MUCOCILIARY TRANSPORT--INHIBITORY NEURAL REGULATION

粘膜纤毛运输——抑制性神经调节

• 批准号: 2757889
• 负责人: Donovan B Yeates
• 金额: $ 22.17万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-15 至 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2757889
• 关键词: C fiber; active transport; biological fluid transport; bronchial mucus; dogs; hexamethonium compound; homeostasis; irritation /irritant; neural inhibition; neuropharmacology; neuroregulation; pulmonary respiration; pulmonary stretch receptors; respiratory airway clearance; respiratory epithelium; respiratory pharmacology; respiratory reflex; secretion; stretch reflex; sulfur oxides; vagus nerve

DESCRIPTION (Applicant's abstract): We have discovered novel inhibitory neural pathways which interact with excitatory neural reflexes to regulate tracheobronchial mucociliary function. We propose that impaired tracheobronchial mucociliary clearance results from activation of predominantly inhibitory reflexes. These neural reflexes, activated by ammonia and SO2 regulate the components of the mucociliary transport system, namely ciliary beat frequency and airway secretory output. Inhalation of acidic irritants, such as SO2, primarily activate inhibitory neural pathways that suppress ciliary activity yet via cause a highly viscous mucus with an large relaxation time. In concert, these responses result in defective mucociliary transport and mucus accumulation in the airways. To delineate the proposed inhibitory neural pathways and their roles in the regulation of the mucociliary transport system, we will use a canine model in which the vagosympathetic trunks are exteriorized in skin tubes. Tracheal mucus velocity, TMV, and bronchial mucociliary clearance, BMC, will be measured using radioaerosol techniques. Airway secretory output, ASO, will be measured using a secretion collecting endotracheal tube and the rheological properties measured using rotational magnetic microrheometry. Ciliary beat frequency, CBF, will be measured in the trachea using heterodyne laser light scattering. SO2 will be used to activate the inhibitory reflex. We will demonstrate two inhibitory reflexes, one that traverses the vagosympathetic trunks and the other the sympathetic ganglia. We will identify the dominant ganglionic and efferent inhibitory and excitatory neural transmitters by cooling the vagosympathetic trunks to 0 degrees C, and by judicious local administration of general and specific inhibitors of ganglionic and receptor function. We will show the causal relationships between the neural transmission of the proposed inhibitory reflexes, and the suppression of CBF, changes in ASO and mucus viscosity and relaxation time. Through the derivation of the airway fluid depth, AFD, and the distance mucus is transported/ciliary beat, we will show the extent to which changes in CBF and/or airway secretory output and viscosity and relaxation time contribute to impaired mucociliary transport. Through the elucidation of the neural regulation of normal mucociliary function and the mechanisms underlying perturbations in this regulation that lead to abnormal mucociliary clearance, we will ascertain new potential pathogenic mechanisms contributing to the pathogenesis of diseases of the airways such as bronchitis, asthma and cystic fibrosis. Also possible sites and agents for therapeutic intervention will be identified.

描述（申请人摘要）： 我们发现了新的抑制性神经通路， 调节气管支气管粘膜纤毛的兴奋性神经反射 功能我们认为受损的气管支气管粘膜纤毛 清除是由主要抑制性反射的激活引起的。 这些被氨和SO2激活的神经反射， 粘膜纤毛运输系统的组成部分，即纤毛搏动 频率和气道分泌输出。吸入酸性刺激物， 例如SO2，主要激活抑制性神经通路， 纤毛活动尚未导致具有大量粘液的高度粘稠粘液 松弛时间这些反应一致地导致有缺陷的 粘液纤毛运输和气道中的粘液积聚。到 描述拟议的抑制性神经通路及其在 调节粘液纤毛运输系统，我们将使用犬 迷走交感神经干外置于皮肤的模型 管.气管粘液流速、TMV和支气管粘膜纤毛 将使用放射性气溶胶技术测量清除率BMC。气道 将使用分泌物收集器测量分泌输出阿索。 气管内插管和流变学特性测量使用 旋转磁显微流变学睫状体搏动频率，CBF，将 使用外差激光散射在气管中测量。SO2 会被用来激活抑制反射我们将展示两个 抑制性反射，一个穿越迷走交感神经干， 另一个是交感神经节。我们会找出 神经节和传出抑制性和兴奋性神经递质 通过将迷走交感神经干冷却到0摄氏度， 神经节细胞的一般和特异性抑制剂的局部给药 和受体功能。我们将展示 神经传输的建议抑制反射，和 CBF抑制、阿索和粘液粘度和松弛的变化 时间通过推导气道液体深度、AFD和 距离粘液运输/纤毛跳动，我们将显示的程度， 其改变CBF和/或气道分泌输出和粘度， 松弛时间导致粘膜纤毛运输受损。通过 正常粘膜纤毛功能的神经调节的阐明 以及这种调节机制的潜在扰动， 异常的粘膜纤毛清除，我们将确定新的潜力， 致病机制有助于疾病的发病机制， 如支气管炎、哮喘和囊性纤维化。也 治疗干预的可能部位和药物将 鉴定