Translational Studies on Electronic Cigarette-derived Oxidants and their Long-term Pulmonary Effects

摘要 香烟烟雾(CS)是活性氧化剂的主要来源。氧化应激和损伤 暴露在自由基和醛等氧化剂中在疾病的发生和发展中起关键作用 大多数由烟草引起的疾病，包括癌症和慢性阻塞性肺病的进展 (COPD)。使用最先进的高分辨率分析方法来检测和测量氧化剂，我们拥有 证明电子烟(EC)气雾剂含有高度活性的自由基和醛； 尽管水平通常比香烟烟雾低10到1000倍。我们发现自由基 在目前市场上的所有几代EC产品中都有生产，但这一水平因 电子商务产品设计与使用行为。基于这些研究和已知的氧化的重要性 肺部疾病的应激/损害，我们的建议集中在暴露于EC衍生的毒物引起的毒性 自由基和醛及其在慢性阻塞性肺疾病发展中的作用具体地说，我们假设1) EC气雾剂暴露将与对肺部健康的负面长期影响有关，尽管影响较小 比可燃香烟烟雾暴露的程度更大，以及2)从可燃香烟转换为EC将 导致氧化剂暴露减少，从而改善COPD的预后。在这个提案中，我们将利用 一种高度翻译的方法，在CS诱导的COPD小鼠中进行长期体内暴露研究 轻、中度COPD吸烟者改用EC的模型及初步临床干预研究。具体的 目的是量化动物模型中暴露点的EC或CS氧化剂的绝对水平 并通过检查肺功能(初级)来确定这些氧化剂的相对影响 端点)。还将检查氧化应激和炎症的肺部生物标记物。具体的 目的是为了彻底评估使用EC的长期健康后果 幼稚和CS暴露的小鼠比较高和低氧化产物的效果，以及选择性 氧化剂诱导的小鼠肺损伤的过滤(目标1)；改用香烟烟雾的影响 暴露在EC气雾剂中以模拟人体开关(目标2)；以及#年实验室发现的可译性 患有轻中度COPD的吸烟者(目标3)。总体而言，这些研究将极大地促进 烟草监管科学，重点关注特定EC氧化剂暴露的毒理学重要性 设备。这些数据将对FDA制定旨在 减少烟草产品造成的危害。

Abstract Cigarette smoke (CS) is a major source of reactive oxidants. Oxidative stress and damage resulting from exposure to oxidants such as free radicals and aldehydes play critical roles in the development and progression of most tobacco-caused diseases, including cancer and chronic obstructive pulmonary disease (COPD). Using state-of-the-art high resolution analytical methods to detect and measure oxidants, we have demonstrated that electronic cigarettes (EC) aerosols contain highly reactive free radicals and aldehydes; albeit at levels which are typically 10- to 1000-fold lower than in cigarette smoke. We found that free radicals were produced in all generations of EC products currently on the market, but that levels vary significantly by EC product design and usage behaviors. Based on these studies and the known importance of oxidative stress/damage in pulmonary diseases, our proposal focuses on toxicities caused by exposure to EC-derived free radicals and aldehydes and their role in the development of COPD. Specifically, we hypothesize that 1) EC aerosol exposure will be associated with negative long-term pulmonary health effects, albeit to a lesser extent than combustible cigarette smoke exposure, and 2) switching from combustible cigarettes to EC will lead to reductions in oxidant exposures and, thus, improved prognosis in COPD. In this proposal, we will utilize a highly translational approach, conducting long-term in vivo exposure studies in a CS-induced COPD mouse model and a pilot clinical intervention study of switching to EC in mild-moderate COPD smokers. The specific objectives are to quantitate absolute levels of EC or CS oxidants at the point of exposure in the animal model and to determine the relative impact of these oxidants through the examination of lung function (primary endpoint). Pulmonary biomarkers of oxidative stress and inflammation will also be examined. The specific aims have been designed to allow for a thorough evaluation of the long term health consequences of EC use in naïve and CS exposed mice comparing effects of high vs. low oxidant products, and the impact of selective filtration of oxidant-induced lung damage in the mouse (Aim 1); impact of switching from cigarette smoke exposure to EC aerosols to mimic switching in humans (Aim 2); and translatability of laboratory findings in smokers with mild-moderate COPD (Aim 3). Overall, these studies will significantly contribute to the field of tobacco regulatory science by focusing on the toxicological importance of oxidant exposure from specific EC devices. These data will be of particular value to the FDA for the development of regulatory policies aimed at reducing harm imposed by tobacco products.