POSTJUNCTIONAL MECHANISMS OF AIRWAY HYPERREACTIVITY

气道高反应性的结后机制

• 批准号: 3367339
• 负责人: William T Gerthoffer
• 金额: $ 16.55万
• 依托单位: UNIVERSITY OF NEVADA RENO
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-04-01 至 1996-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3367339
• 关键词: asthma; bacterial toxins; biomechanics; bronchoconstrictors; bronchospasm; calcium; caldesmon; cyclic nucleoside monophosphate; cytoskeletal proteins; dogs; high performance liquid chromatography; histamine; inositol phosphates; laboratory rabbit; leukotrienes; methacholine; muscle contraction; myosins; phosphatidylinositols; phosphorylation; prostaglandin F; respiratory hypersensitivity; second messengers; serotonin; smooth muscle; trachea

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.

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 介质以增加支气管运动张力。 除了这些重要的 细胞与细胞之间的相互作用也有证据表明连接后 气道高反应性的组成部分，其中介质在气道相互作用 气道平滑肌细胞水平。 初步研究表明 低浓度组胺和血清素的协同作用 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-收缩耦合的结后事件。 建立 这种现象的意义和机制六种致痉剂将 测试协同效应：乙酰甲胆碱、组胺、血清素、 前列腺素 F2α、白三烯 D4 和 E4。 该项目的目标是： 1. 定义介体协同组合的机械效应 支气管痉挛。 2. 测量响应组合而形成的第二信使的变化 的调解员。 3. 确定介质是否增强 Ca2+ 诱导的收缩 发生在透化的气管平滑肌中。 4. 确定介体组合对收缩的影响 蛋白质磷酸化。 5. 建立第三和第三层增强的意义和机制 第四代细支气管平滑肌。 结果将定义结后成分对 气道高反应性由多种重要介质产生 支气管收缩。 结果还将检验以下观点： 增强作用可以发生在兴奋-收缩耦合的几个步骤中 它可能会随着气道生成的变化而变化。 改进 了解气道高反应性的机制可能有助于 开发改进的治疗哮喘的治疗策略。