Cholinergic mechanisms involved in transduction of airway defensive reflexes

胆碱能机制参与气道防御反射的转导

• 批准号: 10000962
• 负责人: BRENDAN J CANNING
• 金额: $ 51.72万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10000962
• 关键词: Acetylcholine; Action Potentials; Acute; Address; Afferent Neurons; Agonist; Airway Disease; Allergens; Allergic inflammation; Anatomy; Animals; Antitussive Agents; Applications Grants; Asthma; Brain Stem; Breathing; Bronchial Spasm; C Fiber; Cavia; Cell Nucleus; Cells; Cellular Structures; Chest; Cholinergic Receptors; Chronic; Chronic Disease; Chronic Obstructive Airway Disease; Coughing; Disease; Dyspnea; Electronic cigarette; Enzymes; Epithelial Cells; Esthesia; Fiber; Gene Expression; Gene Silencing; Goals; Health; Homeostasis; Human; Human Volunteers; Hypersensitivity; Imaging Techniques; Immune; Immune response; Immunohistochemistry; Infection; Inflammatory; Institution; Irritants; Laboratories; Lung; Lung diseases; Maps; Methods; Microinjections; Modeling; Molecular; Mucous Membrane; Nerve; Neural Crest; Neuromuscular Junction; Neurons; Nicotine; Nicotinic Receptors; Nociception; Obstructive Lung Diseases; Organ; Pathway interactions; Patients; Pattern; Peripheral; Peripheral Nerves; Peripheral Nervous System; Physiological; Physiological Processes; Play; Positron-Emission Tomography; Process; Receptor Activation; Reflex action; Regulation; Regulatory Pathway; Research; Research Proposals; Role; Sensory; Signal Transduction; Site; Sleep; Smoker; Smoking; Stimulus; Structure of parasympathetic ganglion; Sympathetic Ganglia; Symptoms; Synapses; Synaptic Transmission; System; Techniques; Tissues; Transgenic Organisms; Up-Regulation; Visceral; afferent nerve; airway epithelium; airway hyperresponsiveness; airway obstruction; autonomic reflex; cholinergic; cholinergic neuron; cholinergic synapse; exposure to cigarette smoke; in vivo imaging; irritation; mucus hypersecretion; nicotine vapor; novel; patch clamp; receptor; recruit; respiratory; respiratory reflex; response; sensory system; visceral afferent nerve

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.

阻塞性肺疾病的症状包括气道高反应性、可逆性气道 阻塞、胸闷、呼吸困难、粘液分泌过多和咳嗽，在很大程度上是由于 支配气道和肺的迷走传入神经的过度和/或不适当的激活。 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 在我们的实验室进行的研究。内脏传入神经通常依赖于专门的化学感觉 在其神经末梢的信号传导机制，以刺激粘膜刺激。我们最近描述了一个 呼吸道粘膜中依赖于递质乙酰胆碱的化学感受性转导途径， 乙酰胆碱受体（nAChRs）的烟碱亚类，以响应于 粘膜刺激。nAChR的参与是值得注意的，因为它们的活性是不适当的， 在暴露于香烟烟雾或含尼古丁蒸汽的患者的气道中过度招募， 电子烟这项研究建议的中心假设是，nAChR在以下方面发挥重要作用： 转导反射启动内源性刺激物作用于迷走感觉神经的亚群，并调节 呼吸道防御反射在外周和中枢。我们还假设， nAChR被与哮喘和COPD相关的慢性粘膜刺激以及吸烟破坏。 本文提出的研究旨在：1）表征负责nAChR的迷走传入神经亚型。 阻塞性肺疾病的依赖性加重和所涉及的nAChR亚型; 2a）确定 nAChR依赖性咳嗽和其他气道防御反射的转导机制， 外周神经末梢和中枢神经嵴C-纤维的终止位点， 通过nAChR激活刺激; 2b）一旦建立了nAChR依赖性反射的机制 在健康动物中，我们将评估慢性尼古丁摄入后转导机制的变化， 给药和过敏原诱导的咳嗽超敏反应期间;和3）建立在我们最近有趣的 发现α7 nAChR亚型依赖性抑制诱发咳嗽通过中枢作用位点，我们将 确定nAChR激活对气道防御反射的CNS影响，以及这些中枢调节 途径被慢性尼古丁给药和咳嗽过敏期间改变。对于所有这些 研究，我们将利用我们实验室独有的技术，包括单细胞记录和 分子方法、反射生理记录和nAChR占用的体内成像。我们 预计这些拟议研究的结果将揭示nAChRs在以下方面的新颖和重要作用： 在患有气道和肺部慢性疾病的患者的气道中转导粘膜刺激。