Chemosensitivity of Tachykinin-containing Lung Afferents

含速激肽的肺传入神经的化学敏感性

• 批准号: 7091504
• 负责人: LU-YUAN LEE
• 金额: $ 24.59万
• 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 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7091504
• 关键词: C fiber; action potentials; asthma; carbon dioxide tension; chemical hypersensitivity; electrophysiology; enzyme activity; hydrogen ions; inflammation; laboratory rat; lung injury; mucosa; neuropharmacology; ozone; prostaglandin endoperoxide synthase; tachykinin; vagus nerve; voltage /patch clamp

DESCRIPTION (provided by applicant): Vagal bronchopulmonary C-fiber sensory nerves play an important role in regulating airway functions. Hypersensitivity of these afferents is believed to be involved in the manifestation of airway hyperresponsiveness associated with mucosal injury, a prominent feature of asthma. During airway inflammatory reaction, a number of low molecular weight, highly cationic proteins are secreted by inflammatory cells such as eosinophils that infiltrate into the airways. It is well documented that the release of these proteins can induce mucosal injury and airway hyperresponsiveness. Our recent studies have established the first direct evidence demonstrating an intense and sustained effect of both human eosinophil granule-derived and synthetic cationic proteins on vagal bronchopulmonary C-fiber endings. However, the mechanism underlying both the initial stimulatory and the sustained sensitizing effects of cationic proteins on these sensory nerves is poorly understood. Our central hypothesis is that the cationic charge carried by these proteins acts on the airway mucosa, triggering the release of certain inflammatory mediators that in turn exert potent effects on the C-fiber terminals. The mast cells located in the airway mucosa probably play an important role in the interaction between cationic proteins and sensory endings. Sensitization of these afferents can then lead to airway hyperresponsiveness via both cholinergic reflex pathways and tachykininergic mechanisms. Single-fiber and whole-cell patch-clamp recording techniques will be employed to measure the activity of bronchopulmonary C fibers in anesthetized rats and in isolated neurons, respectively. The results obtained from this study should provide critical information for gaining new insights into the mechanisms underlying the airway hyperresponsiveness induced by cationic proteins.

描述（由申请人提供）：迷走支气管肺C纤维感觉神经在调节气道功能中起着重要作用。据信这些传入的超敏反应与粘膜损伤相关的气道高反应性表现涉及，这是哮喘的重要特征。在气道炎症反应中，许多低分子量，高阳离子蛋白被炎症细胞（例如嗜酸性粒细胞）分泌，这些细胞会渗入气道中。有充分的文献证明，这些蛋白质的释放可以诱导粘膜损伤和气道高反应性。我们最近的研究已经建立了第一个直接证据，证明了人嗜酸性粒细胞衍生和合成阳离子蛋白对迷走支气管肺C纤维末端的强烈和持续作用。然而，对这些感觉神经的初始刺激和持续敏感性作用的基础机制尚不清楚。我们的中心假设是，这些蛋白质携带的阳离子电荷作用于气道粘膜上，引发了某些炎症介质的释放，而这些炎症介质反过来又对C纤维末端产生了有效的影响。位于气道粘膜中的肥大细胞可能在阳离子蛋白与感觉末端之间的相互作用中起重要作用。然后，这些传入的敏化可以通过胆碱能反射途径和速气素能机制导致气道高反应性。将采用单纤维和全细胞斑块记录技术来分别测量麻醉大鼠和孤立的神经元中支气管肺C纤维的活性。从这项研究中获得的结果应提供关键信息，以获取对阳离子蛋白引起的气道高反应性基础机制的新见解。