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: 9980676
• 负责人: JOHN P RICHIE
• 金额: $ 47.18万
• 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/9980676
• 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; Estrogen receptor positive; 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; Research; Research Priority; Resolution; Respiratory physiology; Role; Smoker; Source; Symptoms; Tobacco; 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; outcome forecast; oxidative damage; primary endpoint; primary outcome; 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.

摘要 香烟烟雾（CS）是活性氧化剂的主要来源。氧化应激和损伤导致的 暴露于氧化剂如自由基和醛类在发育中起关键作用， 大多数烟草引起的疾病的进展，包括癌症和慢性阻塞性肺病 （COPD）。使用最先进的高分辨率分析方法来检测和测量氧化剂， 证明电子香烟（EC）气溶胶含有高度活性的自由基和醛; 尽管其含量通常比香烟烟雾中低10- 1000倍。我们发现自由基 目前市场上的所有几代EC产品都产生了这些物质，但这些物质的含量因 电子商务产品设计和使用行为。根据这些研究和已知的氧化的重要性， 在肺部疾病的应激/损伤中，我们的建议侧重于暴露于EC衍生的 自由基和醛及其在COPD发展中的作用。具体来说，我们假设：1） EC气溶胶暴露将与负面的长期肺部健康影响有关，尽管影响较小， 程度超过可燃香烟烟雾暴露，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。在本提案中，我们将利用 一种高度转化的方法，在CS诱导的COPD小鼠中进行长期体内暴露研究 模型和在轻中度COPD吸烟者中转换为EC的初步临床干预研究。具体 目的是定量动物模型中暴露点处EC或CS氧化剂的绝对水平 并通过检查肺功能（主要 端点）。还将检查氧化应激和炎症的肺部生物标志物。具体 目标的设计是为了全面评估使用EC的长期健康后果， 比较高氧化剂产品与低氧化剂产品的作用，以及选择性抗氧化剂的影响。 小鼠中氧化剂诱导的肺损伤的过滤（目标1）;从香烟烟雾转换的影响 暴露于EC气溶胶以模拟人类的转换（目标2）;以及 轻度-中度COPD吸烟者（目标3）。总的来说，这些研究将大大有助于该领域的 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 装置.这些数据将对FDA制定监管政策具有特别价值， 减少烟草制品的危害。