AIRWAY EPITHELIUM AND SENSORY NEUROEXCITABILITY

在呼吸道上皮内和下方是感觉神经纤维的密集丛。这些纤维通过引发反射如咳嗽、血管舒张、腺体分泌和支气管痉挛提供保护功能。感觉纤维的反应性不是一个静态的功能。炎症介质可导致感觉神经纤维中离子通道的调节，从而引起其兴奋性的变化。在炎症性气道疾病中，感觉纤维的敏感性可能会扭曲到反射（如咳嗽）变得刺激性和非生产性的程度。干咳也可能是周围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的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来积极促进炎症过程。尽管大多数感觉神经纤维位于上皮细胞内并位于上皮细胞下方，但令人惊讶的是，对气道中上皮细胞产物和感觉神经兴奋性之间的通信知之甚少。这一提议的核心假设是上皮细胞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，有必要首先定义支配上皮的感觉神经的表型。其次，有必要确定离子电流，这是重要的调节这些神经纤维的兴奋性。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。本建议旨在实现这些目标。

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.