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

描述（由申请人提供）：烟草行业在香烟中添加了多种化学物质，以提高产品稳定性，改变烟雾的味道和感官质量。虽然《家庭吸烟预防和烟草控制法案》禁止烟草香料添加剂，但薄荷醇却不受监管。薄荷烟特别受初吸烟者和受慢性阻塞性肺病、肺癌和高血压不成比例影响的少数人群的欢迎。最近，作为无毒尼古丁输送装置的电子烟已成为流行的烟草替代品。电子香烟含有大量的化学香料和感官添加剂，包括刺激性萜烯，如芳樟醇，这些添加剂在香烟中是被禁止使用的。我们的研究表明，薄荷醇，在薄荷香烟的烟雾中含量相似或更低，强烈地抑制了小鼠对烟草烟雾刺激物的呼吸刺激反应。电子烟的气溶胶在小鼠中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是支配呼吸系统的感觉神经元中表达的两种化学感觉离子通道。我们假设：1)薄荷醇作为一种抗刺激物，通过与TRPA1或TRPM8相互作用，阻断感觉神经元对吸入有害化学物质的反应。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，从而加速尼古丁依赖和肺部疾病。3)电子烟中添加的大量化学添加剂是为了模拟烟草烟雾的感官影响，并可能引起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：目标1)。明确TRPA1和TRPM8在薄荷醇诱导的急性呼吸刺激抑制中的作用。目标2。)研究薄荷醇和薄荷相关化合物对刺激诱导的感觉神经元激活的药理作用。目标3。)确定薄荷醇吸入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作用。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中薄荷醇和其他添加剂的监管工作提供科学依据。

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.