Measuring relative cardiovascular health risks of inhaled tobacco products

描述（由申请人提供）：拟议的研究将使用主要研究者实验室开发的创新生理测定法评估各种吸入性烟草产品的相对心血管毒性，以响应FOA PAR-12-267，“烟草控制监管研究”。“这种独特而创新的方法的结果将告知FDA不同类型的香烟和相关的吸烟烟草产品对血管内皮细胞的有害影响是如何变化的，这是心血管疾病的一个重要因素。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选。该提案使用最近开发的基于微超声的方法来测量活体大鼠中以流量介导的血管舒张（FMD）形式的内皮功能，该功能在人类中受到主动吸烟和二手烟暴露的损害。这种方法能够检测到在真实世界水平上短暂暴露于烟草烟雾所导致的急性心血管毒性。大鼠具有优于人类的优势，包括最小的受试者间变异性和采集和分析组织的能力，并且FMD测量方法比主动脉分离节段的经典离体研究更具生理相关性。因此，这种方法可以评估在生理条件下暴露于不同烟草制品的相对毒性，而不需要人类研究固有的遗传学和生活方式的混杂变量。大鼠也可以暴露于烟雾的纯化成分，这些成分被怀疑是内皮功能障碍的介质，以及这些成分的拮抗剂，从而能够确定这些成分是否产生有害的心血管作用，因此可以用于评估新兴产品的毒性。该项目将确定FMD的损伤程度，以及剂量反应和短期恢复，并将阐明暴露后血浆对离体和体内内皮细胞的影响差异。目的1是测量不同类型的吸烟烟草产品（具有不同量的尼古丁和薄荷醇的消费者香烟和参考香烟、小雪茄和小雪茄）之间的血管毒性差异。这提供了有关不同吸烟烟草产品毒性的相对程度和原因的信息，并建立了坚实的科学基础，以告知小雪茄和小雪茄是否应该像香烟一样受到监管。目的2是确定参与急性内皮细胞毒性的特定烟雾成分。这确定了特定的烟雾成分是否参与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。目的3是评估和了解不同尼古丁水平和载体化学成分的电子烟蒸汽的心血管毒性。这为这些吸入尼古丁递送蒸气相对于烟草烟雾吸入的心血管毒性评估提供了关键，并为有关电子烟的监管决策建立了坚实的科学基础。

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.