POSTJUNCTIONAL MECHANISMS OF AIRWAY HYPERREACTIVITY

哮喘患者的气道对支气管收缩反应过度 激动剂，很可能是神经，肥大细胞，嗜酸性粒细胞，气道 上皮细胞和气道平滑肌细胞都通过多种方式相互作用， 以增加支气管张力。 除了这些重要的 细胞间相互作用也有证据表明， 气道高反应性的组成部分，其中介质在气道高反应性的 气道平滑肌细胞水平。 初步研究表明， 低浓度组胺和5-羟色胺的协同作用 狗气管和支气管平滑肌的毒蕈碱反应。 这表明气道高反应性的部分机制涉及 兴奋-收缩偶联的连接后事件。 建立 这一现象的意义和机制六种痉挛剂将 测试协同作用：乙酰甲胆碱，组胺，血清素， 前列腺素F2 α和白三烯D4和E4。 该项目的目标是： 1.定义介质协同组合的机械效应 支气管痉挛 2.测量第二信使的变化，以响应组合 调解员。 3.确定是否通过介质增强Ca 2+诱导的收缩 发生在透化的气管平滑肌中。 4.确定介质组合对收缩的影响 蛋白质磷酸化 5.确定第三和第四阶段增强的意义和机制， 第四代细支气管平滑肌。 结果将定义连接后成分对 气道高反应性产生的几个重要介质 支气管收缩 研究结果也将检验这样一种观点， 在兴奋-收缩偶联中，增强可以在几个步骤中发生 并且它可以作为气道生成的函数而变化。 改进 了解气道高反应性的机制可能有助于 开发用于治疗哮喘的改进的治疗策略。

The airways of asthmatic humans are hyperreactive to bronchoconstricting agonists, and it is likely that nerves, mast cells, eosinophils, airway epithelia and airway smooth muscle cells all interact by means of a variety of mediators to increase bronchomotor tone. In addition to these important cell-cell interactions there is also evidence for a postjunctional component of airway hyperreactivity in which mediators interact at the level of airway smooth muscle cells. Preliminary studies demonstrate synergistic effects of low concentrations of histamine and serotonin on the muscarinic response of tracheal and bronchial smooth muscle of the dog. This suggests part of the mechanism of airway hyperreactivity involves postjunctional events of excitation-contraction coupling. To establish the significance and mechanisms of this phenomenon six spasmogenic agents will be tested for synergistic effects: methacholine, histamine, serotonin, prostaglandin F2alpha, and leukotrienes D4 and E4. The aims of the project are to: 1. Define the mechanical effects of synergistic combinations of mediators of bronchospasm. 2. Measure changes in second messengers formed in response to combinations of mediators. 3. Determine whether potentiation of Ca2+-induced contraction by mediators occurs in permeabilized tracheal smooth muscle. 4. Determine the effects of combinations of mediators on contractile protein phosphorylation. 5. Establish the significance and mechanism(s) of potentiation in third and fourth generations of bronchiolar smooth muscle. The results will define the contribution of a postjunctional component to airway hyperreactivity produced by several important mediators of bronchoconstriction. The results will also test the notion that potentiation can occur at several steps in excitation-contraction coupling and it might vary as a function of airway generation. Improved understanding of the mechanism of airway hyperreactivity may contribute to development of improved therapeutic strategies for treatment of asthma.