POSTJUNCTIONAL MECHANISMS OF AIRWAY HYPERREACTIVITY

哮喘患者的呼吸道对支气管收缩有高反应性 激动剂，很可能是神经、肥大细胞、嗜酸性粒细胞、呼吸道 上皮细胞和呼吸道平滑肌细胞都通过多种方式相互作用 增加支气管运动张力的中介物。除了这些重要之外 细胞-细胞相互作用也有证据表明后连接 呼吸道高反应性的组成部分，在该成分中，介质在 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 犬气管和支气管肌的毒鼠碱反应。 这表明，呼吸道高反应性的部分机制包括 兴奋-收缩耦合的节后事件。要建立 这一现象的意义和机制六种致痉挛药物将 进行协同效应测试：乙酰甲胆碱、组胺、5-羟色胺、 前列腺素F2α，白三烯D4和E4。 该项目的目标是： 1.确定调解剂协同组合的机械效应 支气管痉挛的症状。 2.测量响应组合而形成的第二信使的变化 调停人。 3.确定Ca~(2+)的增强是否通过介质引起收缩 发生在通透性的气管平滑肌中。 4.确定调节剂组合对收缩的影响 蛋白质磷酸化。 5.确立增强作用的意义和机制(S) 第四代细支气管肌。 结果将定义后置成分对 几种重要的炎症介质引起的气道高反应性 支气管收缩。这一结果也将检验这样一种观点： 在兴奋-收缩耦合中，增强可以在几个步骤中发生 它可能会随着呼吸道生成的不同而不同。改进 对呼吸道高反应性机制的了解可能有助于 开发改进的治疗哮喘的治疗策略。

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.