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的每日发病率增加呈正相关。 最近的发现强烈暗示了新鲜车辆排气的作用，清楚地表明，冠状动脉事件与交通曝光急剧有关。 临床和实验研究表明，空气污染物可以急性诱导血管收缩的机制，尽管尚未确认此类研究与最终的心脏后遗症之间的明确联系。 拟议的研究将寻求验证我们以前的观察结果，即发动机排气的特定气态组成部分（这是造成环境空气污染的重要原因），可能通过粘贴冠状动脉扩张和增强收缩具有病理性血管活性。 当吸入新鲜柴油或汽油排气时，APOE-/ - 小鼠的ECG和血管异常发生，但不老化，重悬的道路灰尘，表明在收集或浓缩的颗粒中可能会损失心血管响应的新鲜排放中某些化合物。 在整个排气的气态和颗粒相中，新鲜排放中的许多挥发性和半化合物都可以存在，并且可能是试图通过消除气态collut剂来确定滤波器收集或浓缩的PM的毒性可能低估了不良健康的影响。在这项研究中，我们有三个主要的假设：（1）我们假设整个排放的气态成分可以直接对血管组织发挥作用，并通过氧化修饰的内源性循环磷脂的氧化作用，从而改变这些脂质的天然功能。 我们在循环中氧化的低密度脂蛋白以及发动机发射暴露小鼠脉管中的脂质过氧化副产物的发现，如果没有明显的肺部或全身炎症，这表明在肺中可能存在轻度的氧化过程，可以系统地转移肺部。 （2）我们假设驱动膨胀功能受损的主要机制是形成过氧亚硝酸盐和内皮一氧化氮合酶的解偶联。 慢性低水平的汽油排气暴露后的脉管系统中，硝基酪氨酸在脉管系统中被上调，但是过氧亚硝酸盐对血管的急剧影响尚不清楚。 （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的损害，从而导致脆弱受试者中冠状动脉流动和心肌缺血减少。 空气污染引起的大鼠和小鼠心电图异常的发现尚未根据绝对心血管病理的验证。我们预测，在易感小鼠菌株（APOE - / - ）中，冠状动脉流量减少和轻度缺血将发生。 公共卫生相关性的空气污染的心血管影响已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空气污染暴露对健康影响的个人风险。