Effects of Air Pollution on Stem Cell Health

摘要 大量证据表明，暴露在环境颗粒物(PM)中会造成全球负担 疾病的威胁。在世界范围内，空气污染与700万人过早死亡有关；在美国，PM是 每年导致200,000人死亡，其中大部分是由于心血管疾病(CVD)。 然而，PM暴露导致心血管损伤的机制仍不清楚。 了解这些机制对于开发经过机制验证的PM诱导的生物标志物很重要 因此，我们有必要加强对亚临床伤害的认识，并制定有效的治疗干预措施。轻症患者的机械学研究 中度心血管疾病风险与内皮功能障碍和炎症有关，是PM的关键介质。 然而，由于这些介质也是CVD的关键特征，因此尚不清楚PM是否 直接影响内皮功能，或者这些变化是否继发于CVD的加重 下午。我们发现，在年轻、健康的人中，暴露于高水平的细颗粒物(PM2.5)会抑制 循环内皮祖细胞(EPC)水平。慢性内皮祖细胞抑制预示着早期 内皮损伤，在前瞻性研究中，预测心血管疾病的死亡率。然而，这些机制是由 哪些PM2.5抑制EPC水平仍不清楚，也不清楚PM2.5是否影响EPC功能和 它们具有促进组织修复和血管生成的能力。我们的初步数据显示，暴露在 高浓度的PM2.5会降低内皮祖细胞的代谢活性，降低其修复血管组织的能力。 我们还发现，PM2.5的影响通过过度表达细胞外超氧化物而减弱 肺中的歧化作用。基于这些观察，我们认为吸入PM2.5后，肺 超氧化物的产生损害了EPC信号和新陈代谢，从而损害了EPC维持 有益血管内皮健康，促进血管生成。为了检验这一假设，我们将确定 PM2.5暴露对EPC代谢的影响；评估PM2.5暴露对EPC功能的影响；以及阐明 PM2.5暴露诱导内皮祖细胞代谢和功能改变的机制。完成这项工作 项目不仅将导致更好地理解PM如何导致EPC功能障碍，而且还可以确定 PM2.5诱导的心血管损伤的选择性、特异性和机械验证的生物标记物。总的来说， 我们的结果将进一步提出一个新的概念，即PM2.5引起的心血管损伤是由于EPC缺陷造成的 新陈代谢-并可能导致开发一种新的方法，可以在未来很容易地进行测试 减少PM2.5引起的心血管疾病死亡率和发病率的临床研究。

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.