Endothelial Progenitor Cells and Particulate Air Pollution

描述（由申请人提供）：多项流行病学和实验研究报告，急性或慢性暴露于空气污染与不良心血管事件有关，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直接由化石燃料燃烧产生的细颗粒物和超细颗粒物（PM）组分密切相关，它们存在于汽车尾气、木材或煤烟以及冶炼厂、造纸厂、钢铁厂或水泥厂的工业排放物中。pm相关心血管疾病的一个共同特征是内皮功能失调的建立和维持。由于内皮功能障碍是心血管疾病的早期症状，也是动脉粥样硬化急性血栓性并发症（如稳定性和不稳定性心绞痛、心肌梗死和缺血性卒中）的重要因素，因此它可能是PM暴露相关心血管毒性的关键介质。成人内皮是一种分化的细胞层，在实质细胞和外周血之间提供非血栓形成的界面。由于这一层的正常“磨损”造成的损伤可以通过骨髓驻留的多能细胞或内皮祖细胞（EPCs）的动员和归巢来修复，这也促进了血管生成和伤口愈合。我们最近确定了PM暴露与循环EPC水平之间的负相关。在这里，我们假设EPC动员或功能的缺陷是氧化应激诱导的pm诱导的全身性炎症的结果。我们将用三个目标来检验这一假设。首先，我们将检测暴露于高浓度环境空气颗粒（CAPS）或过滤空气的小鼠外周血和骨髓中pm诱导的EPC种群变化。我们将确定这些影响的时间过程，是否存在动员缺陷本身，是否特定的EPCs群体和位置受到影响，以及这种反应是否对EPCs或其他干细胞（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，以测试暴露于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，我们将评估暴露于cap如何影响EPCs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引起的EPC数量和功能的缺陷。最后，目的3是研究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、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。该项目的研究结果也可以为开发新的PM暴露生物标志物或减轻PM毒性的新策略奠定基础。

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.