Mitochondrial reactive oxygen species induce airway sensory nerve activity

描述（由申请人提供）：在了解气道局部炎症如何扭曲迷走神经感觉c -纤维功能，导致过度和慢性咳嗽，呼吸困难，粘液分泌和支气管痉挛的气道疾病，包括哮喘，病毒加重和COPD中，存在根本性的空白。因此，在减少这些衰弱的神经元反应方面，没有比安慰剂更有效的治疗方法。气道内的c -纤维末端密集地包裹着线粒体。此外，炎症信号导致线粒体电子传递链产生活性氧（ROS）。初步数据表明，神经末梢线粒体电子传递链的调节导致ros依赖性的(i) c -纤维激活和（ii） c -纤维兴奋性增加（高兴奋性）。核心假设是感觉末端线粒体作为一种综合转导机制，将炎症信号转化为神经元内活性氧，从而有效地增加电活动。这一假说是创新的，因为它将首次确定神经末梢线粒体是神经衰弱的关键启动者

DESCRIPTION (provided by applicant): There is a fundamental gap in understanding how local inflammation in the airways perverts vagal sensory C-fiber function, resulting in excessive and chronic cough, dyspnea, mucus secretion and bronchospasm in airway diseases including asthma, viral exacerbations and COPD. Consequently, there are no treatments available that are more effective than placebo at reducing these debilitating neuronal responses. C-fiber terminals in the airways are densely packed with mitochondria. Furthermore inflammatory signaling causes reactive oxygen species (ROS) production from the mitochondrial electron transport chain. Preliminary data indicates that modulation of the nerve terminal mitochondrial electron transport chain causes ROS-dependent (i) C-fiber activation and (ii) increased C-fiber excitability (hyperexcitability). The central hypothesis is that sensory terminal mitochondria function as an integrated transduction mechanism that converts inflammatory signaling into intraneuronal ROS, which potently increase electrical activity. The hypothesis is innovative because it will, for the first time, identify nerve terminal mitochondria as critical initiators of excessive C-fiber- associated symptoms in airway disease. The contribution of this study is expected to be a complete understanding of the mechanisms involved in the activation and hyperexcitability of airway C-fibers following mitochondrial modulation and its contribution to inflammation-induced hyperreflexia in vivo. Based on strong preliminary data, the hypothesis will be tested by pursing three specific aims: (1) Determine the mechanism by which modulation of the mitochondrial electron transport chain activates airway C-fibers. It is hypothesized that this activation is dependent on transient receptor potential ankyrin 1 (TRPA1) channel activation by mitochondrially-derived ROS. (2) Identify the mechanism underlying the hyperexcitability of airway C-fibers following modulation of the mitochondrial electron transport chain. It is hypothesized that this hyperexcitability is via ROS-mediated PKC¿ modulation of voltage-gated Na+ channels. (3) Determine the contribution of oxidative stress in airway sensory nerve terminals to in vivo hyperreflexia in a murine ovalbumin model of allergic asthma. It is hypothesized that allergic inflammation in the lung causes excessive airway reflexes due to mitochondrial ROS production in airway sensory nerve terminals. This study is significant because it is an absolute requirement for understanding the causal link between inflammation and the debilitating neuronal responses of cough, dyspnea, hypersecretion and bronchospasm. Mitochondria represent a potential bottleneck between multiple parallel inflammatory signaling pathways and aberrant sensory nerve activity. The approach is innovative because mechanisms will be studied directly at the C-fiber terminal using novel electrophysiological and isolation techniques. Thus these studies will have a transformative impact upon our understanding of aberrant C-fiber function during inflammation, and are expected to identify novel therapeutic targets for the treatment of inflammatory airway diseases such as asthma, viral exacerbations and COPD.