AIRWAY EPITHELIUM AND SENSORY NEUROEXCITABILITY

在呼吸道上皮内和正下方是致密的感觉神经纤维丛。这些纤维通过启动咳嗽、血管扩张、腺体分泌和支气管痉挛等反射来提供保护功能。感觉纤维的反应性不是一种静态的功能。炎症介质可导致感觉神经纤维离子通道的调节，导致其兴奋性的改变。在炎症性呼吸道疾病中，感觉纤维的敏感性可能会扭曲，以至于咳嗽等反射变得刺激性和无效性。无效性咳嗽也可能是外周呼吸道潜意识自主神经反射紊乱的标志。因此，上皮下神经丛的不适当兴奋性可能会导致症状，甚至可能导致呼吸道疾病的病理生理学。众所周知，上皮细胞通过产生各种介质和细胞因子积极参与炎症过程。虽然大多数感觉神经纤维位于上皮内和下方，但令人惊讶的是，人们对呼吸道上皮细胞产物与感觉神经兴奋性之间的联系知之甚少。这一建议的核心假设是，上皮的主要功能是在宿主防御机制中招募神经系统。这是通过释放介质和细胞因子来实现的，这些介质和细胞因子增加了邻近传入神经末梢的兴奋性。为了理解这一过程，有必要首先确定支配上皮的感觉神经的表型。其次，有必要确定在调节这些神经纤维的兴奋性方面起重要作用的离子电流。最后，重要的是要确定上皮中可能调节传入神经兴奋性的分子。这项建议旨在满足这些目标。

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.