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（ecig）的使用越来越受到从不吸烟者和主动吸烟者的欢迎， 通过激烈的广告宣传，将其作为香烟烟雾的健康替代品。除了井- 我们已经证实了香烟烟雾对肺部的有害作用，我们已经证明纳米尺寸的炭黑 由烟草不完全燃烧产生的颗粒激活抗原呈递细胞并促进 肺气肿ENDS中加热蒸发的内容物（如丙二醇（PG）、植物甘油（VG）） 有或没有尼古丁）是一个安全的替代吸烟的积极或前吸烟者，仍然 未知我们已经建立了一个强大的小鼠模型的传统和电子香烟（ecig）暴露 并取得了一些新的发现，为肺中ecig的毒理学提供了独特的见解。我们 他们发现，长期吸入烟雾和尼古丁（含或不含尼古丁）会激发DNA加合物， 导致肺部细胞变化。此外，当小鼠从香烟烟雾过渡到ecig时， 显著抑制肺固有粘膜免疫。针对这种RFA，我们建议使用新的 毒理学方法，以确定生物标志物，以及测试心血管和呼吸系统健康的影响， ecig及其组件，以帮助FDA制定适用于ENDS行业的法规。实现 我们的目标是，我们设计了一个临床前模型，密切模拟人类行为，探索如何过渡 从烟雾到电子烟免疫球蛋白都能增强它们在肺部的毒性。此外，通过利用现有的 参加神经认知行为研究的吸烟者，进行辅助研究， 生物标志物，并确定是否ecig与尼古丁改变先天免疫功能，并促进 血清累积炎症电位。为了实现我们的目标，我们将检查肺DNA加合物， 代谢组学、脂质组学和全身先天免疫在小鼠暴露于慢性烟雾和过渡到 电子烟我们还将研究有和没有尼古丁的ecig对全身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 使用慢性吸烟转变的临床前模型研究ecig在DNA加合物形成中的组分 到吸入式雾化吸入假设：PG/VG的比例改变了肺中的DNA加合物。目标2：确定有毒物质 使用从慢性吸烟到CIG吸入转变的临床前模型的细胞对CIG的反应。 假设：暴露于烟雾的小鼠中的慢性ecig暴露和/或向ecig的过渡改变了内皮和/或 免疫细胞反应。目的3：使用一组活跃吸烟者来鉴定对ecig的毒性细胞反应 EIG用户。假设：暴露于ecig改变内皮细胞和/或免疫细胞的反应。成功 拟定临床前和人体转化研究的完成提供了相关毒理学结果 并告知FDA如何监管ENDS产品的分销和营销，以保护公众健康。