Tobacco Products and Atherosclerotic Disease

描述：吸烟是可预防死亡的主要原因。尽管吸烟会增加患几种慢性病的风险，但近一半与吸烟相关的死亡可能与心血管死亡有关。因此，对香烟和其他烟草产品的监管可以显著降低全球心血管疾病(CVD)的负担。《家庭吸烟预防和烟草控制法案》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，要制定烟草产品的标准，重要的是要知道如何衡量新出现的烟草产品对心血管的影响，以及烟草产品的哪些成分会导致心血管损伤。由于心血管疾病是一种经过几年发展的慢性疾病，迫切需要烟草引起的心血管损伤的生物标记物来评估心血管疾病的风险，时间框架足够用于产品评估。此外，要将伤害的生物标记物与接触特定有害和潜在有害(HPHC)烟草成分联系起来，至关重要的是确定反映烟草产品特定成分暴露的生物标记物。阐明暴露生物标记物和损伤生物标记物之间的关系将有助于比较不同烟草产品的毒性，并为未来评估烟草产品对心血管影响的人体研究提供设计依据。因此，我们项目的总体目标是确定暴露于烟草产品的生物标记物，并将它们与动脉粥样硬化联系起来，动脉粥样硬化是几种心血管疾病的根本原因。为了实现这一目标，我们将研究烟草对apoE基因缺失小鼠和apoE基因缺失大鼠的损伤作用。我们将使动物暴露在不同强度的烟草烟雾和无烟烟草中，我们将识别暴露衍生的醛的尿代谢物，并确定它们与暴露的程度和时间、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性别、暴露种类和暴露时间的影响。在这些实验中，我们将确定动脉粥样硬化和血栓形成的特定指标，以及这些损伤的生物标记物如何与暴露的生物标记物相关。为了阐明HPHC的作用，我们将确定烟草和烟草烟雾中哪些成分有助于动脉粥样硬化，我们将研究暴露于尼古丁、丙烯醛和巴豆醛的单个暴露成分的小鼠的动脉粥样硬化，并确定去除这些成分如何影响烟草烟雾导致的动脉粥样硬化，以及暴露于这些醛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。该项目的成功完成将导致开发有效的动物模型来建立标准毒性 可与烟草暴露措施相关的心血管损伤的新生物标志物的变化和发现。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香烟烟雾和无烟烟草的心血管毒性的贡献的新信息。这些发现将有助于评估HPHCs对烟草产品对人体的毒性的贡献；评估PREP中减少危害的程度，以及制定管制无烟烟草、香烟和新兴烟草产品中HPHCs的政策。PHS 398/2590(06/09版)页面续格式页面

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