Toxic Effects of Ecigs Following Transition From Conventional Cigarettes

从传统香烟过渡到电子烟后的毒性作用

• 批准号: 9982334
• 负责人: Farrah Kheradmand
• 金额: $ 44.75万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9982334
• 关键词: Ancillary Study; Antigen-Presenting Cells; Behavior; Biological Markers; Carbon Black; Cells; Chronic; Cigarette; DNA Adduction; DNA Adducts; Data; Electronic Nicotine Delivery Systems; Electronic cigarette; Endothelial Cells; Endothelium; Experimental Models; Exposure to; Functional Magnetic Resonance Imaging; Genetic Transcription; Glycerol; Goals; Habits; Human; Human Volunteers; Immune; Immune response; Immunity; Incidence; Industry; Inflammatory; Inhalation; Injury; Innate Immune Response; Interferons; Link; Long-Term Effects; Lung; Lung infections; Marketing; Modeling; Mucosal Immunity; Mus; Natural Immunity; Neurocognitive; Nicotine; Pathology; Pathway Analysis; Pathway interactions; Perception; Policies; Policy Making; Population; Pre-Clinical Model; Propylene Glycols; Proteins; Public Health; Pulmonary Emphysema; Pulmonary Surfactant-Associated Protein D; Pulmonary Surfactant-Associated Proteins; Regulation; Risk; Role; Serum; Smoke; Smoker; Solvents; Testing; Tobacco; Tobacco smoke; Toxic effect; Toxicology; Toxin; Vegetables; Weight maintenance regimen; behavioral study; cardiovascular health; cigarette smoke; cigarette smoking; cohort; design; electronic cigarette use; electronic cigarette user; exposure to cigarette smoke; imaging study; innate immune function; insight; metabolomics; mouse model; nanosized; novel; novel marker; particle; pathogen; pathogenic bacteria; pathogenic virus; peripheral blood; pre-clinical; recruit; respiratory; respiratory health; response; smoke inhalation; surfactant; translational study; vapor

The use of electronic cigarette (ecig), is gaining popularity among never and active smokers who are persuaded by intense ad campaigns that brands their use as a healthy alternative to cigarette smoke. In addition to the well- established noxious effects of cigarette smoke in the lungs, we have demonstrated that nano-sized carbon black particles, generated by incomplete combustion of tobacco, activate antigen presenting cells and promotes emphysema. Whether heated vaporized contents in ENDS (e.g. propylene glycol (PG), vegetable glycerol (VG) with or without nicotine) is a safe alternative to cigarette smoking in active or former smokers, remains unknown. We have developed a robust mouse model of conventional and electronic cigarette (ecig) exposure and made several novel discoveries that provide unique insights into the toxicology of ecig in the lungs. We have found that chronic inhalation of smoke, and ecig (with or without nicotine) elicits DNA adducts, and results cellular changes in the lungs. Further, when mice are transitioned from cigarette smoke to ecig, there is a significant suppression of lung innate mucosal immunity. In response to this RFA, we propose to use novel toxicology approaches to identify biomarkers, as well as test cardiovascular and respiratory health effects of ecig and its components to aid the FDA in formulating regulations applicable to the ENDS industry. To achieve our goal, we have designed a preclinical model that closely simulates human behavior to explore how transition from smoke to ecig could escalate their toxicity in the lungs. In addition, by tapping into an existing cohort of smokers who participate in neurocognitive behavior studies at BCM, conduct ancillary studies to identify novel biomarkers and determine whether ecig with and without nicotine alters innate immune function, and promote serum cumulative inflammatory potentials. To accomplish our goal, we will examine lung DNA adducts, metabolomics, lipidomics, and systemic innate immunity in mice exposed to chronic smoke and transitioned to ecig. We will also examine the role of ecig with and without nicotine on systemic immunity and metabolomics in human volunteers. We will test the following three specific aims: Aim 1: To examine the effects of components of ecig in DNA adduct formation using a preclinical model of transition from chronic smoke to ecig inhalation. Hypothesis: The ratio of PG/VG alters DNA adducts in the lungs. Aim 2: To identify toxic cellular responses to ecig using a preclinical model of transition from chronic smoke to ecig inhalation. Hypothesis: Chronic ecig exposure and/or transition to ecig in mice exposed to smoke alters endothelial and/or immune cell responses. Aim 3: To identify toxic cellular responses to ecig using a cohort of active smokers and ecig users. Hypothesis: Exposure to ecig alters endothelial and/or immune cell responses. Successful completion of the proposed preclinical and human translational studies provides relevant toxicological findings and inform the FDA how to regulate distribution, and marketing of ENDS products to protect public health.

电子烟的使用在从不吸烟和经常吸烟的人中越来越受欢迎，他们被说服了 通过激烈的广告宣传，将其作为香烟的健康替代品。除了油井之外- 确定了香烟烟雾对肺部的有害影响，我们已经证明了纳米碳黑 烟草不完全燃烧产生的颗粒，激活抗原提呈细胞，促进 肺气肿。末端的加热汽化含量(如丙二醇(PG)、植物甘油(VG)) 无论有没有尼古丁)是吸烟的安全替代品，对于正在吸烟或曾经吸烟的人来说， 未知。我们开发了一种健壮的传统香烟和电子香烟(Ecg)暴露小鼠模型。 并做出了几项新的发现，为肺内ECG的毒理学提供了独特的见解。我们 已经发现，长期吸入烟雾和ECG(无论有没有尼古丁)会引起DNA加合物，以及 结果肺组织中的细胞改变。此外，当小鼠从吸烟转为吸烟时，会有一个 明显抑制肺固有黏膜免疫功能。针对这种RFA，我们建议使用小说 毒理学方法，以确定生物标志物，以及测试对心血管和呼吸健康的影响 ECig及其组件，以帮助FDA制定适用于终端行业的法规。要实现 我们的目标是，我们设计了一个临床前模型，接近模拟人类的行为，以探索如何过渡 从烟雾到粉尘，可能会增加它们对肺部的毒性。此外，通过利用现有的一批 在BCM参与神经认知行为研究的吸烟者，进行辅助研究以确定新的 生物标志物和确定是否有尼古丁和不加尼古丁的ECG改变先天性免疫功能并促进 血清累积炎症潜能值。为了实现我们的目标，我们将检测肺DNA加合物， 慢性烟雾暴露小鼠的代谢组学、脂质组学和系统天然免疫 ECig.我们还将研究加和不加尼古丁的ecg对系统免疫和代谢组学的作用。 在人类志愿者中。我们将测试以下三个具体目标：目标1：检查 使用慢性烟雾过渡的临床前模型研究DNA加合物形成中的ECIG组分 特别是吸入。假设：PG/VG的比例改变了肺部的DNA加合物。目标2：识别有毒物质 使用从慢性吸烟到吸入的临床前模型对ecg的细胞反应。 假设：烟雾暴露小鼠的慢性ECG暴露和/或向ECG的转变改变了内皮细胞和/或 免疫细胞反应。目标3：使用一组活跃的吸烟者来确定对ECG的毒性细胞反应 和SECG用户。假设：暴露于特定抗原会改变内皮细胞和/或免疫细胞的反应。成功 拟议的临床前和人体翻译研究的完成提供了相关的毒理学发现 并告知FDA如何规范终端产品的分销和营销，以保护公众健康。