Electronic cigarette cardiotoxicity varies by flavorings: What can we learn from mice?

电子烟的心脏毒性因香料而异：我们可以从老鼠身上学到什么？

• 批准号: 10219729
• 负责人: Gabriele Grunig
• 金额: $ 21.19万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10219729
• 关键词: A/J Mouse; Adolescence; Adolescent; Adult; Adverse effects; Aerosols; Age; Americas; Apple; Area; Belief; Blood Vessels; Brain; Cardiopulmonary; Cardiotoxicity; Cardiovascular system; Categories; Cessation of life; Chronic; Cigarette; Cinnamon - dietary; Climacteric; Communication; Data; Development; Devices; Diacetyl; Disease; Education; Electronic Nicotine Delivery Systems; Electronic cigarette; Emerging Tobacco Products; Exposure to; Family Smoking Prevention and Tobacco Control Act; Female; Flavoring; Genus Vanilla; Glycerol; Health; High School Student; Hospitalization; Human; Individual; Inflammation; Inflammatory; Inflammatory Response; Ingestion; Inhalation; Inhalation Exposure; Knowledge; Label; Laboratories; Lead; Learning; Life; Liquid substance; Lung; Marketing; Measurable; Measures; Menthol; Molecular; Morphology; Mouse Strains; Mus; Nicotine; Outcome; Outcome Measure; Peach; Plasma; Poison; Policies; Propylene Glycols; Public Health; Publishing; Pulmonary Emphysema; Pulmonary Heart Disease; Pulmonary Hypertension; Regulation; Research; Research Priority; Risk; Sales; Science; Serum Markers; Smokeless Tobacco; Smoking Behavior; Structure; System; Testing; Time; Tobacco; Tobacco smoking behavior; Tobacco use; Toxic effect; Translating; Vaporizer; Youth; addiction; aerosolized; base; cardiovascular health; cigarette smoke-induced; cigarette smoking; comparative; cytokine; e-cigarette aerosols; electronic cigarette use; electronic cigarette user; electronic liquid; hookah; innovation; junior high school; male; nicotine exposure; public education; sex; tobacco products; vaping; vascular injury; water vapor; young adult

Abstract Tobacco Center of Regulatory Science recognizes 7 categories of research priorities, of which 2 important domains are toxicity and health consequences, with emphasis on cardiopulmonary impacts of new and emerging tobacco products and ENDS. The proposed study informs the FDA in regulations regarding the comparative toxicity of e-cigarette (e-cig) flavorings using cardiovascular health, particularly pulmonary hypertension (PH) in mice as an outcome. The over-arching hypothesis is that long-term inhalation exposure (3-mo) of adolescent A/J mice to e-cig aerosols induce changes in pulmonary vasculature predisposing adult male and female mice to pulmonary hypertension, and these changes arise and/or exacerbated by flavoring-induced inflammation. Moreover, that e-cig-induced cardiovascular toxicity can be compared and the toxicity of individual flavorings graded based on the extent of adverse change. Mice (3.5-wk-of-age) will be exposed by inhalation into adulthood (4-mo-of-age) to e-cig aerosols from a self-made tank system containing propylene glycol, glycerin, nicotine and with and without flavoring; selection of flavors (vanilla, cinnamon, menthol, double apple hookah and peach schnapps) are based on human usage and published diacetyl levels. A single aim (with multiple sub-aims) is proposed: 1A) to determine whether long-term (3-mo.) inhalation exposure of adolescent mice of both sexes to e-cig aerosols (with or without flavorings) produces structural, morphological and/or molecular remodeling of the pulmonary vasculature. The toxicity of e-cig flavorings will be classified based on extent of cardiopulmonary alterations using a paradigm previously developed in this laboratory for ordering smokeless tobacco products; 1B) using the same mice exposed in SA1A to investigate the time course of effects by examining non-terminal systemic changes associated with the development of pulmonary hypertension and/or emphysema, e.g., serum markers of vascular injury and pro-inflammatory cytokines on days -30, -60, -90 during e-cig exposure; 1C) to determine persistent effects of e-cig aerosols 90 days after cessation of the 3-mo exposure on the same pulmonary hypertension and cardiopulmonary/inflammatory outcomes measured in aims 1A and 1B. Results of these studies will empower the FDA to promulgate more explicit warning labels on e-cig packaging that could, in turn, educate the public on health risks associated with use of flavored e-cigs. Moreover, unequivocal demonstration of how flavored e-cig use could lead to life-threatening health issues could result in banning the sale of specific flavorings/types of e-cigarettes. These innovative studies introduce a new and understudied public health query: e-cig use, like long-term cigarette smoking, can induce cardiopulmonary/inflammatory effects, including vascular changes in the lungs that can lead to PH, an understudied area of cardiovascular research. Identifying a relationship between vaping and PH has critical implications for setting policies/imposing regulations. These studies that assess cardiopulmonary implications of “vaping” can begin to fill knowledge gaps on toxicity and health that to date impede the launch of new regulations.

摘要 烟草监管科学中心确认了7类研究优先事项，其中2项重要 领域是毒性和健康后果，重点是新的和正在出现的心肺影响 烟草制品和烟叶。拟议的研究在有关比较的法规中通知了FDA 电子烟(e-cig)香料的毒性与心血管健康，特别是肺高压(PH) 结果就是老鼠。最重要的假设是青少年长期吸入暴露(3个月) A/J小鼠对e-CIG气雾剂诱导的肺血管改变易致成年雌雄小鼠 导致肺动脉高压，而这些变化会因调味品诱导的炎症而出现和/或加剧。 此外，电子烟引起的心血管毒性可以与个别调味品的毒性进行比较。 根据不利变化的程度进行分级。小鼠(3.5周龄)将通过吸入暴露到成年 (4个月龄)到e-CIG气雾剂从自制的储罐系统中含有丙二醇、甘油、尼古丁和 加和不加调味品；有多种口味(香草、肉桂、薄荷、双层苹果水烟和桃子) 杜松子酒)是基于人类使用和公布的双乙酰水平。单一目标(有多个子目标)是 建议：1)确定是否长期(3个月)吸入染毒对青春期小鼠的影响 E-CIG气雾剂(加或不加调味料)产生结构、形态和/或分子重塑 肺血管系统。电子烟调味品的毒性将根据心肺疾病的程度进行分类 使用本实验室先前开发的订购无烟烟草产品的范例进行更改； 1b)使用暴露在SA1A中的相同小鼠通过检查非末端来研究作用的时间过程 与肺动脉高压和/或肺气肿发展相关的全身性变化，例如血清 电子烟暴露期间-30天、-60天、-90天血管损伤和促炎细胞因子的标记物；1C)至 确定电子烟雾剂在停止3-mo暴露90天后对同一物质的持续影响 在AIMS 1A和1B中测量的肺动脉高压和心肺/炎症结果。结果： 这些研究将授权FDA在电子烟包装上发布更明确的警告标签， 反过来，教育公众与使用调味电子烟相关的健康风险。此外，毫不含糊地 展示调味电子烟的使用如何导致危及生命的健康问题，可能会导致禁止 销售特定调味品/类型的电子烟。这些创新的研究引入了一种新的、未被充分研究的 公共卫生质疑：电子烟的使用，就像长期吸烟一样，会导致心肺/炎症 影响，包括肺内血管的变化，可能导致肺高压，这是一个未被研究的心血管领域 研究。确定蒸发和PH值之间的关系对于制定政策/实施政策具有关键意义 规章制度。这些评估“蒸发”对心肺影响的研究可以开始填补知识空白。 关于毒性和健康的问题，到目前为止阻碍了新法规的推出。