Endothelial Progenitor Cells and Particulate Air Pollution

内皮祖细胞和颗粒空气污染

• 批准号: 10374023
• 负责人: Aruni Bhatnagar
• 金额: $ 61.32万
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10374023
• 关键词: Acute; Adult; Adverse effects; Affect; Age; Air Pollution; Angiogenesis Inhibition; Animal Model; Antioxidants; Arrhythmia; Arteries; Atherosclerosis; Attenuated; Automobile Exhaust; Biological Markers; Blood Vessels; Bone Marrow; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Carnosine; Cell physiology; Cells; Characteristics; Chronic; Clinical Trials; Coal; Defect; Development; Dipeptides; Double-Blind Method; Endothelium; Enrollment; Ethnic Origin; Event; Exposure to; Fossil Fuels; Grant; Growth Factor; Guidelines; Health; Heart Arrest; Heart failure; Hematopoiesis; Human; Impairment; Individual; Industrialization; Inflammation; Inflammatory Response; Injury; Insulin Resistance; Intervention; Lead; Link; Lipid Peroxidation; Measures; Mediating; Mediator of activation protein; Mus; Myocardial Infarction; Myocardial Ischemia; Oxidative Stress; Participant; Particulate; Particulate Matter; Peripheral; Placebo Control; Population; Populations at Risk; Predisposing Factor; Predisposition; Reactive Oxygen Species; Reporting; Risk; Risk Factors; Smoke; Socioeconomic Status; Stroke; Testing; Therapeutic Intervention; Thrombosis; Toxic effect; Vascular Diseases; Wood material; Work; adverse outcome; ambient particle; arterial stiffness; atherogenesis; base; biological adaptation to stress; burden of illness; cardiovascular disorder risk; cardiovascular effects; cardiovascular injury; cohort; cytokine; design; efficacy evaluation; endothelial stem cell; epidemiology study; experimental study; fine particles; indexing; mortality; novel; oral supplementation; pollutant; prevent; randomized trial; repaired; sex; sudden cardiac death; vascular injury; volatile organic compound

ABSTRACT 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 particulate matter (PM2.5) fraction which is generated directly from the combustion of fossil fuels and is found in automobile exhaust, wood or coal smoke and industrial emissions. However, the mechanisms by which PM2.5 induces cardiovascular injury remain unclear and the pathophysiological conditions and co-exposures that determine individual susceptibility to PM2.5 toxicity have not been identified. Our previous work has shown that in young healthy adults, exposure to PM2.5 is associated with inflammation, decreases in vascular reparative circulating angiogenic cells (CACs), and changes in cytokine/growth factor profiles consistent with an inhibition of angiogenesis. In addition, we found increased levels of circulating endothelial microparticles, evidence of subclinical vascular injury. We obtained similar results in mouse exposure studies, which show that exposure to concentrated ambient particles depletes circulating angiogenic cells, and leads to defective hematopoiesis and functional defects in bone marrow-derived cells. In pilot experiments, we have found that these PM2.5-induced defects in mice could be prevented by treatment with the endogenous nucleophile carnosine, which quenches reactive oxygen species and removes toxic products of lipid peroxidation. Furthermore, in a human cohort with mild-to-moderate CVD risk, we also found that those with high CVD risk are more susceptible to the effects of PM2.5 and that individuals with high carnosine levels are relatively impervious to the adverse cardiovascular effects of PM2.5 exposure. Thus we hypothesize that individual risk factors determine cardiovascular susceptibility to PM2.5 and that means to limit electrophiles/oxidative stress will mitigate the adverse consequences of PM2.5 exposure. These ideas will be tested in three Aims. In the first we will assess the impact of PM2.5 exposure on vascular function (arterial stiffness, flow-mediated dilation, peripheral artery tone) in a population with mild-to- moderate CVD risk and determine whether exposure exacerbates composite CVD risk and whether changes inflammation, oxidative stress, or thrombosis are associated with PM2.5-induced vascular dysfunction. In the second Aim, we will determine whether the relationship between vascular injury and dysfunction is mediated by individual-level demographic characteristics (e.g., sex, age, ethnicity), co-exposure to gaseous pollutants, or systemic levels of carnosine. In the third Aim, we will enroll a subset of individuals with inherently low carnosine levels, and determine whether daily, oral supplementation with carnosine attenuates the association between PM2.5 exposure and vascular dysfunction as well as PM2.5 -induced changes in biomarkers of cardiovascular injury and indices of cardiovascular function. The results of this project will provide better estimates of CVD burden due to PM2.5 exposure, identify specific risk factors that increase susceptibility to PM2.5-induced injury, and assess the efficacy of carnosine in attenuating PM2.5 toxicity. Findings of this project could potentially lead to the development of a novel and practical therapeutic intervention to prevent PM2.5 toxicity.

