Diesel Exhaust and Atherosclerotic Plaque Stability

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于空气污染与心血管疾病的发病率和死亡率联系起来。柴油废气等污染物导致心血管疾病的机制尚不清楚，但已经提出了多种可能性。这些反应包括对肺部污染物引起的常见分子介质的反应。已有研究表明，小颗粒可通过肺内多种细胞类型诱导氧化应激和促炎细胞因子的表达。因此，肺部的这种炎症反应很可能也会影响血管中正在进行的炎症。炎症机制与动脉粥样硬化病变的发生和发展有关。细胞因子和其他促炎因子在动脉粥样硬化病变中由白细胞、内皮细胞和平滑肌细胞表达，并被认为通过进一步诱导局部氧化应激而导致一氧化氮介导的扩张丧失，增加基质金属蛋白酶的表达和分泌，导致细胞死亡，从而导致斑块的不稳定。巨噬细胞和平滑肌细胞的死亡在很大程度上是坏死核的形成和纤维帽变薄的原因。这些变化反过来会降低斑块的抗张强度，导致斑块破裂、闭塞性血栓形成和缺血，这些都是心肌梗死和中风的最终原因。在这项提案中，研究人员将借鉴他们在不稳定动脉粥样硬化和氧化应激小鼠模型方面的丰富经验，以及他们在测量小鼠心脏和血管功能方面的经验。他们将研究在独特的受控曝光室中急性和长期暴露于柴油废气对细胞因子分泌、血流介导的扩张、心脏的电特性以及晚期动脉粥样硬化病变的进展和稳定性的影响。研究人员还将通过采用独特的小鼠模型直接研究氧化应激在柴油尾气影响中的作用，这些小鼠模型要么具有增加的能力，特别是在巨噬细胞中产生主要的内源性抗氧化剂谷胱甘肽，要么相反，小鼠产生谷胱甘肽的能力降低。

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.