Measuring relative cardiovascular health risks of inhaled tobacco products

描述(由申请人提供)：这项拟议的研究将使用首席调查者实验室开发的一种创新的生理学测试方法，对各种吸入性烟草产品的相对心血管毒性进行评估，以回应FOA PAR-12-267，“烟草控制监管研究”。这一独特和创新的方法的结果将向FDA通报不同类型的香烟和相关的吸烟烟草产品对血管内皮细胞衬里的有害影响的不同，血管内皮衬里是心血管疾病的重要诱因。这项研究还将为新的和新兴的烟草产品提供有价值的上市前毒性筛查。这项建议使用最近开发的基于显微超声的方法来测量活体大鼠的血流介导血管扩张(FMD)形式的内皮功能，在人类中，主动吸烟和二手烟暴露都会损害FMD。这一方法使得能够在现实世界水平上检测到短暂暴露于烟草烟雾所造成的急性心血管毒性。与人类相比，大鼠具有优势，包括最小的受试者间变异性以及采集和分析组织的能力，而且FMD测量方法比经典的体外主动脉节段研究更具生理学意义。因此，这种方法可以评估在生理条件下接触不同烟草产品的相对毒性，而不需要人类研究固有的遗传和生活方式的混淆变量。大鼠还可以暴露于被怀疑为内皮功能障碍媒介的净化烟雾成分以及这些成分的拮抗剂中，从而能够确定这些成分是否对心血管产生有害影响，从而可以用于评估新兴产品的毒性。该项目将确定FMD的损害程度，以及剂量反应和短期恢复，并将阐明暴露后血浆对体外和体内内皮细胞影响的差异。目标1是测量不同类型的吸烟烟草产品(消费香烟和含有不同数量的尼古丁和薄荷醇的参考香烟、雪茄和少量雪茄)之间的血管毒性差异。这提供了有关不同吸烟烟草产品的相对毒性程度和原因的信息，并为告知是否应该像香烟一样对雪茄和小雪茄进行监管奠定了坚实的科学基础。目的2确定特定烟雾成分在急性内皮细胞毒性中的作用。这确定了特定的烟雾成分是否参与了烟雾诱导的内皮功能障碍，并可用于评估新兴烟草产品的毒性。目标3是评估和了解不同尼古丁水平和车辆化学成分的电子烟蒸气的心血管毒性。这为这些吸入尼古丁释放的蒸气相对于烟草烟雾吸入提供了关键的心血管毒性评估，并为有关电子烟的监管决定奠定了坚实的科学基础。

DESCRIPTION (provided by applicant): The proposed research will evaluate relative cardiovascular toxicities of diverse, inhaled tobacco products, using an innovative physiological assay developed in the Principal Investigator's laboratory, in response to FOA PAR-12-267, "Tobacco Control Regulatory Research." The results of this unique and innovative approach will inform the FDA about how different types of cigarettes and related smoked tobacco products vary in their harmful effects on the endothelial lining of blood vessels, an important contributor o cardio-vascular disease. The research will also yield valuable pre-market toxicity screens for new and emerging tobacco products. This proposal uses a recently-developed micro-ultrasound-based approach to measure endothelial function in living rats in the form of flow-mediated vasodilation (FMD), which is impaired in humans by both active smoking and secondhand smoke exposure. This approach has enabled detection of acute cardiovascular toxicity resulting from brief exposure to tobacco smoke at real-world levels. Rats have advantages over humans including minimal inter-subject variability and the ability to harvest and analyze tissue, and the FMD measurement approach is more physiologically relevant than classic ex vivo studies of isolated segments of aorta. Therefore, this approach can assess relative toxicity of exposure to different tobacco products under physiological conditions without the confounding variables of genetics and lifestyle that are inherent to human studies. Rats can also be exposed to purified constituents of smoke that are suspected mediators of endothelial dysfunction, and to antagonists of those constituents, enabling determination of whether these constituents exert deleterious cardiovascular effects and thus can be used to evaluate toxicity of emerging products. The project will determine extent of impairment of FMD, as well as dose response and short-term recovery, and will illuminate differences in effects of post-exposure plasma on endothelial cells ex vivo and in vivo. Aim 1 is to measure differences in vascular toxicity between different types of smoked tobacco products (consumer and reference cigarettes with varying amounts of nicotine and menthol, cigarillos, and little cigars). This provides information about relative extents and causes of toxicity from different smoked tobacco products, and establishes a solid scientific basis to inform whether cigarillos and little cigars should be regulated like cigarettes. Aim 2 is to determine involvement of specific smoke components in acute endothelial toxicity. This establishes whether specific smoke constituents are involved in smoke-induced endothelial dysfunction and can be used to evaluate toxicity of emerging tobacco products. Aim 3 is to evaluate and understand cardiovascular toxicity of vapors from e-cigarette of varying nicotine levels and vehicle chemical composition. This provides crucial cardiovascular toxicity assessment of these inhaled nicotine-delivery vapors relative to tobacco smoke inhalation, and establishes a solid scientific basis for regulatory decisions regarding e-cigarettes.