Mitochondrial reactive oxygen species induce airway sensory nerve activity

线粒体活性氧诱导气道感觉神经活动

• 批准号: 8562734
• 负责人: Thomas Edward Taylor-Clark
• 金额: $ 34.66万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8562734
• 关键词: Action Potentials; Allergic inflammation; Ankyrins; Asthma; Biochemical; Bladder; Bronchial Spasm; C Fiber; Cell Nucleus; Chronic; Chronic Obstructive Airway Disease; Coughing; Data; Development; Disease; Dyspnea; Electron Transport; Extrinsic asthma; Gastrointestinal tract structure; Goals; Health; Health Care Costs; Heart; Human; Hyperreflexia; In Situ; Inflammation; Inflammatory; Knowledge; Lead; Link; Lung; Lung Inflammation; Mediating; Mission; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Mucous body substance; Mus; Nerve; Neurobiology; Neurons; Nociception; Organelles; Outcome; Ovalbumin; Oxidation-Reduction; Oxidative Stress; Physiology; Placebos; Process; Production; Protein Kinase C; Public Health; Reactive Oxygen Species; Reflex action; Research; Reticulum; Role; Sensory; Signal Pathway; Signal Transduction; Sodium; Source; Stimulus; Structure; Symptoms; Techniques; Testing; Time; Viral; Visceral; Work; afferent nerve; base; cost; in vivo; innovation; neuronal cell body; neuronal excitability; new therapeutic target; novel; novel therapeutics; public health relevance; receptor; response; voltage

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.

描述（由申请方提供）：在理解气道局部炎症如何使迷走神经感觉C纤维功能发生改变，导致气道疾病（包括哮喘、病毒性急性发作和COPD）中过度和慢性咳嗽、呼吸困难、粘液分泌和支气管痉挛方面存在根本性差距。因此，没有比安慰剂更有效地减少这些衰弱性神经元反应的治疗方法。气道中的C纤维末端密集地填充有线粒体。此外，炎症信号传导导致活性氧（ROS）从线粒体电子传递链产生。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（i）C-纤维激活和（ii）C-纤维兴奋性增加（过度兴奋）。核心假设是感觉末梢线粒体作为一种整合的转导机制发挥作用，将炎症信号转化为神经元内ROS，从而有效地增加电活动。这一假设是创新的，因为它将首次将神经末梢线粒体确定为神经元凋亡的关键启动者。 气道疾病中的过度C纤维相关症状。本研究的贡献预计将是一个完整的理解的机制，参与激活和过度兴奋的气道C-纤维线粒体调制后，其贡献炎症诱导的反射亢进体内。基于强有力的初步数据，该假设将通过追求三个具体目标来检验：（1）确定线粒体电子传递链的调节激活气道C纤维的机制。据推测，这种激活是依赖于瞬时受体电位锚蛋白1（TRPA 1）通道激活的神经源性活性氧。(2)确定线粒体电子传递链调节后气道C纤维过度兴奋的潜在机制。据推测，这种过度兴奋是通过ROS介导的PKC调节电压门控Na+通道。(3)在过敏性哮喘的小鼠卵清蛋白模型中确定气道感觉神经末梢中氧化应激对体内反射亢进的贡献。假设肺中的过敏性炎症由于气道感觉神经末梢中的线粒体ROS产生而引起过度气道反射。这项研究意义重大，因为它是理解炎症与咳嗽、呼吸困难、分泌过多和支气管痉挛等衰弱性神经元反应之间因果关系的绝对必要条件。线粒体代表了多个平行的炎症信号传导途径和异常感觉神经活动之间的潜在瓶颈。该方法是创新的，因为机制将直接在C-纤维终端使用新的电生理和隔离技术进行研究。因此，这些研究将对我们理解炎症期间异常C纤维功能产生变革性影响，并有望确定用于治疗炎症性气道疾病（如哮喘、病毒性急性发作和COPD）的新治疗靶点。