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

电子烟衍生氧化剂及其长期肺部影响的转化研究

• 批准号: 10191030
• 负责人: JOHN P RICHIE
• 金额: $ 46.52万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10191030
• 关键词: Acrolein; Activated Charcoal; Address; Aerosols; Aldehydes; Animal Model; Animals; Behavior; Biological Markers; C57BL/6 Mouse; Chemicals; Chronic; Chronic Disease; Chronic Obstructive Airway Disease; Cigarette; Clinical; Data; Development; Devices; Disease; Disease model; Electronic cigarette; Evaluation; Exposure to; Female; Filtration; Free Radicals; Generations; Health; Histology; Human; Inflammation; Inflammatory; Intervention Studies; JUUL; Laboratory Animals; Laboratory Finding; Liquid substance; Lung; Lung diseases; Malignant Neoplasms; Measures; Monitor; Mus; Nicotine; Nose; Outcome Study; Oxidants; Oxidative Stress; Oxides; Patients; Pattern; Play; Policies; Prognosis; Research; Research Priority; Resolution; Role; Smoker; Source; Symptoms; Tobacco; Tobacco use; Toxic effect; Toxicology; Work; air filter; analytical method; arm; base; cigarette smoke; cigarette smoke-induced COPD; cigarette smoking; combustible cigarette; design; disease phenotype; e-cigarette aerosols; electronic cigarette use; electronic liquid; exposure to cigarette smoke; improved; in vivo; lung injury; male; mouse model; oxidative damage; primary endpoint; primary outcome; pulmonary function; respiratory; smoking cessation; specific biomarkers; tobacco products; tobacco regulatory science; toxicant; translational approach; translational study

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.

抽象的 香烟烟雾（CS）是反应性氧化物的主要来源。氧化应激和由 暴露于自由基和醛等氧化剂中 大多数烟草引起的疾病的进展，包括癌症和慢性阻塞性肺部疾病 （COPD）。使用最先进的高分辨率分析方法来检测和测量氧化物，我们有 证明电子烟（EC）气溶胶含有高反应性的自由基和醛。 尽管处于通常比香烟烟雾低10至1000倍的水平。我们发现自由基 是目前市场上所有几代EC产品生产的，但水平的差异很大 EC产品设计和使用行为。基于这些研究以及氧化的已知重要性 肺部疾病的压力/损害，我们的建议重点是暴露于EC衍生的毒性 自由基和醛及其在COPD发展中的作用。具体来说，我们假设这是1） EC气溶胶暴露将与负长期肺部健康作用有关，尽管较小 程度多于混合的香烟烟雾，2）从混合香烟转换为EC 导致氧化物暴露量减少，从而改善COPD的预后。在此提案中，我们将利用 一种高度翻译的方法，在CS诱导的COPD小鼠中进行了长期的体内暴露研究 模型和试点临床干预研究，将在温和度中度COPD吸烟者中改用EC。具体 目标是在动物模型中量化EC或CS氧化的绝对水平 并通过检查肺功能来确定这些氧化剂的相对影响（主要 端点）。还将检查氧化应激和炎症的肺生物标志物。具体 目的旨在允许对EC使用的长期健康后果进行全面评估 幼稚和CS暴露的小鼠比较了高氧化物和低氧化物的影响，以及选择性的影响 氧化剂诱导的肺损伤过滤小鼠（AIM 1）；从香烟烟中转换的影响 暴露于EC气溶胶中，以模仿人类的模拟转换（AIM 2）；和实验室发现的可翻译性 带有温和中度COPD的吸烟者（AIM 3）。总体而言，这些研究将大大促进 烟草监管科学专注于氧化物暴露于特定EC的毒理学重要性 设备。这些数据对FDA特别有价值，以制定针对的监管政策 减少烟草产品施加的伤害。