Role of TRPV1 in asthma exacerbation

TRPV1 在哮喘恶化中的作用

• 批准号: 9083578
• 负责人: LU-YUAN LEE
• 金额: $ 38.12万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-15 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9083578
• 关键词: Advanced Development; Afferent Neurons; Air; Allergens; Allergic inflammation; Animal Model; Asthma; Breathing; Bronchial Provocation Tests; Bronchial Spasm; Bronchoconstriction; C Fiber; Cations; Chronic; Coughing; Data; Development; Devices; Disease; Exhibits; Extrinsic asthma; Heating; Hyperventilation; Inflammation; Inflammation Mediators; Inflammatory; Institutional Review Boards; Ion Channel; Ipratropium; Irritants; Kentucky; Laboratories; Lead; Ligands; Lung; Measures; Mediating; Membrane; Mucous Membrane; Names; Neurons; Patients; Persons; Physiological; Pilot Projects; Play; Property; Protocols documentation; Rattus; Reaction; Reflex action; Reporting; Research; Research Personnel; Respiratory Signs and Symptoms; Respiratory System; Respiratory tract structure; Risk; Role; Sensory; Sensory Nerve Endings; Series; Symptoms; Technology; Teleconferences; Temperature; Testing; Tissues; Training; Universities; Vanilloid; Wisconsin; afferent nerve; airway hyperresponsiveness; allergic airway inflammation; asthmatic; asthmatic airway; asthmatic patient; cholinergic; clinically relevant; constriction; defense response; design; disabling symptom; experience; human subject; insight; interest; irritation; novel; novel therapeutic intervention; prevent; public health relevance; receptor; response; sensor; translational study

 DESCRIPTION (provided by applicant): Inflammatory reaction is known to lead to an increase in tissue temperature, but whether airway tissue temperature increases during asthma exacerbation is not yet known. Transient receptor potential vanilloid type 1 receptor (TRPV1), a ligand gated non-selective cation channel with a distinct sensitivity to heat, is selectively and abundantly expressed in vagal bronchopulmonary C-fiber sensory nerves. A series of studies carried out in our lab have established the first evidence that an increase in temperature within the normal physiological range can activate and sensitize these TRPV1-expressing sensory neurons innervating the lung and airways; activation of these C-fiber afferents can elicit reflex bronchoconstriction, cough and other airway defense responses. Indeed, our recent study has demonstrated that an increase in airway temperature by hyperventilating humidified hot air triggered cough and bronchoconstriction in patients with mild and stable asthma, but not in healthy subjects. The airway constriction was mediated through cholinergic reflex because it was completely prevented by pretreatment with ipratropium. The accompanying airway irritation and coughing further suggested an involvement of airway sensory nerves, presumable TRPV1-expressing C-fiber afferents. In the light of these novel findings, this proposed study aims to tes the following hypotheses: 1) in patients with allergic asthma, the airway tissue temperature is elevated locally in the region when the inflammatory reaction is evoked by a segmental bronco-provocation with allergen. 2) Both the thermal sensitivity of these neurons and the expression of TRPV1 at the sensory nerve terminals are enhanced by chronic airway allergic inflammation. Thus, a slight increase in local tissue temperature can lower the activation thresholds and enhance the sensitivity of TRPV1-expressing C-fiber sensory nerves in the airways of asthmatics. The synergistic effects of these factors may play a major part in the development of the airway hypersensitivity during chronic inflammation. This translational study will be performed in both asthmatic patients and in an animal model of allergic asthma. Results obtained from these studies should provide novel insights into the involvement of TRPV1 in the pathogenic mechanisms of airway hypersensitivity, and help to uncover the mechanisms underlying the debilitating symptoms associated with airway inflammatory diseases.

 描述（由适用提供）：已知炎症反应会导致组织温度升高，但是在哮喘加剧期间气道组织温度是否升高。瞬态受体电位香草型1型受体（TRPV1），一种对热的配体门控的非选择性阳离子通道，在迷走神经支气管肺C纤维感觉神经中选择性地表达。在我们的实验室中进行的一系列研究确定了第一个证据，表明正常生理范围内温度的升高可以激活和敏感这些表达TRPV1的感觉神经元，从而支配肺和气道。这些C纤维传入的激活可以引起反射支气管收缩，咳嗽和其他气道防御反应。确实，我们最近的研究表明，通过过度换气的热空气诱发了轻度和稳定稳定的哮喘患者，但在健康受试者中却没有引发咳嗽和支气管收缩来升高。气道收缩是通过胆碱能反射介导的，因为它是通过用ipratropium预处理的。参与的气道刺激和咳嗽进一步提出了气道感觉神经的参与，可能表达TRPV1的C纤维传统。鉴于这些新发现的结果，这项提出的研究旨在提出以下假设：1）在过敏性哮喘患者中，当炎症反应通过与过敏蛋白的节段野马促进引起炎症反应时，气道组织温度在该地区局部升高。 2）这些神经元的热敏感性和在感觉神经末端的TRPV1的表达都通过慢性气道过敏性注射增强。这一点，局部组织温度的略有升高可以降低激活阈值，并提高哮喘患者气道中表达TRPV1的C纤维感觉神经的敏感性。这些因素的协同作用可能在慢性感染期间气道超敏反应的发展中起主要作用。这项翻译研究将在哮喘患者和过敏性哮喘的动物模型中进行。从这些研究中获得的结果应为TRPV1参与气道超敏反应的致病机制提供新的见解，并有助于发现与气道炎症性疾病相关的令人衰弱的症状的机制。