ENHANCEMENT OF CORONARY CONSTRICTION BY COMBUSTION-SOURCE AIR TOXICS

描述（由申请人提供）：空气污染与每日心肌梗死和心血管死亡率增加呈正相关。最近的研究结果强烈暗示了新鲜车辆尾气的作用，清楚地表明，冠状动脉事件的增加与交通暴露密切相关。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。该研究将试图验证我们之前的观察结果，即发动机尾气中的特定气体成分是环境空气污染的重要贡献者，可能通过减弱冠状动脉扩张和增强收缩而具有病理性血管活性特性。ApoE-/-小鼠的心电图和血管异常发生在吸入新鲜柴油或汽油废气时，而不是老化的、重悬浮的道路灰尘，这表明新鲜排放物中驱动心血管反应的某些化合物可能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废气的气态和颗粒相中，可能是试图确定过滤器收集或浓缩的PM的毒性可能低估了通过消除气态共污染物对健康的不利影响。在这项研究中，我们有三个主要的假设需要验证：(1)我们假设整个排放物的气体成分可以通过氧化修饰内源性循环磷脂直接对血管组织产生影响，也可以通过间接影响内源性循环磷脂，从而改变这些脂质的天然功能。我们的研究发现，在没有明显肺部或全身炎症的情况下，暴露于发动机排放的小鼠循环中氧化的低密度脂蛋白和血管中的脂质过氧化副产物表明，肺部可能存在轻度氧化过程，并在全身转移；(2)我们假设导致扩张功能受损的主要机制是过氧亚硝酸盐的形成和内皮型一氧化氮合酶的解偶联。长期低浓度的汽油废气暴露后，血管中的硝基酪氨酸水平上调，但过氧亚硝酸盐对血管的急性影响程度尚不清楚；(3)我们假设观察到的t波异常反映了发射诱导的内皮细胞功能损伤，导致易感受试者冠状动脉血流减少和心肌缺血。来自几个实验室的空气污染引起的大鼠和小鼠心电图异常的发现尚未在绝对心血管病理学方面得到证实；我们预测易感小鼠品系（ApoE-/-）会出现冠状动脉血流减少和轻度缺血。与公共卫生相关的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学和化学机制。这些研究的结果将有助于评估和管理接触空气污染对个人健康的影响风险。

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.