MUCOCILIARY TRANSPORT--INHIBITORY NEURAL REGULATION

粘膜纤毛运输——抑制性神经调节

• 批准号: 6489859
• 负责人: Donovan B Yeates
• 金额: $ 23.81万
• 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/6489859
• 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)： 我们已经发现了新的抑制性神经通路，它们相互作用 兴奋性神经反射对气管、支气管壁粘液纤毛的调节 功能。我们认为受损的气管、支气管壁粘液纤毛 清除是由主要的抑制性反射激活引起的。 这些神经反射，由氨和二氧化硫激活，调节 粘液纤毛运输系统的组成部分，即纤毛搏动 频率和呼吸道分泌量。吸入酸性刺激物， 如二氧化硫，主要激活抑制抑制的神经通路 纤毛活动通过引起高度粘稠的粘液和大的 放松时间。这些反应一致地导致了缺陷 粘液纤毛运输和粘液在呼吸道中的堆积。至 描述了所提出的抑制性神经通路及其在 调节粘液纤毛运输系统，我们会用一只犬科动物 迷走神经干皮肤外化模型 管子。气管粘液速度、TMV和支气管粘液纤毛 清除，BMC，将使用无线电气雾剂技术测量。气道口 分泌物输出，ASO将使用分泌物收集来测量 气管插管及其流变性的测定 旋转磁微流变仪。纤毛搏动频率、CBF、Will 用外差激光光散射法在气管内测量。二氧化硫 将被用来激活抑制反射。我们将演示两个 抑制反射，一种穿越迷走神经干和 另一个是交感神经节。我们将确定占优势的 神经节和传出抑制性和兴奋性神经递质 通过将迷走神经干冷却到0摄氏度，并明智地 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。我们将展示两者之间的因果关系 所提出的抑制性反射的神经传递，以及 抑制脑血流、ASO和粘液粘度变化及松弛 时间到了。通过推导出呼吸道液体深度、AFD和 粘液运输距离/纤毛搏动，我们将显示 CBF和/或气道分泌输出量和黏度的变化和 松弛时间导致粘液纤毛运输受损。穿过 正常粘液纤毛功能的神经调节机制 以及这一法规中潜在的扰动机制 对于异常的粘液纤毛清除，我们将确定新的潜力 三病致病机制的探讨 支气管炎、哮喘、囊性纤维化等呼吸道疾病。也是 治疗干预的可能地点和代理将是 确认身份。