Role of TRPV1 in Airway Hypersensitivity Induced by Inflammation

TRPV1 在炎症引起的气道过敏中的作用

基本信息

批准号：
7699013
负责人：
LU-YUAN LEE
金额：
$ 34.61万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7699013
关键词：
Acute Afferent Neurons Allergens Allergic Animal Model Asthma Breathing Bronchitis Bronchoconstriction C Fiber Capsaicin Cations Chronic Coughing Critiques Development Disease Dyspnea Exhibits Fever Human Hypersensitivity Inflammation Inflammatory Investigation Ion Channel Irritants Lung Mediating Mediator of activation protein Neurons Ovalbumin Pathogenesis Patients Physiological Play Rattus norvegicus Reaction Reporting Research Research Project Grants Research Proposals Respiratory System Respiratory tract structure Role Sensory Study Section Symptoms TRPV channel Temperature Testing Therapeutic Transducers Tumor Necrosis Factor-alpha Tumor Necrosis Factors Vanilloid afferent nerve airway inflammation allergic airway inflammation cytokine design insight irritation novel public health relevance receptor research study response selective expression sensor

项目摘要

DESCRIPTION (provided by applicant): Airway hypersensitivity, characterized by exaggerated sensory and reflexogenic responses to inhaled irritants, is a prominent pathophysiological feature of various airway inflammatory diseases (e.g., asthma, bronchitis, etc). Increasing and compelling evidence indicates that vagal bronchopulmonary C-fibers play a pivotal role in the manifestation of airway hypersensitivity. Recent investigations further suggest that the TRPV1 receptor, a non-selective cation channel and a polymodal transducer selectively expressed in C-fiber afferents, is likely involved in the airway hypersensitivity generated by airway inflammatory reaction. Indeed, a recent study in our lab has demonstrated that allergen sensitization-induced airway inflammation markedly enhanced the sensitivity of pulmonary C-fiber afferents and, more importantly, induced TRPV1 expression in myelinated pulmonary afferents that normally do not exhibit any capsaicin sensitivity. However, the physiological implication and the mechanism underlying the TRPV1 over- expression during airway inflammation are yet not fully understood. In this proposal, a research plan is designed to characterize the role of TRPV1 in the development of airway hypersensitivity when chronic airway inflammation is induced by allergen sensitization. Our hypothesis is that the enhanced airway sensitivity results from a combination of increased expression and excitability of this channel in the vagal bronchopulmonary sensory terminals. We further hypothesize that tumor necrosis factor 1, a pro-inflammatory cytokine and known to be released in the lung during allergic airway inflammation, is an important contributor to the over-expression of TRPV1 in these sensory neurons. Results obtained from these studies should provide important information about the mechanism that up-regulates the expression and excitability of the TRPV1 channel in the airway sensory neurons, and bring a new insight into the pathogenesis and therapeutic strategy for alleviating the airway hypersensitivity caused by allergic airway inflammation. PUBLIC HEALTH RELEVANCE: In airway inflammatory diseases such as asthma and bronchitis, the respiratory tract becomes overly sensitive to inhaled irritants. This research proposal is designed to test our hypothesis that a specific ion channel, namely TRPV1, plays a major role in the exceedingly high excitability of airway sensory nerves caused by allergic inflammation. The results obtained from these studies should bring a new insight into the pathogenesis and therapeutic strategy for alleviating the airway hypersensitivity.

描述（由申请人提供）：气道超敏反应，其特征是对吸入刺激物的感觉和反射生成反应，是各种气道炎症性疾病（例如哮喘，支气管炎等）的重要病理生理特征。增加和引人注目的证据表明，迷走神经支气管肺C纤维在气道超敏反应的表现中起关键作用。最近的研究进一步表明，TRPV1受体，一种非选择性的阳离子通道和在C纤维传统中选择性表达的多峰传感器可能参与气道炎症反应产生的气道超敏反应。确实，我们实验室中的一项研究表明，过敏原诱导的气道炎症显着增强了肺C纤维传入的敏感性，更重要的是，在髓鞘肺传入中诱导的TRPV1表达通常不会表现出任何辣椒素敏感性。但是，气道炎症期间TRPV1过度表达的生理意义和机制尚未完全了解。在该提案中，研究计划旨在表征当过敏原敏化引起慢性气道炎症时，TRPV1在气道高敏性发展中的作用。我们的假设是，增强的气道敏感性是由于该通道在迷走神经肺感觉末端的表达和兴奋性的结合而产生的。我们进一步假设肿瘤坏死因子1是一种促炎性细胞因子，已知在过敏性气道炎症期间在肺中释放，是这些感觉神经元中TRPV1过表达的重要促进者。从这些研究中获得的结果应提供有关在气道感觉神经元中TRPV1通道的表达和兴奋性的机制的重要信息，并为缓解气道超敏性引起的发病机理和治疗策略带来了新的见解。公共卫生相关性：在气道炎症性疾病（如哮喘和支气管炎）中，呼吸道对吸入刺激物变得过于敏感。该研究建议旨在检验我们的假设，即特定的离子通道（即TRPV1）在由过敏性炎症引起的气道感觉神经的极高兴奋性中起主要作用。从这些研究中获得的结果应为减轻气道超敏反应的发病机理和治疗策略带来新的见解。