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.

摘要 香烟烟雾是活性氧化剂的主要来源，包括自由基和醛类， 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起关键作用。与 随着电子烟（EC）的迅速普及，人们越来越担心其潜在的危害。 与他们的使用有关。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气溶胶含有显着水平的高活性自由基， 醛类。虽然这些氧化剂在所有测试的EC中均被检测到，但它们的水平因EC的不同而有很大差异。 产品设计、风味添加剂和使用行为。根据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，我们的建议侧重于潜在的影响 EC衍生的自由基和醛类参与肺癌发展的机制。具体地说， 我们假设暴露于使用EC的氧化剂将导致氧化应激/损伤和炎症， 导致对癌症的易感性增加。我们将利用一种转换方法来测试这一点 假设首先，在实验室中，确定主要自由基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， 从传统香烟长期转换为EC对相关氧化应激/损伤的影响， 炎症生物标志物（目的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， 确定代表性EC装置中的主要自由基种类（包括NIDA开发的标准化EC， SREC）。目标2将包括A/J小鼠的多次短期暴露研究，包括未处理动物和 那些预先暴露在香烟烟雾中的人，也将测试香料，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 途径。此外，我们将确定和比较EC气溶胶和香烟烟雾暴露的影响 对NNK诱导的A/J小鼠模型中肺肿瘤发生的影响。在目标3中，从传统模式转向 将向EC提供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 测定我们的研究方法是创新的基础上，其新颖的重点是EC衍生的自由基，使用 创新的方法和生物标志物，及其整合的翻译设计。随着这些研究的完成， 我们希望提供急需的信息， 烟草制品中的自由基和氧化剂暴露，可用于制定 针对EC产品/使用的政策。