Combustion-Generated EPFRs: Assessing Cardiovascular Risks of Exposure

燃烧产生的 EPFR：评估暴露的心血管风险

• 批准号: 10116407
• 负责人: TAMMY R DUGAS
• 金额: $ 28.87万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10116407
• 关键词: Address; Agonist; Air; Airborne Particulate Matter; Alveolar; Archives; Aryl Hydrocarbon Receptor; Binding; Biological Markers; Blood; Blood Pressure; Blood Vessels; Cardiac; Cardiopulmonary; Cardiovascular Diseases; Cardiovascular system; Catheters; Collaborations; Communities; Complement; Data; Data Analyses; Development; Devices; Endothelial Cells; Endothelium; Epithelial; Epithelial Cells; Exposure to; Free Radicals; Functional disorder; Hazardous Waste; Health; Heart; Heart Diseases; Histology; Industrialization; Inhalation; Inhalation Exposure; Inhalation Toxicology; Injury; Knowledge; Left; Left Ventricular Function; Ligands; Link; Lipids; Lung; Mass Spectrum Analysis; Measures; Mediating; Mediator of activation protein; Membrane; Membrane Lipids; Modeling; Morphology; Mus; Myocardial dysfunction; Oxidation-Reduction; Oxidative Stress; Oxides; Particulate Matter; Physiologic intraventricular pressure; Physiological; Play; Pulmonary Vascular Resistance; Reactive Oxygen Species; Receptor Activation; Research; Risk; Risk Assessment; Rodent; Role; Secondary to; Signal Recognition Particle; Site; Soil; Source; Superfund; System; Technology; Telemetry; Testing; Tissues; Toxic effect; Vascular Diseases; Ventricular; Work; air filter; alveolar epithelium; aryl hydrocarbon receptor ligand; biological systems; body system; cardiovascular risk factor; data management; design; endothelial dysfunction; environmental chemistry; epidemiologic data; free radical oxygen; heart function; mortality; novel; oxidation; oxidized lipid; particle; pollutant; pressure; response; small molecule; superfund site; uptake; vascular injury; web portal

Project Summary/Abstract: Project 2 Particulate matter (PM) is consistently associated with cardiopulmonary and cardiovascular mortality. Despite the risk of exposure, little is known about the mechanisms underlying PM-mediated toxicity. Our Center has shown that PM emissions from the thermal treatment (TT) of hazardous organics or contaminated soils at Superfund sites produce environmentally persistent free radicals (EPFRs). EPFRs are a unique particle- pollutant system capable of redox cycling to generate reactive oxygen species (ROS) in biological systems. EPFRs are present in contaminated Superfund soils and airborne PM near industrialized Superfund sites. Our prior Superfund project focused on the role of EPFRs in modulating cardiac function and disease. Although inhalation of EPFRs decreased baseline cardiac function, we found that these effects were secondary to changes in pulmonary vascular resistance. The mechanism(s) underlying these vascular effects are unknown; however, our preliminary data suggest that EPFR-mediated activation of the aryl hydrocarbon receptor (AhR) in pulmonary epithelial cells resulting in the release of vasoactive factors may play an important pathophysiological role. Our central hypothesis is that EPFR-mediated activation of AhR at the air-blood interface and mobilization of vasoactive mediators leads to activation/dysfunction of the pulmonary and systemic vasculature, resulting in cardiovascular disease. To test this hypothesis, Specific Aim 1 will test whether EPFR-mediated activation of the AhR in lung epithelium is responsible for the increase in pulmonary pressure and decreased diastolic filling that underlies EPFR induced cardiac dysfunction. After establishing the vasculature as the locus of injury, Specific Aim 2 will elucidate the cellular mechanisms of vascular injury by testing whether EPFRs induce vascular dysfunction via activation of the AhR. In both aims, control littermate mice and mice deficient in AhR specifically in alveolar type II will be exposed subchronially to EPFRs, non- EPFR PM, or filtered air using a recently designed inhalation system. Millar pressure-volume catheters will be used to measure left ventricular function and pulmonary arterial pressure in exposed mice. Telemetry devices will be used to record blood pressure. Endothelium-dependent vascular reactivity, as well as markers for both endothelial dysfunction and activation, will be assessed. Specific Aim 3 will identify a putative ligand promoting EPFR-induced AhR activation and test whether this metabolite is associated with EPFR-mediated vascular dysfunction. In collaboration with Project 1, this aim will use novel mass spectrometry approaches to identify and characterize EPFR-induced lipid oxidation products that may serve as endogenous AhR agonists so that we may correlate tissue and blood levels of these metabolites with vascular dysfunction. Completion of these Aims will provide important new data linking EPFR-mediated oxidative stress in epithelial cells, AhR activation, and cardiovascular disease. This information is critical for assessing risks to those living in proximity to sites using TT technologies to remediate Superfund or other hazardous wastes.

项目摘要/摘要：项目2 颗粒物（PM）始终与心肺和心血管死亡率有关。尽管 暴露的风险，对PM介导的毒性的基本机制知之甚少。我们的中心有 表明在危险有机物或受污染的土壤的热处理（TT）中的PM排放 超级基金站点会产生环境持续的自由基（EPFR）。 EPFR是一个独特的粒子 - 能够在生物系统中产生活性氧（ROS）的污染物系统。 EPFR存在于受污染的超级基金土壤和工业化超级基金地点附近的空中PM中。我们的 先前的超级基金项目的重点是EPFR在调节心脏功能和疾病中的作用。虽然 吸入EPFR降低了基线心脏功能，我们发现这些作用是继发的 肺血管抗性的变化。这些血管作用的基础机制尚不清楚； 但是，我们的初步数据表明EPFR介导的芳基烃受体（AHR）的激活 在导致血管活性因子释放的肺上皮细胞中，可能起着重要的作用 病理生理作用。我们的中心假设是EPFR介导的AHR在气血处的激活 血管活性介质的界面和动员导致肺部激活/功能障碍 全身性脉管系统，导致心血管疾病。为了检验这一假设，具体目标1将测试 EPFR介导的肺上皮中AHR的激活是否导致肺部增加 压力和减少舒张期EPFR引起的心脏功能障碍。建立后 脉管系统作为损伤的根源，特定的目标2将通过 测试EPFR是否通过激活AHR诱导血管功能障碍。在这两个目标中，控制同窝脚架 专门在II型肺泡II中缺乏AHR的小鼠和小鼠将在下次下暴露于EPFR，非 - EPFR PM或使用最近设计的吸入系统过滤空气。 Millar压力容量导管将是 用于测量暴露小鼠中左心室功能和肺动脉压。遥测设备 将用于记录血压。内皮依赖性血管反应性，以及两个标记 内皮功能障碍和激活将被评估。特定目标3将确定推定的配体促进 EPFR诱导的AHR激活并测试该代谢物是否与EPFR介导的血管相关 功能障碍。与项目1合作，此目标将采用新颖的质谱法来识别 并表征EPFR诱导的脂质氧化产物，可能用作内源性AHR激动剂，以便 我们可以将这些代谢产物的组织和血液水平与血管功能障碍相关联。这些完成 AIMS将提供重要的新数据，将EPFR介导的上皮细胞中的EPFR介导的氧化应激，AHR激活， 和心血管疾病。此信息对于评估居住在网站附近的人的风险至关重要 使用TT技术来补救超级基金或其他危险废物。