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: 10413133
• 负责人: Zachary T Bitzer
• 金额: $ 24.98万
• 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 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10413133
• 关键词: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; A/J Mouse; Activated Charcoal; Address; Adult; Aerosols; Aldehydes; Animals; Ascorbic Acid; Behavior; Biological Markers; Blood; Carcinogens; Cations; Cells; Cessation of life; Chemicals; Chronic Disease; Chronic Obstructive Pulmonary 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 香烟烟是反应性氧化物的主要来源，包括正在玩的自由基和醛 在包括肺癌在内的大多数烟草引起的疾病的发展和进展中的关键作用。和 电子公民（EC）迅速增长的流行，人们对潜在伤害的关注日益加剧 与他们的使用相关。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气溶胶包含高度反应性的自由基和 醛。尽管在所有类型的EC测试中都检测到这些氧化剂，但它们的水平大大差异 产品设计，风味添加剂和使用行为。基于这些研究以及已知的重要性 氧化应激/损伤和肺癌发生的炎症，我们的建议重点是潜在影响 涉及肺癌发展的机制中的EC衍生的自由基和醛。具体来说， 我们假设暴露于EC使用中的氧化剂将导致氧化应激/损伤和炎症 肺导致对癌症的敏感性增加。我们将利用一种翻译方法来测试 首先，在实验室中的假设确定了化学身份和对主要自由的伤害的潜力 EC产生的自由基（AIM 1），其次在相关的小鼠模型中进行受控的暴露研究 关于EC-AEROSOLS对特定肺癌相关终点和肺部肿瘤发展的影响（AIM 2）， 第三，进行由NIDA资助的EC临床试验产生的样品进行的次要分析以检查 长期从常规香烟转换为EC的影响对相关氧化物应力/损害和 炎症生物标志物（AIM 3）。在AIM 1中，我们利用高级电子顺磁共振（EPR） 光谱技术和液相色谱串联质谱法（LC-MS/MS）方法 确定代表EC设备的主要激进物种（包括NIDA开发了标准化的EC， SREC）。 AIM 2将由A/J小鼠的多次短期暴露研究组成，无论是在幼稚的动物和 那些预先暴露于香烟烟雾的人，还将测试口味，激素和醛的特定影响 关于氧化应激/损伤，注射和肺癌相关的全身性和组织特异性生物标志物 途径。此外，我们将确定并比较EC气雾剂和香烟烟雾的影响 NNK诱导的A/J小鼠模型中的肺肿瘤发生。在AIM 3中，从传统的转换的影响 健康的成年吸烟者的氧化应激/损害和感染的生物标志物向EC的香烟将是 决定。我们的研究方法是基于其对EC衍生的自由基的新颖的专注，使用的创新方法 创新方法和生物标志物及其集成的翻译设计。这些研究完成， 我们希望提供有关与潜在的肺癌相关伤害的急需信息 烟草产物的自由基和氧化剂暴露，可用于开发调节 针对EC产品/使用的政策。