Tobacco Products and Atherosclerotic Disease

吸烟是可预防死亡的主要原因。虽然吸烟会增加患几种慢性疾病的风险，但近一半与吸烟有关的死亡可能与心血管死亡有关。因此，对香烟和其他烟草制品的监管可以显著降低心血管疾病（CVD）的全球负担。《家庭吸烟预防和烟草控制法》授权FDA监管烟草产品的制造、营销和分销，以保护公众健康。然而，要为烟草制品制定标准，重要的是要知道如何衡量新的和新兴的烟草制品对心血管的影响，以及烟草制品的哪些成分会引起心血管损伤。由于CVD是一种慢性疾病，发展了几年，烟草引起的心血管损伤的生物标志物是迫切需要的，以评估CVD的风险，在足够的时间框架内进行产品评估。此外，为了将损伤的生物标志物与暴露于特定有害和潜在有害（HPHC）烟草成分相关联，必须鉴定反映暴露于烟草制品的特定成分的生物标志物。阐明暴露的生物标志物和损伤的生物标志物之间的关系将使不同烟草制品的毒性之间的比较，并告知未来的人体研究的设计，以评估烟草制品使用的心血管影响。因此，我们项目的总体目标是确定暴露于烟草制品的生物标志物，并将其与动脉粥样硬化（几种心血管疾病的根本原因）联系起来。为了实现这一目标，我们将在apoE基因敲除小鼠和apoE基因敲除大鼠中研究烟草诱导的损伤。我们将动物暴露于不同强度的烟草烟雾和无烟烟草，我们将确定尿液中的醛类代谢产物，并确定它们与暴露程度和持续时间以及动脉粥样硬化病变形成和病变稳定性的关系，以及损伤生物标志物和暴露生物标志物之间的关系如何受到性别和物种以及暴露持续时间的影响。在这些实验中，我们将确定动脉粥样硬化和血栓形成的具体指标，以及这些损伤的生物标志物如何与暴露的生物标志物相关。为了描述HPHC的贡献，我们将鉴定烟草和烟草烟雾的哪些成分有助于动脉粥样硬化形成，我们将检查暴露于暴露的单个成分-尼古丁、丙烯醛和巴豆醛的小鼠中的动脉粥样硬化形成，并确定这些成分的去除如何影响烟草烟雾引起的动脉粥样硬化，以及暴露于这些醛类和相关活性化学物质的程度增加是否会加剧动脉粥样硬化。动脉粥样硬化本项目的成功完成将导致开发经验证的动物模型以建立标准毒性 变化和发现新的心血管损伤生物标志物，可以与烟草暴露的措施。该项目的研究结果将提供有关丙烯醛和巴豆醛等活性醛对卷烟烟雾和无烟烟草心血管毒性的贡献的新信息。这些研究结果将有助于评估HPHC对人类烟草产品毒性的贡献;评估PREP的危害减少程度，并制定政策以规范无烟烟草，卷烟和新兴烟草产品中的HPHC。PHS 398/2590（Rev.06/09）

DESCRIPTION: Smoking is the leading cause of preventable deaths. Although cigarette smoking increases the risk of several chronic diseases, nearly half of smoking related mortality could be linked to cardiovascular deaths. Therefore, regulation of cigarettes and other tobacco products could significant lower the global burden of cardiovascular disease (CVD). The Family Smoking Prevention and Tobacco Control Act gives the FDA the authority to regulate the manufacturing, marketing and distribution of tobacco products to protect public health. However, to set standards for tobacco products, it is important to know how cardiovascular effects of new and emerging tobacco products could be measured and which components of tobacco products induce cardiovascular injury. Because CVD is a chronic disease that develops over several years, biomarkers of tobacco-induced cardiovascular injury are urgently needed to assess CVD risk in a time-frame sufficient for product evaluation. Moreover, to relate biomarkers of injury with exposure to specific harmful and potentially harmful (HPHC) tobacco constituents, it is essential to identify biomarkers that reflect exposure to specific constituents of tobacco products. Elucidation of the relationship between biomarker of exposure and biomarkers of injury will enable comparisons between the toxicities of different tobacco products and inform the design of future human studies for evaluating the cardiovascular effects of tobacco product use. Accordingly, the overall goal of our project is to identify biomarkers of exposure to tobacco products and to relate them to atherosclerosis, the underlying cause of several cardiovascular diseases. To accomplish this goal we will examine tobacco-induced injury in apoE-null mice and apoE-null rats. We will expose animals to varying intensities of tobacco smoke and smokeless tobacco, we will identify urinary metabolites of exposure-derived aldehydes and determine how they relate to the extent and duration of exposure as well as to atherosclerotic lesion formation and lesion stability and how the relationship between the biomarkers of injury and biomarkers of exposure is affected by gender and the species and duration of exposure. In these experiments, we will identify specific indices of atherosclerosis and thrombosis and how these biomarkers of injury are related to the biomarkers of exposure. To delineate the contribution of HPHCs, we will identify which constituents of tobacco and tobacco smoke contribute to atherogenesis, we will examine atherogenesis in mice exposed to individual constituents of exposure - nicotine, acrolein and crotonaldehyde, and determine how removal of these constituents affects atherosclerosis due to tobacco smoke and whether increases in the extent of exposure to these aldehydes and related reactive chemicals exacerbate atherosclerosis. Successful completion of this project will lead to the development of validated animal models to establish standard toxicity changes and the discovery of novel biomarkers of cardiovascular injury that can be associated with measures of tobacco exposure. The findings of this project will provide new information regarding the contribution of reactive aldehydes such as acrolein and crotonaldehyde to the cardiovascular toxicity of cigarette smoke and smokeless tobacco. These findings will be useful in evaluating the contribution of HPHCs to tobacco product toxicity in humans; assessing the extent of harm reduction in PREPs and in developing policies for regulating HPHCs in smokeless tobacco, cigarettes and emerging tobacco products. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page