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: 9061125
• 负责人: Thomas Edward Taylor-Clark
• 金额: $ 0.33万
• 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/9061125
• 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（由申请人提供）：对于气道局部炎症如何破坏迷走神经感觉 C 纤维功能，导致气道疾病（包括哮喘、病毒性加重和慢性阻塞性肺病）过度和慢性咳嗽、呼吸困难、粘液分泌和支气管痉挛的理解存在根本性差距。因此，在减少这些使人衰弱的神经元反应方面，没有比安慰剂更有效的治疗方法。气道中的 C 纤维末端密集地充满线粒体。此外，炎症信号传导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会导致 ROS 依赖性 (i) C 纤维激活和 (ii) C 纤维兴奋性（过度兴奋性）增加。中心假设是感觉末端线粒体作为一种整合的转导机制发挥作用，将炎症信号转变成神经元内的 ROS，从而有效地增加电活动。该假说具有创新性，因为它将首次将神经末梢线粒体确定为神经末梢线粒体的关键启动子。 气道疾病中过多的 C 纤维相关症状。这项研究的贡献预计将是全面了解线粒体调节后气道 C 纤维激活和过度兴奋的机制及其对体内炎症诱导的反射亢进的贡献。基于强有力的初步数据，该假设将通过三个具体目标进行检验：（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，这种激活依赖于线粒体衍生的 ROS 激活瞬时受体电位锚蛋白 1 (TRPA1) 通道。 (2) 确定线粒体电子传递链调节后气道 C 纤维过度兴奋的机制。据推测，这种过度兴奋是通过 ROS 介导的 PKC™ 对电压门控 Na+ 通道的调节实现的。 (3)确定过敏性哮喘小鼠卵清蛋白模型中气道感觉神经末梢氧化应激对体内反射亢进的贡献。据推测，由于气道感觉神经末梢中线粒体活性氧的产生，肺部过敏性炎症会导致过度的气道反射。这项研究意义重大，因为它是了解炎症与咳嗽、呼吸困难、分泌过多和支气管痉挛等神经元反应衰弱之间的因果关系的绝对必要条件。线粒体代表了多个并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，因为将使用新颖的电生理学和隔离技术直接在 C 纤维末端研究机制。因此，这些研究将对我们对炎症期间异常 C 纤维功能的理解产生变革性影响，并有望确定治疗哮喘、病毒性加重和慢性阻塞性肺病等炎症性气道疾病的新治疗靶点。