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（由适用提供）：了解气道中的局部炎症如何使迷走性感觉C纤维功能变化，从而导致过度和慢性咳嗽，呼吸困难，粘液分泌和支气管痉挛，包括哮喘，病毒性恶心和COPD。因此，没有比安慰剂更有效的治疗方法可以减少这些令人衰弱的神经元反应。气道中的C纤维终端被线粒体堆满了。此外，炎症信号传导导致线粒体电子传输链产生活性氧（ROS）。初步数据表明，神经末端线粒体电子传输链的调节会导致ROS依赖性（I）C纤维激活，并且（II）增加C纤维兴奋性（过度兴奋性）。中心假设是感觉末端线粒体充当一种综合转导机制，可将炎症信号转化为鼻内ROS，从而可能增加电活动。该假设具有创新性，因为它将首次将神经终端确定为线粒体作为关键启动者 气道疾病中的C纤维相关症状过多。预计这项研究的贡献将是对线粒体调节后气道C纤维激活和过度兴奋性及其对炎症诱导的体内高反复反射症的贡献的完全理解。基于强大的初步数据，该假设将通过追求三个具体目的来检验：（1）确定线粒体电子传输链的调节的机制激活气道C纤维。假设该激活取决于线粒体衍生的ROS通过线粒体衍生的ROS激活瞬态接收器电位arnkyrin 1（TRPA1）。 （2）确定线粒体电子传输链调节后气道C纤维过度兴奋的机制。假设这种过度兴奋性是通过ROS介导的PKC。电压门控的Na+通道的调节。 （3）确定气道感觉神经终末中氧化物的贡献对过敏性哮喘的鼠卵形蛋白模型中的体内高反射症的贡献。假设肺中的过敏感染会导致气道感觉神经末端的线粒体ROS产生过多的气道反射。这项研究很重要，因为它是理解感染与咳嗽，呼吸困难，过度分泌和支气管痉挛的神经元反应之间的因果关系的绝对要求。线粒体代表了多个平行炎症信号通路和异常感觉神经活动之间的潜在瓶颈。该方法具有创新性，因为将使用新型的电生理学和隔离技术直接研究机制。这些研究将对我们对炎症过程中异常C纤维功能的理解产生变革性的影响，并有望确定用于治疗炎症性气道疾病（例如哮喘，病毒加剧和COPD）的新型治疗靶标。