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

电子烟衍生的自由基、氧化应激和炎症在肺癌发展中的作用

• 批准号: 10592334
• 负责人: JAY Louis ZWEIER
• 金额: $ 55.42万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-15 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10592334
• 关键词: 3-nitrotyrosine; Acetaldehyde; Address; Adenocarcinoma; Adverse effects; Aerosols; Aldehyde oxidase; Aldehydes; Alveolus; Biochemical; Biological Assay; Blood; Bronchioles; Cell Proliferation; Cell physiology; Chronic; DNA Damage; Detection; Development; Devices; Electron Spin Resonance Spectroscopy; Electron Transport; Electronic Nicotine Delivery Systems; Electronic cigarette; Enzyme-Linked Immunosorbent Assay; Enzymes; Epithelium; Evaluation; Exposure to; Female; Fluorescence; Formaldehyde; Free Radicals; Gender; Generations; Histopathology; Image; Imaging Techniques; Immunohistochemistry; Incidence; Inflammation; Inflammatory; Inhalation; Injury; Knowledge; Longitudinal Studies; Lung; Lung Neoplasms; Lung diseases; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of lung; Malondialdehyde; Measurement; Measures; Mediating; Mesenchymal; Metabolism; Mitochondria; Modeling; Mus; NADPH Oxidase; Nicotine; Nicotine Dependence; Nitric Oxide Synthase; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxidative Stress Induction; Pathology; Pathway interactions; Peroxonitrite; Phase; Poison; Premalignant Cell; Process; Production; Proteins; Public Health; Pulmonary Inflammation; Pulmonary Pathology; Reactive Oxygen Species; Reporting; Research; Risk; Role; SOD2 gene; Solid; Spin Trapping; Stress; Structure of parenchyma of lung; Superoxides; Therapeutic; Therapeutic Intervention; Time; Tissues; Tobacco; Toxic effect; Tumor Markers; Western Blotting; Work; X-Ray Computed Tomography; adenoma; animal imaging; antioxidant enzyme; cancer initiation; cancer risk; carcinogenesis; catalase; cigarette smoking; comparative; cytokine; e-cigarette aerosols; electronic cigarette use; electronic cigarette user; electronic liquid; glutathione peroxidase; histopathological examination; inflammatory lung disease; inhibitor; innovation; insight; lung carcinogenesis; lung imaging; lung injury; male; microCT; mouse model; neoplastic; non-invasive imaging; oxidative DNA damage; prevent; public health relevance; stemness; superoxide dismutase 1; toxicant; tumor; vaping

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.

项目摘要 电子烟 (e-cig) 已被宣传为电子尼古丁 (NIC) 传输系统 (ENDS)，无需 吸烟（CS）的不利影响。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严重炎症性肺部疾病的毒性。虽然有很强的 CS 诱导的氧化应激、炎症和癌症之间存在关联，但这一点尚未确定 电子烟的使用。电子烟会产生有毒物质，包括自由基和活性乙醛，其含量为 这些有毒物质随着设备功率的增加而增加。这些有毒化学物质会产生活性氧 物种（ROS），可能导致不受控制的炎症和细胞失调的 DNA 损伤 增殖从而引发癌变。在我们的小鼠慢性电子烟暴露模型中，我们观察到电子烟 含有 NIC 的电子烟液体产生的气溶胶在 50 ℃ 的研究中，50% 的小鼠诱发了肺部肿瘤 显微 CT 成像首次检测到暴露数周。肿瘤的组织病理学检查 显示腺癌或腺瘤伴局灶性混合支气管肺泡肿瘤细胞和癌前细胞。 在肺泡和肺泡中检测到超氧自由基、炎症、DNA 损伤和干性标记物 细支气管，在较早暴露时间出现癌症之前。自由基和高水平 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的过程 ROS 的产生可能是致癌的主要触发因素。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程度 强度/持续时间关系，以及电子烟气溶胶自由基水平和 NIC 在癌症发展中的作用。 因此，我们将进行纵向研究，并确定所需的小组规模，以明确解决 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) 癌症的发作和/或进展是否是 NIC- 依赖？ 4) 设备功率和由此产生的气溶胶自由基水平如何影响它？ 5) 癌症是否发病 和/或进展取决于性别？ 6）电子烟暴露触发ROS的机制是什么 肺部的生成和炎症？纵向显微 CT、MRI、EPR 光谱、EPR- 的研究 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将确定 暴露时间、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 导致致癌的触发因素或步骤。了解这些机制的作用并评估 阻止它们的抑制剂，我们将确定可用于改善电子烟的治疗干预措施 诱发肺部炎症和癌变。因此，这项研究将提供重要的见解，定义 使用电子烟的致癌风险及其潜在的暴露依赖性触发因素和机制。