Endothelial Progenitor Cells and Particulate Air Pollution

内皮祖细胞和颗粒空气污染

• 批准号: 8508267
• 负责人: Aruni Bhatnagar
• 金额: $ 52.76万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-23 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8508267
• 关键词: Acetylcholine; Acute; Admission activity; Adult; Affect; Air; Air Pollution; Animals; Antioxidants; Aorta; Arrhythmia; Atherosclerosis; Automobile Exhaust; Biological Markers; Blood Cells; Blood Pressure; Blood Vessels; Bone Marrow; Breathing; Cardiotoxicity; Cardiovascular Diseases; Cardiovascular Pathology; Cardiovascular system; Cell Count; Cell Death; Cell Survival; Cell physiology; Cells; Cessation of life; Chronic; Coagulation Process; Coal; Defect; Deposition; Development; Endothelium; Epidemiologic Studies; Event; Exposure to; Flow Cytometry; Fossil Fuels; Free Radicals; Functional disorder; Generations; Goals; Health; Heart Arrest; Heart failure; Hematopoietic; Hematopoietic stem cells; Homing; Hospitals; Human; Inflammation; Inflammatory Response; Injury; Intervention; Ischemic Stroke; Lead; Location; Maintenance; Measures; Mediator of activation protein; Mesenchymal Stem Cells; MicroRNAs; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Oxidation-Reduction; Oxidative Stress; Paper; Particulate; Particulate Matter; Plants; Plasma; Population; Reaction; Relaxation; Reporting; Risk; Smoke; Steel; Stem cells; Stroke; Symptoms; Testing; Thrombosis; Time; Toxic effect; Ultrafine; Unstable angina; Wood material; Wound Healing; air filter; angiogenesis; atherogenesis; base; cardiovascular disorder risk; cardiovascular risk factor; cell growth; human tissue; insight; novel; particle; peripheral blood; prevent; repaired; research study; response; tissue repair; young adult

DESCRIPTION (provided by applicant): Multiple epidemiological and experimental studies report that acute or chronic exposure to air pollution is associated with adverse cardiovascular events including myocardial ischemia, stroke, arrhythmias, heart failure, sudden cardiac arrest and atherogenesis. These effects of air pollution are most strongly correlated with fine and ultrafine particulate matter (PM) fractions which are generated directly from the combustion of fossil fuels and are found in automobile exhaust, wood or coal smoke and industrial emission from smelters, paper or steel mills or cement plants. A common feature of PM-associated cardiovascular disorders is the establishment and maintenance of a dysfunctional endothelium. Because endothelial dysfunction is an early symptom of cardiovascular disease and an important factor in acute thrombotic complications of atherosclerosis such as stable and unstable angina, myocardial infarction, and ischemic stroke, it could be a key mediator of the cardiovascular toxicity associated with PM exposure. The adult endothelium is a differentiated cell layer that provides a non-thrombotic interface between parenchymal cells and peripheral blood. Damages due to normal "wear-and-tear" in this layer are repaired by the mobilization and homing of bone-marrow resident pluripotent cells or endothelial progenitor cells (EPCs), which also promote angiogenesis and wound healing. We have recently identified a negative correlation between PM exposure and circulating EPC level. Here, we hypothesize that defects in EPC mobilization or function are a consequence of PM-induced systemic inflammation induced by oxidative stress. We will test this hypothesis in three aims. First we will examine PM-induced changes in EPC populations in the peripheral blood and bone marrow of mice exposed to concentrated ambient air particles (CAPS) or filtered air. We will determine the time course of these effects, whether there is a mobilization defect per se, whether specific populations and locations of EPC are affected and whether this response is selective to EPCs or other stem cells such as the hematopoietic stem cells and mesenchymal stem cells are affected as well. In addition we will measure circulating levels of EPC-derived microparticles to test whether exposure to PM increases EPC activation or cell death. The second aim is to delineate the mechanisms by which PM exposure affects EPC function. For this, we will assess how exposure to CAPs affects the ability of EPCs to grow, differentiate, migrate and promote wound healing. We will examine whether these changes in EPC are accompanied by an increase in systemic inflammation and oxidative stress and whether antioxidant interventions or strategies to increase NO availability would prevent PM-induced deficits in EPC number and function. Finally, Aim 3 is to examine whether PM-induced changes in human peripheral blood EPC number and function are accompanied by an increase in systemic inflammation, oxidative stress, and microparticle or miRNA biomarkers and whether anti-oxidant intervention could reverse such changes. Successful completion of this project will provide novel insights into the cardiovascular toxicity of PM and how it affects the abundance and the reparative capacity of stem cells. Findings of this project could also form the basis for the development of new biomarkers of PM exposure or new strategies to mitigate PM toxicity.

描述（由申请人提供）：多项流行病学和实验研究表明，急性或慢性暴露于空气污染与不良心血管事件相关，包括心肌缺血、中风、心律失常、心力衰竭、心脏骤停和动脉粥样硬化。空气污染的这些影响与细颗粒物和超细颗粒物 (PM) 成分密切相关，这些颗粒物直接由化石燃料燃烧产生，存在于汽车尾气、木材或煤烟以及冶炼厂、造纸厂或钢厂的工业排放物中或水泥厂。 PM 相关心血管疾病的一个共同特征是功能失调的内皮细胞的建立和维持。由于内皮功能障碍是心血管疾病的早期症状，也是稳定型和不稳定型心绞痛、心肌梗死和缺血性中风等动脉粥样硬化急性血栓并发症的重要因素，因此它可能是与PM暴露相关的心血管毒性的关键介质。成体内皮是分化的细胞层，在实质细胞和外周血之间提供非血栓界面。该层因正常“磨损”而造成的损伤可通过骨髓多能细胞或内皮祖细胞 (EPC) 的动员和归巢来修复，这也能促进血管生成和伤口愈合。我们最近发现 PM 暴露与循环 EPC 水平之间存在负相关关系。在这里，我们假设 EPC 动员或功能缺陷是 PM 诱导的氧化应激引起的全身炎症的结果。我们将从三个目标来检验这个假设。首先，我们将检查暴露于浓缩环境空气颗粒 (CAPS) 或过滤空气的小鼠外周血和骨髓中 PM 引起的 EPC 群体变化。我们将确定这些影响的时间过程、本身是否存在动员缺陷、EPC 的特定群体和位置是否受到影响以及这种反应是否对 EPC 或其他干细胞（例如造血干细胞和间充质干细胞）具有选择性也受到影响。此外，我们将测量 EPC 衍生微粒的循环水平，以测试接触 PM 是否会增加 EPC 激活或细胞死亡。第二个目标是描述 PM 暴露影响 EPC 功能的机制。为此，我们将评估接触 CAP 如何影响 EPC 生长、分化、迁移和促进伤口愈合的能力。我们将研究 EPC 的这些变化是否伴随着全身炎症和氧化应激的增加，以及抗氧化干预或增加 NO 可用性的策略是否可以预防 PM 诱导的 EPC 数量和功能缺陷。最后，目标 3 是检查 PM 诱导的人外周血 EPC 数量和功能的变化是否伴随着全身炎症、氧化应激以及微粒或 miRNA 生物标志物的增加，以及抗氧化干预是否可以逆转这种变化。该项目的成功完成将为 PM 的心血管毒性及其如何影响干细胞的丰度和修复能力提供新的见解。该项目的研究结果还可以为开发 PM 暴露的新生物标志物或减轻 PM 毒性的新策略奠定基础。