Assessing Toxicant Properties of Cigarillo and Hookah Aerosols in Lung Epithelial and Cardiac Cells Through Aerosol Exposure

通过气溶胶暴露评估小雪茄和水烟气溶胶对肺上皮和心肌细胞的毒性特性

• 批准号: 9976518
• 负责人: Steven A Belinsky
• 金额: $ 63.86万
• 依托单位: LOVELACE BIOMEDICAL & ENVIRONMENTAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-20 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9976518
• 关键词: Address; Aerosols; Affect; Age; Aldehydes; Aortic Aneurysm; Aromatic Polycyclic Hydrocarbons; Biological Assay; Biological Markers; Blood; Carcinogens; Cardiac; Cardiac Myoblasts; Cardiopulmonary; Cardiovascular system; Cell Death; Cell Line; Cells; Charcoal; Chemicals; Chronic; Chronic Obstructive Airway Disease; Cigar Smoking; Cigarette; Comet Assay; Complex; Coronary artery; Coronary heart disease; Cotinine; Coupled; DNA Adducts; DNA Damage; DNA strand break; Data; Development; Disease; Dose; Endothelial Cells; Epithelial; Epithelial Cells; Epithelium; Exposure to; Gases; Gene Expression; Generations; Growth; Hazardous Chemicals; Health; Heritability; Human; Immune; Immune response; Immune signaling; In Vitro; Inflammation; Kentucky; Link; Lipid Peroxidation; Literature; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Modeling; Molecular; Mucous body substance; Neutral Red; Nicotine; Nitrosamines; Outcome; Oxidative Stress; Particulate Matter; Pathway interactions; Pharmacodynamics; Physiological; Policies; Property; Pulmonary Emphysema; Pulmonary Heart Disease; Reactive Oxygen Species; Reporting; Research; Risk; Signal Transduction; Smoking; Standardization; System; Thiobarbituric Acid Reactive Substances; Thymidine Kinase; Tissues; Tobacco; Tobacco smoke; Toxic effect; Work; airway epithelium; bronchial epithelium; chemical property; cigarette smoke; cigarillos; comparative; cytokine; cytotoxic; cytotoxicity; design; epidemiology study; evidence base; experience; exposed human population; genotoxicity; hazard; hookah; human model; immunoregulation; in vitro Model; inflammatory milieu; insight; lung development; particle; physical property; predictive tools; respiratory; response; smoke inhalation; stem cells; tobacco exposure; tobacco products; toxicant; transcriptome; transcriptome sequencing; treatment response; uptake; whole genome; young adult

Project Summary Nearly 16% of US young adults ages 18–24 report smoking cigars and a recent review documents growing evidence linking this product to lung cancer, coronary heart disease, aortic aneurysm and COPD. Similarly, epidemiological studies link waterpipe tobacco to these same diseases. To date, there are few studies characterizing these tobacco aerosols with respect to toxicant chemicals, and limited information regarding effects on target cells with respect to cytotoxicity, genotoxicity, inflammation, and immune responses. Importantly, no comparative dose response studies to cigarettes have been conducted to study these endpoints, a research gap that is imperative to address for providing pharmacodynamic outcomes for these addictive nicotine-containing products. Our research will allow for establishment of strong evidence- based policies to inform the public of their hazardous properties. The specific aims and research strategy derive from these research gaps and address two of the scientific domains in the RFA, toxicity and health effects. As mandated by the FDA, the studies are not mechanistic, but are designed to compare responses and effects at the cellular level across tobacco products (cigarettes, cigarillos, and hookah). The central hypothesis of this project is that cigarillo and hookah tobacco products will show significantly greater toxicant properties and predicted health effects when compared to cigarettes. Building on more than two decades of experience in characterizing the physical and chemical properties of complex aerosols, Aim 1 will provide the most comprehensive characterization to date for hazardous chemicals linked to cancer and cardiopulmonary diseases in aerosols from eight common hookah tobacco products. The extensive dose response characterization of the TPM generated from aerosols of these products using standardized cytotoxicity, mutagenicity, and genotoxicity assays will also provide key insight regarding the potency of these products for causing toxicity and harm relative to our studies just completed for cigarettes and cigarillos. Through a battery of short-term assays and biomarkers (cytokines, DNA adducts), Aim 2 will critically evaluate complete and fractionated (particles and gas only) aerosols generated from cigarettes, cigarillos, and hookah products in lung epithelial cells, cardiac cells, and endothelial cells. A cumulative hazard score for each product will be derived. Aim 3 focuses on adaptive responses of lung epithelial cells in response to treatment of cells for 4-wk with complete aerosols from one each of these tobacco products. Outcomes from results will include changes in cytokine levels and pathway alterations that may impact immune response, signaling, invasion, and growth. These studies should inform generalized responses of the large and small airway epithelium that could demonstrate a pro-inflammatory environment and/or altered immune signaling documented in the literature to be associated with mucous hypersecretion and/or emphysema.

项目摘要 我们近16％的年轻人18-24岁的年轻人报告抽雪茄和最近的评论文件 越来越多的证据将该产品与肺癌，冠心病，主动脉瘤和COPD联系起来。 同样，流行病学研究将水烟烟草与这些相同的疾病联系起来。迄今为止，很少 这些有关毒素化学物质和信息有限的研究表征了这些烟草气溶胶 关于细胞毒性，遗传毒性，炎症和免疫的影响的影响 回答。重要的是，尚未对香烟进行比较剂量反应研究研究 这些终点，这是一个研究差距，必须解决为提供药效结果的结果 这些其他含尼古丁的产品。我们的研究将允许建立强有力的证据 - 基于政策，以告知公众他们的危险财产。具体目的和研究策略 来自这些研究差距，并解决RFA，毒性和健康中的两个科学领域 效果。根据FDA的要求，研究不是机械的，而是旨在比较响应 以及烟草产品（香烟，雪茄和水烟）的细胞水平的影响。中央 该项目的假设是雪茄和水烟烟草产品将显示出更大的毒性 与香烟相比，特性和预测的健康影响。建立在二十多年的 在表征复杂气溶胶的物理和化学特性方面的经验，AIM 1将提供 迄今为止与癌症和心肺有关的有害化学物质的最全面的特征 来自八种常见水烟烟草产品的气溶胶中的疾病。广泛的剂量反应 使用标准化的细胞毒性，从这些产品的气溶胶产生的TPM表征， 诱变性和遗传毒性测定也将提供有关这些产品效力的关键见解 相对于我们的研究造成毒性和伤害，刚刚完成了香烟和雪茄。通过电池 在短期评估和生物标志物（细胞因子，DNA加合物）中，AIM 2将严格评估完整和 用香烟，香烟和水烟产物产生的分离（仅颗粒和气体）在 肺上皮细胞，心脏细胞和内皮细胞。每种产品的累积危险分数将是 衍生的。 AIM 3的重点是肺上皮细胞的适应性反应，以应对4-WK细胞的治疗 这些烟草产品中的每种都有完整的气溶胶。结果的结果将包括更改 在细胞因子水平和途径改变中，可能会影响免疫反应，信号传导，侵袭和生长。 这些研究应告知大型和小气道上皮的广义反应 演示文献中记录的促炎环境和/或改变的免疫信号传导 与粘液过度分泌和/或肺气肿有关。