MECHANISMS OF CAL CHELATOR INDUCED AIRWAY CONSTRICTION

哮喘受试者表现为非特异性气道高反应性， 对非抗原刺激的过度反应 虽然单独的缺陷 可能对这些夸张的反应负责，可能有一些 共同的道路。 如果是这样的话，沿着共同路径的缺陷沿着可能是 负责对药物的非特异性气道高反应性 从表面上看，两者差别很大 我们建议探索 非特异性刺激诱导支气管收缩的常见机制。 两种不同的螯合钙剂，Na2EDTA和柠檬酸，诱导 当哮喘的人和动物吸入时， 气道高反应性 造成这种现象的机制是 未知，但可能是由于钙稳态的改变。 引起犬肺外周支气管收缩的低碳酸血症可 杂种犬和Basenji-Greyhound（BG）之间的这种反应不同 狗，具有非特异性气道高反应性。 我们将探讨 Na_2EDTA引起犬肺外周支气管收缩的机制 作为非特异性气道反应性的模型。 我们假设钙 螯合剂作用于上皮细胞，增加构建的生产， 减少扩张剂产生的试剂。 我们将测试 钙螯合作用重要性及钙螯合剂气雾剂的测定 和低碳酸血症通过类似的机制发挥作用， 在体内模型中进行干预。 我们将测试假设， 气道上皮细胞参与收缩的产生， 通过使用两种体外制剂分离扩张剂， 上皮表面与浆膜表面。 我们会确认这些特工的身份 通过直接测定支气管肺泡灌洗液。 其中一个体外 制备还允许测量的生物电参数 上皮 最后，我们将使用从体内获得的信息， 在杂种犬中进行的体外研究，以探索体内 在气道高反应性的狗模型中的反应。 这项工作将进一步 阐明钙稳态紊乱的重要性， 支气管高反应性的机制，这将导致更好的 了解哮喘的潜在机制。

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.