Effects of Air Pollution on Stem Cell Health

空气污染对干细胞健康的影响

• 批准号: 9762926
• 负责人: Petra Haberzettl
• 金额: $ 44.82万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9762926
• 关键词: Affect; Aging; Air; Air Pollution; Angiogenic Factor; Animal Model; Atherosclerosis; Attenuated; Biological Markers; Blood Vessels; Bone Marrow; Cardiovascular Diseases; Cardiovascular system; Cell Aging; Cell physiology; Cells; Cellular Metabolic Process; Cessation of life; Chronic; Clinical; Clinical Research; Competence; Data; Defect; Development; Endothelium; Exposure to; Flow Cytometry; Functional disorder; Future; Generations; Glycolysis; Goals; Health; Hypertension; Impairment; In Vitro; Individual; Inflammation; Inhalation; Injury; Insulin; Intervention; Ischemia; Isotopes; Lead; Limb structure; Link; Lung; Mediator of activation protein; Metabolic; Metabolic dysfunction; Metabolism; Morbidity - disease rate; Mus; Nose; Outcome; Oxidative Phosphorylation; Oxidative Stress; Particulate Matter; Pathologic Processes; Phenotype; Proliferating; Prospective Studies; Research; Resistance; Risk; Secondary to; Signal Pathway; Signal Transduction; Stem cells; Superoxide Dismutase; Superoxides; Techniques; Testing; Therapeutic Intervention; Tissues; Treatment Efficacy; Tube; Vascular Endothelial Growth Factors; Work; air filter; angiogenesis; base; burden of illness; cardiovascular disorder risk; cardiovascular injury; endothelial dysfunction; extracellular; fine particles; improved; in vivo; mortality; novel strategies; overexpression; premature; prevent; repaired; response; tissue repair

ABSTRACT Extensive evidence indicates that exposure to ambient particulate matter (PM) contributes to the global burden of disease. Worldwide, air pollution is linked with seven million premature deaths; and in the US, PM is associated with 200,000 deaths per year, most of which are due to cardiovascular disease (CVD). Nevertheless, the mechanisms by which PM exposure induces cardiovascular injury remain unclear. Understanding such mechanisms is important to develop mechanistically validated biomarkers of PM-induced subclinical injury and to develop effective therapeutic interventions. Mechanistic studies in individuals with mild to moderate CVD risk have implicated endothelial dysfunction and inflammation as critical mediators of PM- induced injury; however, because these mediators are also key features of CVD, it is unclear whether PM directly affects endothelial function or whether these changes are secondary to the exacerbation of CVD by PM. We found that in young, healthy individuals exposure to elevated levels of fine PM (PM2.5) suppresses circulating levels of endothelial progenitor cells (EPCs). Chronic suppression of EPCs is indicative of early endothelial injury, and, in prospective studies, predictive of CVD mortality. Nevertheless, the mechanisms by which PM2.5 suppress EPC levels remain obscure, and it is unclear whether PM2.5 affects EPC function and their ability to promote tissue repair and angiogenesis. Our preliminary data show that exposure to concentrated PM2.5 decreases the metabolic activity of EPCs and reduces their ability to repair vascular tissue. We have also found that the effects of PM2.5 are attenuated by overexpressing extracellular superoxide dismutase in the lung. Based on these observations, we propose that upon PM2.5 inhalation, pulmonary generation of superoxide impairs EPC signaling and metabolism, which compromises their ability to maintain a healthy endothelium and to promote angiogenesis. To test this hypothesis, we will determine the effects of PM2.5 exposure on EPC metabolism; assess the impact of PM2.5 exposure on EPC function; and elucidate the mechanisms by which PM2.5 exposure induces metabolic and functional changes in EPCs. Completion of this project will not only lead to a better understanding of how PM causes EPC dysfunction, but could also identify selective, specific, and mechanistically validated biomarkers of PM2.5-induced cardiovascular injury. Overall, our results would further a new concept—that PM2.5-induced cardiovascular injury is due to defective EPC metabolism—and could lead to the development of a novel approach that could be readily tested in future clinical studies to attenuate PM2.5-induced CVD mortality and morbidity.

抽象的 大量证据表明，暴露于环境颗粒物 (PM) 会加重全球负担 在世界范围内，空气污染与 700 万人过早死亡有关；而在美国，PM 与 700 万人的过早死亡有关。 每年导致 20 万人死亡，其中大部分是由于心血管疾病 (CVD)。 然而，PM暴露诱发心血管损伤的机制仍不清楚。 了解此类机制对于开发 PM 诱导的机械验证生物标志物非常重要 亚临床损伤并针对轻度患者制定有效的治疗干预措施。 中度CVD风险表明内皮功能障碍和炎症是PM-的关键介质 诱发损伤；然而，由于这些介质也是 CVD 的关键特征，目前尚不清楚 PM 是否 直接影响内皮功能，或者这些变化是否继发于 CVD 的恶化 我们发现，年轻、健康的人接触高水平的细颗粒物 (PM2.5) 会抑制PM。 内皮祖细胞 (EPC) 的循环水平的慢性抑制表明早期。 然而，在前瞻性研究中，其机制可预测 CVD 死亡率。 PM2.5 抑制 EPC 水平的具体机制仍不清楚，并且尚不清楚 PM2.5 是否影响 EPC 功能和 我们的初步数据表明，它们具有促进组织修复和血管生成的能力。 浓PM2.5会降低EPC的代谢活性，降低其修复血管组织的能力。 我们还发现，过度表达细胞外超氧化物会减弱 PM2.5 的影响 根据这些观察结果，我们认为吸入 PM2.5 后，肺部会出现歧化酶。 超氧化物的产生会损害 EPC 信号传导和新陈代谢，从而损害其维持细胞正常运转的能力 健康的内皮细胞并促进血管生成为了检验这一假设，我们将确定其效果。 PM2.5暴露对EPC代谢的影响；评估PM2.5暴露对EPC功能的影响； PM2.5 暴露引起 EPC 代谢和功能变化的机制。 该项目不仅可以更好地理解 PM 如何导致 EPC 功能障碍，还可以识别 PM2.5 引起的心血管损伤的选择性、特异性和机械验证的生物标志物。 我们的结果进一步提出了一个新概念：PM2.5 引起的心血管损伤是由于 EPC 缺陷所致 新陈代谢——并可能导致开发一种可以在未来轻松测试的新方法 降低 PM2.5 引起的 CVD 死亡率和发病率的临床研究。