Diesel Exhaust and Atherosclerotic Plaque Stability

描述（由申请人提供）： 有流行病学、临床和实验数据将长期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。柴油机尾气等污染物导致心血管疾病的机制尚不清楚，但已提出多种可能性。这些包括对肺部污染物引起的常见分子介质的反应。 小颗粒已被证明可诱导氧化应激和肺内许多细胞类型的促炎细胞因子表达。 因此，肺部的这种炎症反应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进展相关。 细胞因子和其它促炎因子由动脉粥样硬化病变中的白细胞、内皮细胞和平滑肌细胞表达，并且被认为通过进一步诱导局部氧化应激导致一氧化氮介导的扩张的损失、增加基质金属蛋白酶的表达和分泌以及引起细胞死亡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导致了坏死核心的形成和纤维帽的变薄。这些变化反过来又降低了斑块的抗张强度，导致斑块破裂、闭塞性血栓形成和局部缺血，最终导致心肌梗死和中风。 在这项提案中，研究人员将利用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暴露室中急性和慢性暴露于柴油废气如何影响细胞因子分泌，流动介导的扩张，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。 研究人员还将通过采用独特的小鼠模型直接解决氧化应激在介导柴油机尾气影响中的作用，这些小鼠模型具有增加的能力，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，或者相反，小鼠具有减少的能力产生谷胱甘肽。

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.