Counterirritation by Menthol: Molecular Targets and Role in Airway Disease

说明（由申请人提供）：薄荷醇是一种从薄荷中提取的冷却萜，广泛用于治疗咳嗽、呼吸道刺激和疼痛。作为一种卷烟添加剂，薄荷醇尤其受到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。目前尚不清楚薄荷醇是否通过抑制化学感觉神经元介导的呼吸刺激反应而导致这些疾病。最近，发现了两种感觉薄荷醇受体：TRPM8（冷/薄荷醇受体）和TRPA1（反应性刺激受体）。TRPA1被烟草烟雾中含有的丙烯醛和其他刺激物激活。我们的初步研究表明，吸入薄荷醇能有效抑制小鼠对丙烯醛蒸气的呼吸刺激反应。吸入含薄荷醇香烟烟雾的小鼠，其血清中尼古丁代谢物可替宁的含量高于吸入未含薄荷醇香烟的小鼠，这表明吸入尼古丁的量增加了。在电生理和荧光成像实验中，我们发现薄荷醇抑制丙烯醛激活的TRPA1通道。我们假设：1)薄荷醇作为一种抗刺激物，通过与薄荷醇受体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。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。我们提出的研究将为气道刺激和重塑的神经机制提供新的见解，并为针对薄荷醇作为烟草添加剂的监管工作提供科学依据。

DESCRIPTION (provided by applicant): Menthol, the cooling terpene derived from peppermint, is widely used for the treatment of cough, respiratory irritation and pain. As a cigarette additive menthol is especially popular with beginning smokers and in minority populations disproportionally affected by COPD, lung cancer and hypertension. It is currently unclear whether menthol contributes to these disease conditions through inhibition of the respiratory irritation response mediated by chemosensory neurons. Recently, two sensory menthol receptors were identified: TRPM8, the cold/menthol receptor, and TRPA1, a reactive irritant receptor. TRPA1 is activated by acrolein and other irritants contained in tobacco smoke. Our preliminary studies show that inhalation of menthol potently inhibits the respiratory irritation response to acrolein vapor in mice. Mice inhaling smoke from mentholated cigarettes showed higher serum levels of the nicotine metabolite, cotinine, than mice exposed to non-mentholated smoke, suggesting increased exposure to nicotine. In electrophysiological and fluorescent imaging experiments we show that menthol inhibits acrolein-activated TRPA1 channels. We hypothesize that: 1.) Menthol acts as a counterirritant, blocking sensory neuronal responses to inhaled noxious chemicals through interaction with the menthol receptors TRPA1 or TRPM8, and 2) As a tobacco additive, menthol facilitates smoke inhalation through inhibition of neuronal irritant receptor signalling, thereby accelerating nicotine dependence and lung disease. 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. 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 as a tobacco additive. PUBLIC HEALTH RELEVANCE: The natural product menthol is contained in medications against cold symptoms and pain, in food and in cigarettes. This application aims to reveal how menthol reduces irritation, and if menthol causes more severe smoking-related disease. Our work may aid the government in determining whether to regulate menthol as a cigarette additive, and may reveal new treatments for cough and pain.