抽象的 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的是 与不良心血管事件有关，包括心肌缺血，中风，心律不齐，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细的 颗粒物物质（PM2.5）馏分直接从化石燃料的燃烧中产生，并在 汽车排气，木材或煤烟和工业排放。但是，PM2.5的机制 诱导心血管损伤仍然不清楚，并且病理生理状况和共同曝光 确定尚未确定对PM2.5毒性的个体易感性。我们以前的工作表明 在年轻健康的成年人中，暴露于PM2.5与炎症有关，血管恢复降低 循环血管生成细胞（CAC），以及与抑制作用一致的细胞因子/生长因子谱的变化 血管生成。此外，我们发现循环内皮微粒的水平增加了 亚临床血管损伤。我们在小鼠暴露研究中获得了相似的结果，这表明暴露于 浓缩的环境颗粒会耗尽循环血管生成细胞，并导致造血缺陷，并且 骨髓衍生细胞的功能缺陷。在试点实验中，我们发现这些PM2.5诱导 通过用内源性亲核肉肽治疗，可以预防小鼠的缺陷 活性氧和去除脂质过氧化的有毒产物。此外，与 轻度至中度的CVD风险，我们还发现，患有高CVD风险的人更容易受到影响 PM2.5，肌肽水平较高的人对心血管的不良心脏相对不渗透 PM2.5暴露的影响。因此，我们假设各个风险因素决定了心血管敏感性 到PM2.5，这意味着限制电力/氧化应激将减轻PM2.5的不利后果 接触。这些想法将以三个目标进行测试。首先，我们将评估PM2.5暴露对 血管功能（动脉刚度，流动介导的扩张，周围动脉张力）的人群中 中等CVD风险并确定暴露是否加剧了复合CVD风险以及是否改变 炎症，氧化应激或血栓形成与PM2.5诱导的血管功能障碍有关。在 第二个目的，我们将确定血管损伤和功能障碍之间的关系是否由 个人级别的人口特征（例如性别，年龄，种族），与气态污染物的共同曝光或 全身性肌肽水平。在第三个目标中，我们将招募一部分固有肌肽的个体 水平，并确定每天用肉肽补充口服是否会减弱 PM2.5暴露和血管功能障碍以及PM2.5诱导的心血管生物标志物变化 损伤和心血管功能的指标。该项目的结果将提供更好的CVD估计 由于PM2.5暴露造成的负担，确定特定的风险因素，以增加对PM2.5诱导的损伤的敏感性， 并评估肌肽在衰减PM2.5毒性方面的功效。该项目的发现可能会导致 开发一种新颖而实用的治疗干预措施，以防止PM2.5毒性。

项目成果

Cardiovascular Disease and Fine Particulate Matter: Lessons and Limitations of an Integrated Exposure-Response Approach.

• DOI: 10.1161/circresaha.118.312956
• 发表时间: 2018-06-08
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: Pope CA 3rd;Cohen AJ;Burnett RT
• 通讯作者: Burnett RT

Short-Term Exposure to Fine Particulate Matter Air Pollution Is Preferentially Associated With the Risk of ST-Segment Elevation Acute Coronary Events.

• DOI: 10.1161/jaha.115.002506
• 发表时间: 2015-12-08
• 期刊: Journal of the American Heart Association
• 影响因子: 5.4
• 作者: Pope CA;Muhlestein JB;Anderson JL;Cannon JB;Hales NM;Meredith KG;Le V;Horne BD
• 通讯作者: Horne BD