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

项目摘要 近16%的18-24岁的美国年轻人吸食雪茄，最近的一项审查文件显示 越来越多的证据表明，该产品与肺癌、冠心病、主动脉瘤和慢性阻塞性肺病有关。 同样，流行病学研究也将水烟与这些相同的疾病联系起来。到目前为止，几乎没有 关于有毒化学物质的烟草气雾剂特征的研究，以及有限的信息 关于细胞毒性、遗传毒性、炎症和免疫对靶细胞的影响 回应。重要的是，还没有进行对香烟的比较剂量反应研究来研究 这些终点，一个必须解决的研究差距，以提供药效学结果 这些令人上瘾的尼古丁产品。我们的研究将建立强有力的证据- 以政策为基础，告知公众其危险财产。具体目标和研究策略 从这些研究差距中得出结论，并解决RFA中的两个科学领域--毒性和健康 效果。根据FDA的要求，这些研究不是机械性的，而是旨在比较反应 以及烟草产品(香烟、雪茄和水烟)在细胞水平上的影响。中环 该项目的假设是雪茄和水烟产品将表现出明显更大的毒性 与香烟相比，它的特性和预测的健康影响。在二十多年的基础上 在描述复杂气雾剂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有关的危险化学品的最全面的特征 八种常见水烟产品中的气雾剂中的疾病。广泛的剂量反应 使用标准化细胞毒性对这些产品的气雾剂产生的TPM进行表征， 致突变性和遗传毒性测试也将提供有关这些产品的效力的关键见解 对香烟和雪茄造成的毒性和危害与我们刚刚完成的研究有关。通过电池 在短期化验和生物标记物(细胞因子、DNA加合物)中，Aim 2将对完整和 从香烟、雪茄和水烟产品中产生的分级气溶胶(仅限颗粒和气体) 肺上皮细胞、心肌细胞和内皮细胞。每种产品的累积危险分数将为 派生的。目的3重点研究肺上皮细胞对细胞处理4周的适应性反应 这些烟草产品中每一种都有完整的气雾剂。结果的结果将包括更改 细胞因子水平和可能影响免疫反应、信号、侵袭和生长的途径改变。 这些研究应该通知大小呼吸道上皮的普遍反应，这可能 演示文献中记录的促炎环境和/或改变的免疫信号 与粘液高分泌和/或肺气肿有关。

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.