Cholinergic mechanisms involved in transduction of airway defensive reflexes

阻塞性肺疾病的症状，包括呼吸道高反应性、可逆性呼吸道 梗阻、胸闷、呼吸困难、粘液分泌增多和咳嗽在很大程度上是由 过度和/或不适当地激活支配呼吸道和肺的迷走神经传入神经。 了解这些感觉神经在健康和疾病中被激活的机制 由于它们的激活而引起的反射和感觉一直是 在我们的实验室里进行的研究。内脏传入神经通常依赖于特殊的化学感觉 在神经末梢的信号机制，以转导粘膜刺激。我们最近描述了一种 呼吸道粘膜中依赖递质乙酰胆碱的化学感觉转导通路 烟碱型乙酰胆碱受体亚类(NAChRs)启动呼吸模式的改变 粘膜刺激。值得注意的是nAChRs的参与，因为它们的活动不适当和 暴露在香烟烟雾或含有尼古丁的烟雾中的患者的呼吸道中过量吸食 电子烟。这项研究建议的中心假设是nAChRs在 传导反射启动内源性刺激物作用于迷走神经亚群，并调节 呼吸道防御性反射既有外周的，也有中枢的。我们还假设， 与哮喘和慢性阻塞性肺疾病相关的慢性粘膜刺激以及吸烟会破坏nAChRs。 本研究旨在：1)确定与nAChR相关的迷走传入神经亚型。 阻塞性肺疾病的依赖性加重和涉及的nAChR亚型；2a)确定 NAChR依赖咳嗽和其他呼吸道防御反射的转导机制 周围神经末梢和中央选择性地位于神经脊C-纤维的终末部位 通过nAChR激活刺激；2b)一旦nAChR依赖反射的机制建立 在健康动物中，我们将评估慢性尼古丁后转导机制的变化 在过敏原诱导的咳嗽过敏期间给药和治疗；以及3)建立在我们耐人寻味的最近 发现α7nAChR亚型依赖中枢作用部位抑制诱发咳嗽，我们将 确定nAChR激活对呼吸道防御反射的中枢影响，以及这些中枢调节是如何 长期服用尼古丁和咳嗽过敏时，通路会发生变化。对于所有这些 我们将利用我们实验室独有的技术，包括单细胞记录和 NAChR占用的分子途径、反射生理记录和活体成像。我们 预期这些拟议研究的结果将揭示nAChRs在 慢性呼吸道和肺部疾病患者呼吸道粘膜刺激的转导。

The symptoms of obstructive lung diseases, which include airways hyperresponsiveness, reversible airways obstruction, chest tightness, dyspnea, mucus hypersecretion and cough, are in large part the result of an excessive and/ or inappropriate activation of the vagal afferent nerves innervating the airways and lungs. Understanding the mechanisms by which these sensory nerves are activated in health and disease and the reflexes and sensations evoked as a consequence of their activation have been longstanding goals of the research carried out in our laboratories. Visceral afferent nerves often rely on specialized chemosensory signaling mechanisms at their nerve terminals to transduce mucosal irritation. We recently described a chemosensory transduction pathway in the airways mucosa that relies on the transmitter acetylcholine and the nicotinic subclass of acetylcholine receptors (nAChRs) to initiate changes in breathing pattern in response to mucosal irritation. The involvement of nAChRs is noteworthy, as their activity is inappropriately and excessively recruited in the airways of patients exposed to cigarette smoke or the nicotine-containing vapors of eCigarettes. The central hypothesis of this research proposal is that nAChRs play essential roles in transducing reflexes initiated endogenous irritants acting on subsets of vagal sensory nerves, and modulate airway defensive reflexes both peripherally and centrally. We also hypothesize that the regulatory functions of nAChRs are corrupted by chronic mucosal irritation associated with asthma and COPD, and by smoking. Studies proposed herein aim to: 1) characterize the vagal afferent nerve subtypes responsible for nAChR- dependent exacerbations of obstructive lung diseases and the nAChR subtypes involved; 2a) determine the transduction mechanisms for nAChR-dependent coughing and other airway defensive reflexes both at the peripheral nerve terminals and centrally at the termination sites of the neural crest C-fibers that are selectively stimulated through nAChR activation; 2b) once the mechanisms for nAChR-dependent reflexes are established in healthy animals, we will evaluate changes in transduction mechanisms following chronic nicotine administration and during allergen-induced cough hypersensitivity; and 3) building upon our intriguing recent discovery of α7 nAChR subtype dependent inhibition of evoked coughing through central sites of action, we will determine the CNS effects of nAChR activation on airway defensive reflexes, and how these central regulatory pathways are altered by chronic nicotine administration and during cough hypersensitivity. For all of these studies, we will utilize techniques that are unique to our laboratories, including single cell recording and molecular approaches, reflex physiological recordings and in vivo imaging of nAChR occupancy. We anticipate that the results of these proposed studies will reveal the novel and essential roles of nAChRs in transducing mucosal irritation in the airways of patients with chronic diseases of the airways and lungs.