Counter-Irritation by Menthol: Molecular Targets and Role in Airway Disease

薄荷醇抗刺激：分子靶标及其在气道疾病中的作用

基本信息

批准号：
8402151
负责人：
SVEN-ERIC JORDT
金额：
$ 7.44万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8402151
关键词：
Acrolein Acute Address Aerosols Affect Afferent Neurons Analgesics Asthma Behavioral Biochemical Biological Factors Breathing C Fiber Chemicals Chronic Chronic Obstructive Airway Disease Cigarette Cigarette smoke-induced emphysema Cotinine Coughing Dependence Devices Disease Electronics Exposure to Family Smoking Prevention and Tobacco Control Act Flavoring Food Gene Family Goals Health Hypertension Hypesthesia Image Individual Inflammation Inflammatory Inflammatory Response Inhalation Exposure Ion Channel Irritants Lung Inflammation Lung diseases Malignant neoplasm of lung Marketing Mediating Mentha piperita Menthol Minority Modeling Molecular Molecular Target Mouse Strains Mus Nerve Fibers Neurons Neuropeptides Nicotine Nicotine Dependence Nociception Outcome Physiological Pneumonia Population Process Protein Isoforms Publishing Pulmonary Emphysema Receptor Signaling Regulation Research Respiratory System Role Sensory Serum Smoke Smoker Smoking System TRPA1 Channel Taste Perception Terpenes Testing Therapeutic Time Tobacco Tobacco Industry Tobacco smoke Toxic effect addiction afferent nerve base cigarette smoking insight irritation linalool mouse model public health relevance receptor research study respiratory respiratory reflex response smoke inhalation vapor

项目摘要

DESCRIPTION (provided by applicant): The tobacco industry has added a wide range of chemicals to cigarettes to increase product stability and modify taste and sensory qualities of smoke. While the Family Smoking Prevention and Tobacco Control Act outlawed tobacco flavor additives, menthol was exempt from regulation. Mentholated cigarettes are especially popular with beginning smokers and in minority populations disproportionally affected by COPD, lung cancer and hypertension. Recently, electronic cigarettes, marketed as non-toxic nicotine delivery devices, have become popular tobacco cigarette substitutes. Electronic cigarettes contain large amounts of the same chemical flavor and sensory additives outlawed for use in tobacco cigarettes, including irritating terpenes such as linalool. Our research has shown that menthol, at levels similar or below in smoke of mentholated cigarettes, strongly inhibited the respiratory irritation response to tobacco smoke irritants in mice. Aerosols from electronic cigarettes elicited strong irritation responses in mice, comparable to responses elicited by tobacco cigarette smoke. Physiological experiments showed that menthol and linalool are potent modulators of TRPM8 and TRPA1, two chemosensory ion channels expressed in sensory neurons innervating the respiratory system. We hypothesize that: 1.) Menthol acts as a counterirritant, blocking sensory neuronal responses to inhaled noxious chemicals through interaction with TRPA1 or TRPM8, 2) As a tobacco additive, menthol facilitates smoke inhalation through inhibition of neuronal irritant receptor signalling, thereby accelerating nicotie dependence and lung disease and , 3) the high amounts of chemical additives in electronic cigarettes are added to mimic the sensory impact of tobacco smoke and may cause chronic irritation and inflammatory responses. The studies proposed in this application will use physiological, biochemical, molecular and behavioral approaches to: Aim 1.) Define the roles of TRPA1 and TRPM8 in menthol-induced inhibition of acute respiratory irritation. Aim 2.) Examine the pharmacological effects of menthol and menthol-related compounds on irritant-induced activation of sensory neurons. Aim 3.) Determine the effects of menthol inhalation on smoking-induced lung inflammation and emphysema. Aim 4.) Investigate the sensory and inflammatory effects of electronic cigarette aerosols and their chemical additives. Our proposed research will provide new insights into neuronal mechanisms of airway irritation and remodeling, and define a scientific basis for regulatory efforts targeting menthol and other additives to tobacco and electronic cigarettes.

描述（由申请人提供）：烟草业在卷烟中添加了多种化学品，以提高产品稳定性并改变烟雾的味道和感官品质。虽然《家庭吸烟预防和烟草控制法》禁止烟草香精添加剂，但薄荷醇不受监管。含薄荷醇的卷烟特别受初吸烟者和受慢性阻塞性肺病、肺癌和高血压影响的少数人群的欢迎。最近，作为无毒尼古丁输送装置销售的电子烟已成为流行的烟草替代品。电子烟含有大量与烟草香烟相同的化学香料和感官添加剂，其中包括芳樟醇等刺激性萜烯。我们的研究表明，薄荷醇含量与含薄荷醇的香烟烟雾中的含量相似或更低，可强烈抑制小鼠对烟草烟雾刺激物的呼吸道刺激反应。电子烟的气溶胶在小鼠体内引起强烈的刺激反应，与烟草烟雾引起的反应相当。生理实验表明，薄荷醇和芳樟醇是 TRPM8 和 TRPA1 的有效调节剂，TRPM8 和 TRPA1 是在支配呼吸系统的感觉神经元中表达的两种化学感应离子通道。我们假设：1.) 薄荷醇起到反刺激剂的作用，通过与 TRPA1 或 TRPM8 相互作用，阻断感觉神经元对吸入有毒化学物质的反应，2) 作为烟草添加剂，薄荷醇通过抑制神经元刺激受体信号传导促进烟雾吸入，从而加速尼古丁的产生依赖性和肺部疾病，3）电子烟中添加了大量的化学添加剂，以模仿烟草烟雾的感官影响，并可能导致慢性刺激和炎症反应。本申请中提出的研究将使用生理、生化、分子和行为方法来：目标 1.) 定义 TRPA1 和 TRPM8 在薄荷醇诱导的急性呼吸道刺激抑制中的作用。目标 2.) 检查薄荷醇和薄荷醇相关化合物对刺激物诱导的感觉神经元激活的药理作用。目标 3.) 确定吸入薄荷醇对吸烟引起的肺部炎症和肺气肿的影响。目标 4.) 研究电子烟气雾剂及其化学添加剂的感官和炎症影响。我们提出的研究将为气道刺激和重塑的神经元机制提供新的见解，并为针对烟草和电子烟的薄荷醇和其他添加剂的监管工作确定科学基础。