ENHANCEMENT OF CORONARY CONSTRICTION BY COMBUSTION-SOURCE AIR TOXICS

燃烧源空气毒物增强冠状动脉收缩

• 批准号: 8035985
• 负责人: Matthew J Campen
• 金额: $ 32.9万
• 依托单位: UNIVERSITY OF NEW MEXICO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8035985
• 关键词: 3-nitrotyrosine; Acetaldehyde; Affect; Air; Air Pollutants; Air Pollution; Aldehydes; Alkanes; Animal Model; Animals; Antibodies; Apolipoprotein E; Automobile Driving; Automobile Exhaust; Bioavailable; Biological; Biological Assay; Blood Circulation; Blood Vessels; Breathing; Carbon Monoxide; Cardiac; Cardiovascular Pathology; Cardiovascular system; Cell physiology; Chemicals; Chronic; Clinical Research; Complex Mixtures; Coronary; Coronary artery; Dust; Electrocardiogram; Endothelial Cells; Endothelin; Endothelin-1; Engine Exhaust; Epidemiologic Studies; Event; Exposure to; Gases; Gasoline; Health; Hypoxia; Impairment; In Vitro; Incidence; Inflammation; Inhalation Exposure; Ischemia; LOX gene; Laboratories; Link; Lipid Peroxidation; Lipids; Lipoproteins; Lung; Measurement; Measures; Mediator of activation protein; Misonidazole; Modification; Mouse Strains; Mus; Myocardial Infarction; Myocardial Ischemia; Myocardial tissue; Nitric Oxide; Nitrogen Dioxide; Outcome; Particulate; Particulate Matter; Pathologic; Pathway interactions; Peroxonitrite; Phase; Phospholipids; Population Study; Preparation; Process; Property; Public Health; Rattus; Reporting; Risk; Role; Signal Transduction; Source; Superoxides; Testing; Tissues; Toxic effect; Transcript; Vascular Endothelial Growth Factors; Vehicle Emissions; aged; constriction; exhaust; heart rate variability; hexadecane; human NOS3 protein; impaired driving performance; interest; mortality; oxidized lipid; oxidized low density lipoprotein; particle; pollutant; public health relevance; research study; response; sulfo-N-succinimidyl oleate; trafficking; uptake; vascular bed

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.

描述（由申请人提供）：空气污染与心肌梗塞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，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，空气污染物可以急剧诱发血管收缩机制，尽管此类研究与最终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之前的观察结果，即发动机排气中的特定气体成分是造成环境空气污染的重要因素，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。 当 ApoE-/- 小鼠吸入新鲜柴油或汽油废气时，会出现心电图和血管异常，但不会出现老化、再悬浮的道路灰尘，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同时存在于整个废气的气态和颗粒相中，尝试确定过滤器收集的或浓缩的 PM 的毒性可能会低估消除气态副污染物对健康的不利影响。 。我们在这项研究中测试了三个主要假设：（1）我们假设整个排放物的气体成分可以直接对血管组织产生影响，也可以通过氧化修饰内源性循环磷脂来间接影响，从而改变这些脂质的天然功能。 我们的研究发现，在没有明显的肺部或全身炎症的情况下，暴露于发动机排放的小鼠的循环中存在氧化低密度脂蛋白，血管系统中存在脂质过氧化副产物，这表明肺部可能存在轻微的氧化过程，并会全身转移; (2)我们假设驱动扩张功能受损的主要机制是过氧亚硝酸盐的形成和内皮一氧化氮合酶的解偶联。 长期接触低浓度汽油废气后，血管系统中的硝基酪氨酸会上调，但过氧亚硝酸盐对血管的严重影响程度尚不清楚； (3) 我们假设观察到的 T 波异常反映了发射引起的内皮细胞功能损伤，导致脆弱受试者冠状动脉流量减少和心肌缺血。 多个实验室发现的空气污染导致大鼠和小鼠心电图异常的结果尚未在绝对心血管病理学方面得到验证；我们预测易感小鼠品系（ApoE-/-）会出现冠脉流量减少和轻度缺血。 公共卫生相关性 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。这些研究将探讨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暴露对健康影响的个人风险。