Measuring relative cardiovascular health risks of inhaled tobacco products

测量吸入烟草制品的相对心血管健康风险

基本信息

批准号：
8685741
负责人：
MATTHEW Lawrence SPRINGER
金额：
$ 58.92万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8685741
关键词：
Acute Adverse effects Aorta Biological Assay Blood Vessels Breathing Cardiovascular Diseases Cardiovascular system Chemicals Cigar Cigarette Confounding Factors (Epidemiology)Decision Making Detection Dose Economic Burden Economic Models Endothelial Cells Endothelium Environmental Risk Factor Environmental Tobacco Smoke Exposure to Genetic Goals Harvest Health Health Care Costs Human Impairment Laboratories Lead Life Life Style Light Liquid substance Mainstreaming Marketing Measurable Measurement Measures Mediating Mediator of activation protein Menthol Methods Nicotine Nicotine Inhaler Physiological Plasma Principal Investigator Propylene Glycols Public Health Rattus Recovery Regulation Relative (related person)Research Research Priority Risk Smoke Smoking Solid Tissues Tobacco Tobacco smoke Toxic effect Ultrasonography United States Food and Drug Administration Vascular Diseases Vasodilation base cardiovascular risk factor cigarette smoking consumer product endothelial dysfunction improved in vivo innovation particle public health relevance response tobacco control vapor

项目摘要

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.

描述（由申请人提供）：拟议的研究将使用首席研究员实验室开发的创新生理测定来评估各种吸入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”。 ”这种独特和创新方法的结果将向 FDA 通报不同类型的卷烟和相关吸烟产品对血管内皮层的有害影响有何不同，而血管内皮层是心血管疾病的重要诱因。该研究还将为新兴烟草产品提供有价值的上市前毒性筛查。该提案使用最近开发的基于微超声的方法以血流介导的血管舒张（FMD）的形式测量活体大鼠的内皮功能，主动吸烟和二手烟暴露都会损害人类的内皮功能。这种方法能够检测现实世界水平的短暂暴露于烟草烟雾所引起的急性心血管毒性。大鼠比人类具有优势，包括最小的受试者间变异性以及采集和分析组织的能力，并且 FMD 测量方法比主动脉分离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接触不同烟草产品的相对毒性，而无需人类研究固有的遗传学和生活方式的混杂变量。大鼠还可以暴露于被怀疑是内皮功能障碍介质的纯化烟雾成分以及这些成分的拮抗剂，从而能够确定这些成分是否会产生有害的心血管作用，从而可用于评估新兴产品的毒性。该项目将确定 FMD 损伤的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影响的差异。目标 1 是测量不同类型的吸烟烟草产品（尼古丁和薄荷醇含量不同的消费者香烟和参考香烟、小雪茄和小雪茄）之间血管毒性的差异。这提供了有关不同吸食烟草产品毒性的相对程度和原因的信息，并为小雪茄和小雪茄是否应像卷烟一样受到监管奠定了坚实的科学基础。目标 2 是确定特定烟雾成分与急性内皮毒性的关系。这确定了特定的烟雾成分是否与烟雾引起的内皮功能障碍有关，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含量和载体化学成分的电子烟蒸气的心血管毒性。这为这些吸入的尼古丁输送蒸气相对于烟草烟雾吸入提供了重要的心血管毒性评估，并为有关电子烟的监管决策奠定了坚实的科学基础。