MECHANISMS OF CAL. CHELATOR-INDUCED AIRWAY CONSTRICTION

CAL 的机制。

• 批准号: 3087722
• 负责人: KAREN S LINDEMAN
• 金额: $ 9.05万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-07-01 至 1995-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3087722
• 关键词: arachidonate; bronchoconstrictors; calcium channel; calcium channel blockers; citrates; delayed hypersensitivity; diagnostic respiratory lavage; dogs; drug interactions; eicosanoid metabolism; electrophysiology; ethylenediaminetetraacetate; fluorimetry; histamine release; homeostasis; hypocapnia; leukotrienes; radioimmunoassay; respiratory epithelium; respiratory hypersensitivity; statistics /biometry

Asthmatic subjects manifest nonspecific airway hyperreactivity by exaggerated responses to nonantigenic stimuli. Although separate defects may be responsible for these exaggerated responses, there may be some common pathways. If so, a defect along a common pathway could be responsible for nonspecific airway hyperreactivity in response to agents which, superficially, appear to differ greatly. We propose to explore common mechanisms by which nonspecific stimuli induce bronchoconstriction. Two different agents that chelate calcium, Na2EDTA and citric acid, induce bronchoconstriction when inhaled by asthmatic humans and animals with airway hyperreactivity. The mechanism responsible for this phenomenon is not known, but may be due to an alteration of calcium homeostasis. hypocapnia, which induces bronchoconstriction in canine lung periphery, may share this response differs between mongrel dogs and Basenji-Greyhound (BG) dogs, which have nonspecific airway hyperreactivity. We will explore the mechanism of Na2EDTA-induced bronchoconstriction in canine lung periphery as a model of nonspecific airway reactivity. We hypothesize that calcium chelators act on the epithelium, increasing the production of constructing agents of decreasing the production of dilating agents. We will test the importance of calcium chelation and determine if calcium chelator aerosols and hypocapnia act via similar mechanisms by using pharmacologic interventions in the in vivo model. We will test the hypothesis that the airway epithelium is involved in the production of constricting and dilating agents by using two in vitro preparations that isolate the epithelial surface from the serosal surface. We will identify these agents by direct assay of bronchoalveolar lavage fluid. One of the in vitro preparations also allows measurements of bioelectric parameters of epithelium. Finally, we will use the information gained from in vivo and in vitro studies in mongrel dogs to probe the difference in the in vivo response in a dog model of airway hyperreactivity. This work will further clarify the importance of a disturbance of calcium homeostasis as a common mechanism of bronchial hyperreactivity, which will lead to a better understanding of the mechanisms underlying asthma.

哮喘受试者表现出非特异性气道高反应性。 夸大对非抗原刺激的反应。 虽然单独的缺陷 可能负责这些夸张的回应，可能会有一些 通用途径。 如果是这样，沿公共途径的缺陷可能是 负责对代理的非特异性气道高反应性 从表面上看，这似乎有很大差异。 我们建议探索 非特异性刺激引起支气管收缩的常见机制。 两种螯合钙的不同药物，Na2edta和柠檬酸，诱导 当被哮喘的人和动物吸入时，支气管收缩 气道高反应性。 负责这种现象的机制是 尚不清楚，但可能是由于钙稳态的改变。 在犬肺周围诱导支气管收缩的低核酸菌可能 共享这种反应在Mongrel Dogs和Basenji-Greyhound（BG）之间有所不同 狗，具有非特异性气道高反应性。 我们将探索 Na2EDTA诱导的犬肺周围的支气管收缩的机制 作为非特异性气道反应性的模型。 我们假设钙 螯合剂对上皮作用，增加了构造的产生 减少扩张剂产生的药物。 我们将测试 钙螯合的重要性，并确定钙螯合剂气溶胶是否 通过使用药理学，通过相似机制ACT 体内模型中的干预措施。 我们将检验以下假设 气道上皮参与收缩和 通过使用两个分离的体外制剂来扩张剂 浆膜表面上皮表面。 我们将确定这些代理商 通过直接测定支气管肺泡灌洗液。 体外之一 准备工作还允许测量的生物电参数 上皮。 最后，我们将使用从invivo和 在杂种狗中的体外研究以探测体内的差异 气道高反应性模型中的反应。 这项工作将进一步 阐明钙稳态障碍的重要性 支气管高反应性的机制，这将导致更好 了解哮喘的机制。