Diesel Exhaust and Atherosclerotic Plaque Stability

柴油机尾气和动脉粥样硬化斑块的稳定性

• 批准号: 6839894
• 负责人: MICHAEL E ROSENFELD
• 金额: $ 37.38万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-19 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6839894
• 关键词: air pollution; atherosclerotic plaque; cardiovascular disorder; cytokine; disease /disorder model; engine exhaust; environmental exposure; genetically modified animals; glutathione; laboratory mouse; macrophage; myocardium; oxidative stress

DESCRIPTION (provided by applicant): There is epidemiological, clinical, and experimental data linking chronic and acute exposure to air pollution with morbidity and mortality from cardiovascular disease. The mechanisms by which pollutants such as diesel exhaust contribute to cardiovascular disease are unknown but multiple possibilities have been posited. These include responses to common molecular mediators elicited by the pollutants in the lungs. Small particulates have been shown to induce oxidative stress and expression of pro-inflammatory cytokines by many cell types within the lungs. It is likely therefore that this inflammatory response in the lungs also impacts the ongoing inflammation in the blood vessels. Inflammatory mechanisms are associated with both atherosclerotic lesion initiation and progression. Cytokines and other proinflammatory factors are expressed by leukocytes, endothelial cells, and smooth muscle cells in atherosclerotic lesions and are thought to contribute to the destabilization of the plaques by further inducing localized oxidant stress with consequent loss of nitric oxide mediated dilation, increasing expression and secretion of matrix metalloproteinases, and causing cell death. The death of macrophages and smooth muscle cells is largely responsible for the formation of the necrotic core and thinning of the fibrous cap. These changes in turn, reduce the tensile strength of the plaques and lead to plaque rupture, occlusive thrombosis and ischemia, the ultimate causes of myocardial infarction and stroke. In this proposal, the investigators will draw on their extensive experience with mouse models of unstable atherosclerosis and oxidant stress and their experience in measuring cardiac and vascular function in mice. They will investigate how acute and chronic exposures to diesel exhaust in a unique controlled exposure chamber impact on cytokine secretion, flow mediated dilation, the electrical properties of the heart and the progression and stability of advanced atherosclerofic lesions. The investigators will also directly address the role of oxidant stress in mediating the effects of diesel exhaust by employing unique mouse models that have either an increased capacity to produce the main endogenous antioxidant glutathione specifically in macrophages or conversely, mice that have a reduced capacity to produce glutathione.

描述（由申请人提供）： 有流行病学，临床和实验数据，将慢性和急性暴露与空气污染与心血管疾病的发病率和死亡率联系起来。柴油排气等污染物导致心血管疾病的机制尚不清楚，但已提出了多种可能性。这些包括对肺部污染物引起的常见分子介质的反应。 已经显示出小的颗粒物可诱导肺部许多细胞类型的促炎细胞因子的氧化应激和表达。 因此，肺部的这种炎症反应也可能会影响血管中持续的炎症。 炎症机制与动脉粥样硬化病变的启动和进展均相关。 Cytokines and other proinflammatory factors are expressed by leukocytes, endothelial cells, and smooth muscle cells in atherosclerotic lesions and are thought to contribute to the destabilization of the plaques by further inducing localized oxidant stress with consequent loss of nitric oxide mediated dilation, increasing expression and secretion of matrix metalloproteinases, and causing cell death. 巨噬细胞和平滑肌细胞的死亡主要是导致坏死核的形成和纤维帽的变薄。这些变化反过来，降低了斑块的拉伸强度，并导致斑块破裂，闭塞性血栓形成和缺血，这是心肌梗塞和中风的最终原因。 在此提案中，研究人员将利用他们在不稳定的动脉粥样硬化和氧化剂压力的小鼠模型中的丰富经验，以及在小鼠中测量心脏和血管功能方面的经验。 他们将研究如何在独特的受控暴露室中急性和慢性暴露于柴油排气，对细胞因子分泌，流动介导的扩张，心脏的电性能以及晚期动脉粥样硬化病变的进展和稳定性。 研究人员还将通过采用独特的小鼠模型来直接解决氧化应激在介导柴油排气的作用中的作用，这些小鼠模型要么具有提高能力来产生主要的内源性抗氧化剂谷胱甘肽，或者是在巨噬细胞中，或相反的小鼠，其能力降低了产生谷胱甘肽的能力。