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 近16%的美国18-24岁的年轻人报告吸烟雪茄，最近的一份审查文件显示， 越来越多的证据表明该产品与肺癌、冠心病、主动脉瘤和COPD有关。 同样，流行病学研究将水烟与这些疾病联系起来。迄今为止， 关于有毒化学物质的烟草气溶胶特征的研究，以及有限的信息 关于细胞毒性、遗传毒性、炎症和免疫方面对靶细胞的影响， 应答重要的是，没有进行香烟的比较剂量反应研究， 这些终点，这是一个研究空白，必须解决提供药效学结果， 这些含有尼古丁的成瘾产品。我们的研究将提供有力的证据- 根据政策，告知公众其危险属性。具体目标和研究策略 从这些研究空白中得出，并解决RFA中的两个科学领域，毒性和健康 方面的影响.根据FDA的要求，这些研究不是机械性的，而是为了比较反应 以及烟草制品（香烟、小雪茄和水烟）在细胞水平上的影响。中央 该项目假设是，小雪茄和水烟烟草产品将显示出明显更大的毒性， 与香烟相比，它的特性和预测的健康影响。在20多年来 在表征复杂气溶胶的物理和化学性质方面的经验，目标1将提供 迄今为止，与癌症和心肺功能相关的危险化学品的最全面表征 八种常见的水烟烟草产品气溶胶中的疾病。广泛的剂量反应 使用标准化细胞毒性表征这些产品的气溶胶产生的TPM， 致突变性和遗传毒性试验也将提供关于这些产品的效力的关键见解， 相对于我们刚刚完成的香烟和小雪茄的研究，通过电池 短期检测和生物标志物（细胞因子，DNA加合物），目标2将严格评估完整和 香烟、小雪茄和水烟产品产生的分级（仅颗粒和气体）气溶胶， 肺上皮细胞、心肌细胞和内皮细胞。每种产品的累积危险评分将为 推导目的3关注肺上皮细胞对细胞处理4周的适应性反应 每种烟草制品都有完整的气雾剂。结果将包括变化 细胞因子水平和途径改变可能影响免疫应答、信号传导、侵袭和生长。 这些研究应该告知大气道上皮和小气道上皮的一般性反应， 证明文献中记载的促炎环境和/或改变的免疫信号传导， 与粘液分泌过多和/或肺气肿有关。