Electronic cigarette derived free radicals, oxidative stress and inflammation in lung cancer development

项目摘要 电子香烟（e-cig）已被推广为电子尼古丁（NIC）输送系统（ENDS）， 吸烟的副作用（CS）。然而，最近的研究报告了广泛的 在电子烟使用者中观察到电子烟引起的毒性和严重的炎性肺病。虽然有一个强大的 CS诱导的氧化应激，炎症和癌症之间的联系，这还没有建立， 使用电子烟。电子烟产生的有毒物质，包括自由基和活性乙醛， 这些有毒物质随着装置功率的增加而增加。这些有毒化学物质产生活性氧 活性氧（ROS），这可能导致不受控制的炎症和DNA损伤与失调的细胞 引发致癌作用的增殖。在我们的慢性小鼠电子烟暴露模型中，我们观察到电子烟 由含有NIC的电子烟液体产生的气溶胶在50 ℃下在50%的小鼠中诱导了肺肿瘤。 这是首次通过显微CT成像检测到的。肿瘤的组织学检查 显示腺癌或腺瘤伴局灶性混合支气管肺泡肿瘤和癌前细胞。 检测肺泡中的超氧化物自由基、炎症、DNA损伤和干性标志物， 细支气管，在早期暴露时间发生癌症之前。自由基和高水平的 电子烟气溶胶中的醛类以及NIC衍生的亚胺代谢物，可以触发细胞凋亡过程。 ROS的产生，这可能是致癌的中心触发因素。基于关键的公共卫生 这项工作的影响，必须扩大这些观察，以衡量暴露 强度/持续时间关系，以及电子烟气雾剂自由基水平和NIC在癌症发展中的作用。 因此，我们将进行纵向研究，所需的组规模需要明确解决的问题， 关键问题：1）肺癌发生/进展所需的暴露强度和持续时间是多少？ 2)电子烟诱发肺癌的发病率是多少？3)癌症发作和/或进展是否为NIC- 依赖？4)器械功率和产生的气溶胶自由基水平如何影响它？5)是癌症发作吗 和/或性别依赖的进展？6)电子烟暴露触发ROS的机制是什么 肺部的炎症和炎症？纵向显微CT、MRI、EPR波谱、EPR- MRI联合成像和血液肿瘤标志物，随后进行生化测定和组织病理学检查， 暴露持续时间、ENDS功率、NIC和性别对肺癌发生和/或进展的作用。 ROS生成、肺部炎症和继发性上皮间质转化将被评估为 引发或步骤导致致癌作用。了解了这些机制的作用并对 抑制剂，阻止他们，我们将确定治疗干预，可用于改善电子烟 诱发肺部炎症和癌变。因此，这项研究将提供重要的见解， 使用电子烟的致癌风险及其潜在的依赖于安全的触发因素和机制。

Project Abstract Electronic cigarettes (e-cig) have been promoted as electronic nicotine (NIC) delivery systems (ENDS) without the adverse effects of tobacco cigarette smoking (CS). However, recent studies have reported a wide range of e-cig-induced toxicities with severe inflammatory lung disease observed in e-cig users. While there is a strong association between CS-induced oxidative stress, inflammation and cancer, this has not been established for e-cig use. E-cig generate toxic species, including free radicals and reactive acetaldehydes with the levels of these toxicants increased with increasing device power. These toxic chemicals produce reactive oxygen species (ROS), which can lead to uncontrolled inflammation and DNA damage with dysregulated cell proliferation that trigger carcinogenesis. In our chronic mouse e-cig exposure model, we observed that e-cig aerosol, generated from e-cig liquid containing NIC, induced lung tumors in 50% of the mice studied at 50 weeks of exposure, as first detected by micro-CT imaging. Histopathological examination of the tumors showed adenocarcinoma or adenoma with focal mixed broncho-alveolar neoplastic and pre-malignant cells. Superoxide radicals, inflammation, DNA damage and stemness markers were detected in the alveoli and bronchioles, preceding cancer development at earlier exposure times. The free radicals and high levels of aldehydes in e-cig aerosol, as well as the NIC derived iminium metabolite, can trigger processes of cellular ROS generation and this may serve as a central trigger of carcinogenesis. Based on the critical public health implications of this work, it is imperative to expand these observations to measure the exposure intensity/duration relationships, and the role of e-cig aerosol free radical levels and NIC in cancer development. Thus, we will perform longitudinal studies with the requisite group size needed to definitively address the critical questions: 1) What is the exposure intensity and duration required for lung cancer initiation/progression? 2) What is the incidence rate of e-cig-induced lung cancer? 3) Is cancer onset and/or progression NIC- dependent? 4) How is it effected by device power and resultant aerosol free radical levels? 5) Is cancer onset and/or progression gender-dependent? 6) What are the mechanisms by which e-cig exposure triggers ROS generation and inflammation in the lung? Studies with longitudinal micro-CT, MRI, EPR spectroscopy, EPR- MRI co-imaging and blood tumor markers followed by biochemical assays and histopathology will determine the role of exposure duration, ENDS power, NIC, and gender on initiation and/or progression of lung cancer. ROS generation, lung inflammation and secondary epithelial mesenchymal transition will be evaluated as triggers or steps leading to carcinogenesis. With knowledge of the role of these mechanisms and evaluation of inhibitors that block them, we will identify therapeutic interventions that could be used to ameliorate e-cig induced lung inflammation and carcinogenesis. Thus, this research will provide important insights defining the carcinogenesis risk of e-cig use, and its underlying exposure-dependent triggers and mechanisms.