Electronic Cigarette-derived Oxidants and their Impact on Lung Cancer Development

电子烟衍生的氧化剂及其对肺癌发展的影响

• 批准号: 10183202
• 负责人: JOHN P RICHIE
• 金额: $ 64.33万
• 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: 2020-06-05 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10183202
• 关键词: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; A/J Mouse; Activated Charcoal; Address; Adult; Aerosols; Aldehydes; Animals; Ascorbic Acid; Behavior; Biological; Biological Markers; Blood; Carcinogens; Cations; Cells; Cessation of life; Chemicals; Chronic Disease; Chronic Obstructive Airway Disease; Clinical Trials; Communities; Complex Mixtures; Detection; Development; Devices; Disease; Dose; Electron Spin Resonance Spectroscopy; Electronic cigarette; Exposure to; Filtration; Flavoring; Free Radicals; Funding; Glutathione; Health; Inflammation; Inflammatory; Inhalation; Laboratories; Laboratory Animals; Lipids; Liquid Chromatography; Lung; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Measurement; Measures; Medical; Methodology; Methods; Modeling; National Institute of Drug Abuse; Nose; Outcome; Oxidants; Oxidative Stress; Oxides; Pathway interactions; Play; Policies; Predisposition; Reporting; Research; Resolution; Risk; Role; Sampling; Site; Smoker; Source; Standardization; Surgeon; Techniques; Testing; Time; Tissues; Tobacco; Tobacco smoking behavior; Toxicology; Urine; Variant; Youth; analytical method; base; cancer risk; chemical property; cigarette smoke; combustible cigarette; design; e-cigarette aerosols; electronic cigarette use; electronic liquid; environmental tobacco smoke exposure; exposure to cigarette smoke; innovation; interdisciplinary approach; lung carcinogenesis; lung injury; lung tumorigenesis; method development; mouse model; novel; response; secondary analysis; specific biomarkers; tandem mass spectrometry; tobacco exposure; tobacco products; toxicant; translational approach

Abstract Cigarette smoke is a major source of reactive oxidants, including free radicals and aldehydes, which are playing critical roles in the development and progression of most tobacco-caused diseases including lung cancer. With the rapidly growing popularity of electronic cigarettes (EC), there is growing concern about potential harm associated with their use. Using state-of-the-art high resolution analytical methods to detect and measure oxidants, we have demonstrated that EC aerosols contain significant levels of highly reactive free radicals and aldehydes. While these oxidants were detected in all types of EC tested, their levels varied substantially by EC product design, flavor additives, and usage behaviors. Based on these studies and the known importance of oxidative stress/damage and inflammation in lung carcinogenesis, our proposal focuses on the potential impact of EC-derived free radicals and aldehydes in mechanisms involved in lung cancer development. Specifically, we hypothesize that exposure to oxidants from EC use will lead to oxidative stress/damage and inflammation in the lung resulting in increased susceptibility to cancer. We will utilize a translational approach to test this hypothesis by first, in the laboratory, identifying the chemical identity and potential for harm for the major free radicals produced by EC (Aim 1), secondly conducting controlled exposure studies in a relevant mouse model on the impact of EC-aerosols on specific lung cancer-related endpoints and lung tumor development (Aim 2), and thirdly, conduct secondary analyses of samples generated from an NIDA-funded EC clinical trial to examine the impact of long-term switching from conventional cigarettes to ECs on relevant oxidative stress/damage and inflammatory biomarkers (Aim 3). In Aim 1, we utilize advanced electron paramagnetic resonance (EPR) spectroscopy techniques and liquid chromatography-tandem mass spectrometry (LC-MS/MS) methodologies to identify major radical species in representative EC devices (including the NIDA developed standardized EC, SREC). Aim 2 will consist of multiple short-term exposure studies in the A/J mouse, both in naïve animals and those pre-exposed to cigarette smoke, and will also test the specific impact of flavorants, radicals and aldehydes on systemic and tissue specific biomarkers of oxidative stress/damage, inflammation and lung-cancer related pathways. Additionally, we will determine and compare the impact of EC aerosol and cigarette smoke exposure on lung tumorigenesis in an NNK-induced A/J mouse model. In Aim 3, the impact of switching from conventional cigarettes to EC on biomarkers of oxidative stress/damage and inflammation in healthy adult smokers will be determined. Our research approach is innovative based upon its novel focus on EC-derived free radicals, use of innovative methods and biomarkers, and its integrative translational design. With the completion of these studies, we hope to provide much needed information regarding the potential lung-cancer related harm associated with free radical and oxidant exposure from tobacco products which can be used for the development of regulatory policies aimed at EC products/usage.

抽象的 香烟烟雾是活性氧化剂的主要来源，包括自由基和醛类，它们正在发挥作用 在包括肺癌在内的大多数烟草引起的疾病的发生和进展中发挥着关键作用。 电子烟（EC）的迅速普及，人们越来越担心其潜在危害 使用最先进的高分辨率分析方法来检测和测量。 氧化剂，我们已经证明 EC 气溶胶含有显着水平的高活性自由基和 虽然在所有类型的 EC 测试中都检测到了这些氧化剂，但它们的含量因 EC 的不同而有很大差异。 基于这些研究和已知的重要性。 氧化应激/损伤和炎症在肺癌发生中的作用，我们的建议重点关注潜在影响 EC 衍生的自由基和醛类在参与肺癌发展的机制中的作用。 我们发现，使用 EC 时接触氧化剂会导致氧化应激/损伤和炎症 肺部会导致癌症易感性增加，我们将利用转化方法来测试这一点。 假设首先在实验室中确定主要游离物质的化学特性和潜在危害 EC 产生的自由基（目标 1），其次在相关小鼠模型中进行受控暴露研究 EC-气溶胶对特定肺癌相关终点和肺肿瘤发展的影响（目标 2）， 第三，对 NIDA 资助的 EC 临床试验产生的样本进行二次分析，以检查 长期从传统香烟转为电子烟对相关氧化应激/损伤的影响以及 炎症生物标志物（目标 3） 在目标 1 中，我们利用先进的电子顺磁共振 (EPR)。 光谱技术和液相色谱-串联质谱 (LC-MS/MS) 方法 识别代表性 EC 装置中的主要自由基种类（包括 NIDA 开发的标准化 EC、 目标 2 将包括在 A/J 小鼠中进行多项短期暴露研究，包括幼稚动物和 那些预先接触过香烟烟雾的人，还将测试香料、自由基和醛的具体影响 氧化应激/损伤、炎症和肺癌相关的全身和组织特异性生物标志物 其他途径，我们将确定并比较 EC 气溶胶和香烟烟雾暴露的影响 在 NNK 诱导的 A/J 小鼠模型中，对肺肿瘤发生的影响 在目标 3 中，转换传统方法的影响。 香烟对健康成年吸烟者氧化应激/损伤和炎症生物标志物的影响将是 我们的研究方法是创新的，基于其对 EC 衍生自由基的新颖关注，以及使用。 随着这些研究的完成，创新方法和生物标志物及其综合转化设计。 我们希望提供有关与肺癌相关的潜在危害的急需信息 烟草制品中的自由基和氧化剂暴露可用于制定监管措施 针对 EC 产品/使用的政策。