ENHANCEMENT OF CORONARY CONSTRICTION BY COMBUSTION-SOURCE AIR TOXICS

描述（由申请人提供）：空气污染与心肌梗死和心血管死亡率的每日发病率增加呈正相关。 最近的研究结果强烈暗示了新鲜车辆尾气的作用，明确显示了急性交通暴露相关的冠状动脉事件的增加。 临床和实验研究表明，空气污染物可以急性诱导血管收缩机制，尽管这些研究与最终的心脏后遗症之间的明确联系尚未得到证实。 拟议的研究将试图验证我们以前的观察结果，即发动机排气中的特定气体成分是环境空气污染的重要贡献者，可能通过钝化冠状动脉扩张和增强收缩而具有病理性血管活性。 当ApoE-/-小鼠吸入新鲜柴油或汽油废气而不是老化的再悬浮道路灰尘时，会发生ECG和血管异常，这表明新鲜排放物中驱动心血管反应的某些化合物可能会在收集或浓缩的颗粒中丢失。 新鲜排放物中的许多挥发性和半挥发性化合物可以存在于整个排气的气相和颗粒相中，并且可能是试图确定过滤器收集或浓缩的PM的毒性可能低估了消除气态共污染物对健康的不利影响。我们有三个主要的假设，以测试在这项研究中：（1）我们假设，气体成分的整体排放可以直接影响血管组织，以及间接通过氧化修饰内源性循环磷脂，从而改变这些脂质的天然功能。 我们的研究结果表明，在没有明显的肺部或全身炎症的情况下，暴露于发动机排放物的小鼠的循环中的氧化低密度脂蛋白和血管中的脂质过氧化副产物表明，肺部可能存在全身转移的轻度氧化过程;（二）我们推测，导致舒张功能受损的主要机制是过氧亚硝基阴离子的形成和内皮一氧化氮的解偶联。氧化物合酶 慢性低水平汽油废气暴露后，血管系统中的硝基酪氨酸上调，但尚不清楚过氧亚硝酸盐对血管的急性影响程度;（3）我们假设观察到的T波异常反映了排放诱导的内皮细胞功能受损，导致脆弱受试者冠状动脉血流减少和心肌缺血。 从几个实验室的空气污染诱导的大鼠和小鼠心电图异常的调查结果还没有得到验证的绝对心血管病理学方面，我们预测减少冠状动脉血流和轻度缺血将发生在易感小鼠品系（ApoE-/-）。 空气污染对心血管的影响正逐渐被认为是一个主要的公共卫生问题。这些研究将检查空气污染引起的不良冠状动脉事件的生物和化学机制。 这些研究的结果将有助于评估和管理空气污染对健康影响的个人风险。

DESCRIPTION (provided by applicant): Air pollution is positively associated with an increased daily incidence of myocardial infarction and cardiovascular mortality. Recent findings strongly implicate a role for fresh vehicular exhaust, clearly showing elevated coronary events related acutely to traffic exposure. Clinical and experimental research suggests that air pollutants can acutely induce a vasoconstrictive mechanism, though a clear connection between such studies and the ultimate cardiac sequelae has not been confirmed. The proposed study will seek to validate our previous observations that specific gaseous components of engine exhaust, which are a significant contributor to ambient air pollution, may have pathological vasoactive properties by blunting coronary dilation and enhancing constriction. ECG and vascular abnormalities in ApoE-/- mice occurred when exposed by inhalation to fresh diesel or gasoline exhaust, but not aged, resuspended road dust, suggest that certain compounds in fresh emissions that drive cardiovascular responses may be lost in collected or concentrated particles. Many volatile and semivolatile compounds in fresh emissions can exist in both the gaseous and particulate phases of whole exhaust, and it may be that attempts to ascertain toxicity of filter-collected or concentrated PM may underestimate the adverse health effects by eliminating the gaseous co-pollutants. We have three primary hypotheses to test in this study: (1) We hypothesize that gaseous components of whole emissions can exert effects directly on vascular tissue as well as indirectly by oxidatively modifying endogenous circulating phospholipids, thereby altering the native function of those lipids. Our findings of oxidized low density lipoprotein in the circulation and lipid peroxidation by-products in the vasculature of engine emission-exposed mice, in the absence of overt pulmonary or systemic inflammation suggests that there may be a mild oxidative process in the lung that transfers systemically; (2) We hypothesize that the predominant mechanism driving impaired dilatory function is the formation of peroxynitrite and uncoupling of endothelial nitric oxide synthase. Nitrotyrosine is upregulated in the vasculature following chronic, low-level gasoline exhaust exposure, but it is unknown to what degree peroxynitrite impacts acutely on the vessels; and (3) We hypothesize that observed T-wave abnormalities reflect emission-induced impairment of endothelial cell function, leading to diminished coronary flow and myocardial ischemia in vulnerable subjects. Findings of air pollution-induced rat and mouse ECG abnormalities from several laboratories have not been validated in terms of absolute cardiovascular pathology; we predict diminished coronary flow and mild ischemia will occur in the susceptible mouse strain (ApoE-/-). PUBLIC HEALTH RELEVANCE Cardiovascular effects of air pollution are becoming recognized as a major public health concern. These studies will examine both biological and chemical mechanisms of air pollution-induced adverse coronary events. Results from these studies will assist in the assessment and management of personal risk of health effects from air pollution exposure.