AIRWAY EPITHELIUM AND SENSORY NEUROEXCITABILITY

气道上皮和感觉神经兴奋性

基本信息

批准号：
6351557
负责人：
Bradley Joel Undem
金额：
$ 30.32万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-02-01 至 2005-01-31
项目状态：
已结题

项目摘要

Within and just beneath the airway epithelium is a dense plexus of sensory nerve fibers. These fibers provide a protective function by initiating reflexes such as cough, vasodilation, glandular secretion, and bronchospasm. The responsiveness of the sensory fibers is not a static function. Inflammatory mediators can lead to modulation of ionic channels in the sensory nerve fibers causing changes in their excitability. In inflammatory airway disease, the sensitivity of the sensory fibers can become distorted to the extent that reflexes such as cough become irritating and non-productive. The non-productive cough is also likely to be a marker for perturbation in subconscious autonomic reflexes in peripheral airways. The inappropriate excitability of the sub-epithelial nerve plexus, may therefore lead to both the symptoms, and perhaps the pathophysiology of airway diseases. The epithelial cells are known to actively contribute to the inflammatory process by producing a variety of mediators and cytokines. Although the majority of sensory nerve fibers are within and lying just beneath the epithelium, there is surprisingly very little known about the communication between epithelial cell products and sensory nerve excitability in the airway. This proposal centers on the hypothesis that a major function of the epithelium is to recruit the nervous system in host defense mechanisms. This is accomplished by releasing mediators and cytokines that increase the excitability of the neighboring afferent nerve endings. To understand this process it is necessary to first define the phenotype of sensory nerves that innervate the epithelium. Second, it is necessary to identify ionic currents that are important in modulating the excitability of these nerve fibers. Finally, it is important to characterize the molecules in the epithelium that may serve to modulate afferent neuroexcitability. This proposal seeks to satisfy these objectives.

气道上皮内部和正下方是密集的感觉神经纤维丛。这些纤维通过引发咳嗽、血管舒张、腺体分泌和支气管痉挛等反射来提供保护功能。感觉纤维的响应能力不是静态函数。炎症介质可导致感觉神经纤维中离子通道的调节，导致其兴奋性发生变化。在炎症性气道疾病中，感觉纤维的敏感性可能会扭曲，以致咳嗽等反射变得刺激且无效。无痰咳嗽也可能是外周气道潜意识自主反射紊乱的标志。因此，上皮下神经丛的不适当兴奋性可能导致气道疾病的症状和病理生理学。已知上皮细胞通过产生多种介质和细胞因子积极促进炎症过程。尽管大多数感觉神经纤维位于上皮内并位于上皮正下方，但令人惊讶的是，人们对气道中上皮细胞产物与感觉神经兴奋性之间的通讯知之甚少。该提议的中心假设是上皮的主要功能是在宿主防御机制中招募神经系统。这是通过释放增加邻近传入神经末梢兴奋性的介质和细胞因子来实现的。为了理解这个过程，有必要首先定义支配上皮的感觉神经的表型。其次，有必要确定对调节这些神经纤维的兴奋性很重要的离子电流。最后，重要的是表征上皮细胞中可能用于调节传入神经兴奋性的分子。本提案旨在实现这些目标。