CHEMOSENSITIVITY OF TACHYKININ CONTAINING LUNG AFFERENTS

含速激肽的肺传入的化学敏感性

• 批准号: 6184045
• 负责人: LU-YUAN LEE
• 金额: $ 15.87万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6184045
• 关键词: C fiber; action potentials; asthma; carbon dioxide tension; electrophysiology; environmental toxicology; enzyme activity; hydrogen ions; inflammation; laboratory rat; lactates; lung injury; mucosa; neuropharmacology; ozone; prostaglandin endoperoxide synthase; tachykinin; vagus nerve

Bronchial hyperreactivity is a prominent feature of asthma. Indirect but compelling evidence suggests the possible involvement of increased pulmonary C-fiber excitability in the manifestation of bronchial hyperreactivity induced by airway mucosal injury. The objectives of this proposal are the following: 1) to characterize the stimulatory effect of hydrogen ions on pulmonary C-fibers, 2) to elucidate the mechanisms underlying this effect, and 3) to explore its potential role in the development of bronchial hyperreactivity. Proposed experiments are focused on two sources of H+ ions that are produced by tissue metabolism: lactic acid and CO2. An elevated level of lactic acid occurs commonly during severe exercise, tissue ischemia, and various pathologic conditions, but whether pulmonary C-fibers can be activated by excessive production of lactic acid is not known. The following three hypotheses will be tested: 1) pulmonary C-fibers can be activated by an increase in H+ concentration in pulmonary interstitial fluid (PIF), and lactic acid is particularly effective in stimulating these endings; 2) a substantial increase of CO2 tension in the alveolar gas can also exert a stimulatory effect on these afferents, and this action is brought about by an increase in the H+ concentration in the PIF; and 3) the stimulatory effect of H+ ions on these afferents can be potentiated by airway mucosal inflammation, in which the production and release of both cyclooxygenase metabolites and tachykinins are involved. In the proposed studies, mucosal inflammation will be induced by acute exposure of the lung to ozone or by hyperventilation with cold dry air. Pulmonary C-fiber afferent activity will be recorded in anesthetized rats by using a single-fiber recording technique, whereas pH in pulmonary venous blood will be measured continuously for estimation of the changes of pH in PIF during various experimental conditions. The relationship between changes in fiber activity and pulmonary venous pH will be established, and from this the threshold pH for stimulation can be determined. The feasibility and potential significance of the proposed studies have already been demonstrated in the preliminary experiments. These results will provide a more in-depth understanding of the chemosensitive properties of pulmonary C-fibers and their role in regulating the airway functions in various pathophysiological conditions.

支气管高反应性是哮喘的重要特征。间接，但是 令人信服的证据表明可能参与增加 支气管表现中的肺C纤维兴奋性 气道粘膜损伤引起的过度反应性。 目标的目标 该提议如下：1）表征刺激性 氢离子对肺C纤维的影响，2）阐明 这种效果的基础机制，以及3）探索其潜在作用 在支气管高反应性的发展中。 提出的实验 专注于由组织产生的两个H+离子的来源 代谢：乳酸和二氧化碳。 乳酸升高 通常在严重运动，组织缺血和各种情况下发生 病理状况，但是是否可以激活肺C纤维 通过过度生产乳酸。 下列 将测试三个假设：1）可以激活肺C纤维 通过肺间隙液中H+浓度的增加 （PIF），乳酸在刺激这些方面特别有效 结局； 2）肺泡气体中的二氧化碳张力大幅增加 还可以对这些传入和此动作产生刺激作用 由PIF中的H+浓度增加带来；和 3）H+离子对这些传入的刺激作用可能是 由气道粘膜炎症增强，生产和生产 涉及环氧合酶代谢产物和旋转金蛋白的释放。 在拟议的研究中，粘膜炎症将由急性诱导 肺暴露于臭氧或通过冷干空气过度换气。 肺C纤维传入活动将记录在麻醉中 大鼠使用单纤维记录技术，而pH 将连续测量肺静脉血以估计 在各种实验条件下，PIF中pH的变化。 这 纤维活性变化与肺静脉pH的关系 将建立，并从中建立刺激的阈值pH值 可以确定。 可行性和潜在意义 拟议的研究已经在初步中得到证明 实验。 这些结果将提供更深入的理解 肺C纤维的化学敏感性及其作用 在调节各种病理生理的气道功能 状况。