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

• 批准号: 8852703
• 负责人: MATTHEW Lawrence SPRINGER
• 金额: $ 55.31万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 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/8852703
• 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 health; cardiovascular risk factor; consumer product; endothelial dysfunction; environmental tobacco smoke exposure; improved; in vivo; innovation; particle; response; tobacco control; vapor

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）：拟议的研究将根据FOA PAR-12-267，“烟草控制监管研究”，使用在首席研究员实验室开发的创新生理测定法，评估各种吸入烟草制品的相对心血管毒性。这种独特和创新方法的结果将告知FDA不同类型的香烟和相关的吸烟烟草制品对血管内皮的有害影响是如何变化的，血管内皮是心血管疾病的重要因素。这项研究还将为新的和正在出现的烟草制品提供有价值的上市前毒性筛选。本研究采用最近发展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，这种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由于短暂暴露于真实世界水平的烟草烟雾而导致的急性心血管毒性。与人类相比，大鼠的优势包括最小的主体间变异性和收集和分析组织的能力，并且FMD测量方法比传统的离体主动脉段研究更具有生理学相关性。因此，这种方法可以评估在生理条件下接触不同烟草制品的相对毒性，而不需要人类研究中固有的遗传和生活方式等混杂变量。大鼠也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，从而确定这些成分是否对心血管有害，从而可用于评估新兴产品的毒性。该项目将确定口蹄疫损伤的程度，以及剂量反应和短期恢复，并将阐明暴露后血浆对体外和体内内皮细胞影响的差异。目的1是测量不同类型的吸烟烟草制品（含不同量尼古丁和薄荷醇的消费香烟和参考香烟、小雪茄和小雪茄）在血管毒性方面的差异。这提供了关于不同吸烟烟草产品的相对毒性程度和原因的信息，并为告知小雪茄和小雪茄是否应该像香烟一样受到管制建立了坚实的科学基础。目的2是确定特定的烟雾成分参与急性内皮毒性。这项研究确定了特定的烟雾成分是否参与了烟雾引起的内皮功能障碍，并可用于评估新兴烟草制品的毒性。目的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。这为这些吸入的尼古丁释放蒸汽相对于烟草烟雾的吸入提供了至关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。