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

基本信息

批准号：
10456627
负责人：
Raghu Sinha
金额：
$ 45.36万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10456627
关键词：
Acrolein Activated Charcoal Address Aerosols Aldehydes Animal Model Animals Behavior Biological Markers C57BL/6 Mouse Chemicals Chronic Chronic Disease Chronic Obstructive Pulmonary Disease Cigarette Clinical Data Development Devices Disease Disease model Electronic cigarette Evaluation Exposure to Female Filtration Free Radicals Generations Health 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 health lung histology 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

项目摘要

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) 是氧化应激和氧化损伤的主要来源。暴露于自由基和醛等氧化剂在发育和发育过程中起着至关重要的作用。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（慢性阻塞性肺病）。我们使用最先进的高分辨率分析方法来检测和测量氧化剂。证明电子烟（EC）气溶胶含有高活性自由基和醛类；我们发现，自由基的水平通常比香烟烟雾中低 10 至 1000 倍。目前市场上各代 EC 产品均生产这种物质，但其水平因人而异 EC 产品设计和使用行为基于这些研究和已知的氧化重要性。肺部疾病的压力/损伤，我们的建议重点关注接触 EC 衍生的毒性具体来说，我们欺负了自由基和醛类及其在慢性阻塞性肺病发展中的作用 1)。 EC 气溶胶暴露会对肺部健康产生长期负面影响，尽管影响较小程度高于可燃香烟烟雾暴露，并且 2) 从可燃香烟切换到 EC 将导致氧化剂暴露的减少，从而改善慢性阻塞性肺病的预后。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针对轻度至中度 COPD 吸烟者改用 EC 的试点临床干预研究。目标是量化动物模型中接触时 EC 或 CS 氧化剂的绝对水平并通过检查肺功能（初级检查）来确定这些氧化剂的相对影响还将检查氧化应激和炎症的具体肺部生物标志物。目的旨在对 EC 使用的长期健康后果进行全面评估天然小鼠和 CS 暴露小鼠比较高氧化剂与低氧化剂产品的效果，以及选择性的影响过滤小鼠中氧化剂引起的肺损伤（目标 1）；戒烟的影响；暴露于 EC 气溶胶以模拟人类的转换（目标 2）以及实验室研究结果的可转化性；总体而言，这些研究将对患有轻度至中度慢性阻塞性肺病的吸烟者做出重大贡献。烟草监管科学，重点关注特定 EC 中氧化剂暴露的毒理学重要性这些数据对于 FDA 制定监管政策特别有价值。减少烟草制品造成的危害。