Chemokine Modulation of Airway Vagal Sensory Nerves

描述(申请人提供)：过敏性呼吸道疾病的症状和病理生理学涉及呼吸神经调节的扰动。呼吸道中迷走感觉神经的一个子集，即无髓C纤维，向中枢神经系统传递有关吸入的潜在有害或有害物质的信息。支气管肺C纤维的激活导致防御反射的启动，如咳嗽、呼吸困难和胆碱能输出的增加，导致粘液分泌和支气管收缩，以帮助清除呼吸道中的有害物质。然而，在呼吸道变态反应性炎症期间，支气管肺C纤维的活性增强或敏化，可导致过敏性呼吸道疾病的症状，如干咳、支气管痉挛、粘液分泌和呼吸困难。C纤维的兴奋性受炎症介质的强烈影响，然而，在过敏性炎症过程中，C纤维敏化的机制知之甚少。这项建议的总体目的是确定在过敏性和病毒性呼吸道疾病期间强烈上调的一种炎症介质(RANTES)(RANTES)，也称为CC趋化因子配体-5(CCL5)，在支气管肺C纤维的兴奋性中所起的作用。利用基因表达和免疫组织化学研究，我们将确定肺特异性迷走感觉神经元上发现的CCL5的特异性受体。利用电生理学方法，我们将确定CCL5对肺特异性迷走感觉神经元及其周围神经末梢兴奋性的影响。我们推测CCL5受体存在于支气管肺C纤维上，CCL5激活这些受体将刺激和敏化支气管肺C纤维的反应。这些研究的总体结果表明，CCL5不仅在过敏原和病毒诱导的呼吸道炎症过程中作为一种趋化因子招募白细胞，而且还通过敏化迷走神经支气管肺C纤维的活性在呼吸道炎症过程中作为关键分子招募神经系统。 公共卫生相关性：这些研究将为过敏性和病毒性呼吸道疾病的病理生理学提供新的见解。结果可能会对这些复杂、相互关联的疾病的治疗方法的未来发展产生直接影响。

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.