Endothelial Progenitor Cells and Particulate Air Pollution

内皮祖细胞和颗粒空气污染

• 批准号: 8914931
• 负责人: Aruni Bhatnagar
• 金额: $ 5.51万
• 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/8914931
• 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; 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; endothelial dysfunction; 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）：多个流行病学和实验研究报告说，急性或长期暴露于空气污染与心血管不良事件有关，包括心肌缺血，中风，心律不齐，心律失常，心力衰竭，心脏衰竭，心脏骤停和动脉粥样硬化。这些空气污染的影响与直接从化石燃料的燃烧产生的精细和超细颗粒物（PM）分数最密切相关，并且在汽车排气，木材或煤炭烟雾以及冶炼厂，纸或钢厂或水泥厂的工业排放中发现。与PM相关的心血管疾病的一个共同特征是建立和维持功能失调的内皮。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的重要因素，例如稳定且不稳定的型心绞痛，心肌梗塞和缺血性中风，因此它可能是与PM暴露有关的心血管毒性的关键中级。成年内皮是一个分化的细胞层，可在实质细胞和外周血之间提供非脉动界面。由于骨髓居民多能细胞或内皮祖细胞（EPC）的动员和归巢，由于正常的“磨损”造成的损害，这也可以促进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PM诱导的全身性炎症的结果。我们将以三个目标检验这一假设。首先，我们将检查暴露于浓缩环境空气颗粒（CAP）或过滤空气的小鼠外周血和骨髓中EPC群体的变化。我们将确定这些影响的时间过程，无论是动员缺陷本身，EPC的特定种群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质干细胞）也受到影响。此外，我们将测量EPC衍生的微粒的循环水平，以测试暴露于PM会增加EPC激活还是细胞死亡。第二个目的是描述PM暴露会影响EPC功能的机制。为此，我们将评估暴露于CAPS如何影响EPC生长，区分，迁移和促进伤口愈合的能力。我们将检查EPC中的这些变化是否伴随着系统性炎症和氧化应激的增加以及抗氧化剂干预措施或增加无供应的策略是否会阻止PM引起的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数量和功能是否伴随着系统性炎症，氧化应激，微颗粒或miRNA生物标志物的增加，以及抗氧化剂干预是否可以逆转此类变化。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。该项目的发现还可能是开发新的PM暴露生物标志物或减轻PM毒性的新策略的基础。