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

摘要 香烟烟雾是活性氧化剂的主要来源，包括自由基和醛，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展和进展中发挥关键作用。使用 随着电子烟(EC)的迅速普及，人们越来越担心潜在的危害 与它们的使用有关。使用最先进的高分辨率分析方法检测和测量 氧化剂，我们已经证明了EC气溶胶含有大量的高活性自由基和 醛。虽然在所测试的所有类型的EC中都检测到了这些氧化剂，但它们的水平因EC而异 产品设计、风味添加剂和使用行为。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，我们的建议侧重于潜在的影响 EC衍生的自由基和醛在肺癌发生机制中的作用。具体来说， 我们推测，暴露在EC使用的氧化剂中将导致氧化应激/损伤和炎症 肺癌会增加癌症的易感性。我们将使用翻译方法来测试这一点 假设首先，在实验室中，确定化学特性和潜在的危害，主要是免费的 EC产生的自由基(目标1)，其次在相关的小鼠模型中进行受控暴露研究 关于EC气雾剂对特定肺癌相关终点和肺癌发展的影响(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 长期从传统卷烟转向ECS对相关氧化应激/损伤和 炎性生物标志物(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LC-MS/MS方法 确定代表性EC设备中的主要自由基物种(包括NIDA开发的标准化EC， SREC)。目标2将包括在A/J小鼠身上进行的多项短期暴露研究，包括幼稚动物和 那些预先暴露在香烟烟雾中的人，还将测试调味剂、自由基和醛的具体影响 氧化应激/损伤、炎症和肺癌相关的系统和组织特异性生物标志物 小路。此外，我们将确定和比较EC气雾剂和香烟烟雾暴露的影响 NNK诱导的A/J小鼠模型肺肿瘤形成的研究在目标3中，从传统改变的影响 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 下定决心。我们的研究方法是创新的，基于其对EC衍生的自由基的新关注，使用 创新的方法和生物标志物，及其一体化的翻译设计。随着这些研究的完成， 我们希望提供关于与肺癌相关的潜在危害的急需的信息 烟草产品中的自由基和氧化剂暴露可用于制定法规 针对EC产品/使用的政策。

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.