Chemokine Modulation of Airway Vagal Sensory Nerves

描述（由申请人提供）：过敏性气道疾病的症状和病理生理学涉及呼吸神经调节的扰动。气道中迷走感觉神经的一个子集，即无髓鞘C纤维，将关于吸入的潜在有害或有毒物质的信息传递给中枢神经系统。支气管平滑肌C纤维的激活导致防御性反射的启动，如咳嗽冲动、呼吸困难和胆碱能输出增加，导致粘液分泌和支气管收缩，以帮助清除气道中的有害物质。然而，在气道中的过敏性炎症期间，支气管肺纤维C-纤维的活性变得增强或致敏，这可导致过敏性气道疾病的症状，例如持续干咳、支气管痉挛、粘液分泌和呼吸困难。支气管肺泡C纤维的兴奋性受到炎症介质的强烈影响，然而，对过敏性炎症期间支气管肺泡C纤维致敏的机制知之甚少。该提案的总体目的是确定在过敏性和病毒性气道疾病期间强烈上调的炎性介质的作用，“在活化时调节，正常T细胞表达和分泌”（RANTES），也称为CC趋化因子配体-5（CCL 5），对支气管肺炎C纤维的兴奋性具有影响。利用基因表达和免疫组织化学研究，我们将描述肺特异性迷走神经感觉神经元上发现的CCL 5的特异性受体。本研究采用电生理方法，观察CCL 5对肺特异性迷走神经感觉神经元及其周围神经末梢兴奋性的影响。我们假设，CCL 5的受体被发现在支气管肺纤维和CCL 5激活这些受体将激发和敏化支气管肺纤维的反应。来自这些研究的总体结果将涉及CCL 5，其不仅作为在过敏原和病毒诱导的气道炎症期间募集白细胞的趋化因子，而且作为在气道炎症期间通过迷走支气管平滑肌C-纤维活性的敏化募集神经系统的关键分子。 公共卫生相关性：这些研究将为过敏性和病毒性气道疾病的病理生理学提供新的见解。这些结果可能会对这些复杂、相互关联的疾病的未来治疗发展产生直接影响。

DESCRIPTION (provided by applicant): The symptoms and pathophysiology of allergic airway disease involve perturbations in the neural regulation of respiration. A subset of vagal sensory nerves in the airways, the unmyelinated C-fibers, relay information to central nervous system regarding inhaled substances that are potentially harmful or noxious. Activation of bronchopulmonary C-fibers results in the initiation of defensive reflexes such as urge to cough, dyspnea, and increased cholinergic output leading to mucus secretion and bronchoconstriction to aid in the clearance of harmful substances from the airways. During allergic inflammation in the airways, however, the activity of bronchopulmonary C-fibers becomes enhanced or sensitized which can result in the symptoms of allergic airway disease such the dry incessant cough, bronchospasm, mucus secretion, and dyspnea. The excitability of bronchopulmonary C-fibers is strongly influenced by inflammatory mediators; however, little is known about the mechanism underlying bronchopulmonary C-fiber sensitization during allergic inflammation. The overall aim of this proposal is to determine the role of an inflammatory mediator strongly upregulated during both allergic and viral airway disease, "regulated upon activation, normal T-cell expressed and secreted" (RANTES), also known as CC chemokine ligand-5 (CCL5), has on the excitability of bronchopulmonary C-fibers. Using gene expression and immunohistochemical studies, we will characterize the specific receptors for CCL5 found on lung-specific vagal sensory neurons. Using electrophysiological methods, we will determine the effect of CCL5 on the excitability of lung-specific vagal sensory neurons and their of peripheral nerve terminals. We hypothesize that receptors for CCL5 are found on bronchopulmonary C-fibers and activation of these receptors by CCL5 will both excite and sensitize the responses of bronchopulmonary C-fibers. The overall results from these studies will implicate CCL5, not only as a chemokine recruiting leukocytes during allergen and viral- induced airway inflammation, but also as key molecule in the recruitment of nervous system during airway inflammation through sensitization of vagal bronchopulmonary C-fiber activity. PUBLIC HEALTH RELEVANCE: These studies will provide novel insight into the pathophysiology of allergic and viral airway diseases. Results may have a direct impact on the future development of treatments for these complex, interrelated diseases.