AIRWAY EPITHELIUM AND SENSORY NEUROEXCITABILITY

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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.