。 怀特博士和 他的赞助商艾伦·莱夫（Alan Leff）建立了一个教育环境 将在AIRWAY的新兴领域提供候选人的基本培训 细胞生物学和生理学。 赞助商和合作者一直 确定指导怀特博士的独立发展 研究者。 拟议的申请将允许候选人 发展职业为学术医师科学家，致力于基本 哮喘和阻塞性气道病理生理学的医学研究 疾病。 该提案中的具体目的将延长较早的询问 进入气道平滑肌收缩的上皮调制。 怀特已经在莱夫博士的指导下开始。 三个直接目标是 确定：1）确定内皮素在气道平滑肌上的作用 收缩力。 新的原位隔离气管上皮准备 在豚鼠中发育将用于测量两种等距力 直接或静脉内的收缩和较低的气道电阻 用内皮素1刺激气道。 这些实验也将测试 气道上皮调节了A的作用的假设 支气管收缩的血管衍生的介体，并进一步测试 假设内皮素的支气管收缩作用是介导的 通过环氧酶途径的代谢产物。 2）确定分泌物 气道平滑肌收缩的类花生酸介质 内皮素或嗜酸性蛋白刺激后的上皮细胞 调解人。 具体而言，生物电势差异的变化和 在刺激后，将确定类固醇介质的分泌 安装的犬类气管或第三代支气管上皮膜 在灌注室。 内皮素将刺激介体分泌 以及已证明引起的蛋白质介质嗜酸性粒细胞 气道音调的实质变化。 这些实验将测试 假设炎性蛋白介质会引起重要变化 重要的气道音调介体的上皮分泌。 3）确定 气道平滑肌对上皮ELL的生理反应 内皮素或嗜酸性蛋白刺激后有条件培养基 调解人。 利用孤立的气管上皮制剂和 培养的气管上皮细胞，第二次进行的研究 将扩展特定目标以检验上皮细胞的假设 内皮素或嗜酸性粒细胞的蛋白质介质激活 导致气道生理上重要的介体的分泌 收缩回应。 这些研究得出的数据应导致 鉴定上皮调节支气管运动的机制 语气。 通过阐明气道上皮调节的病理生理学 动物的收缩反应，这些研究应提出基本 生理和病理生理过程调节 航空公司，导致在管理方面的新治疗方法 哮喘。