Effects of Air Pollution on Stem Cell Health

摘要 大量证据表明，暴露于环境颗粒物（PM）有助于全球负担 疾病。在全球范围内，空气污染与700万人过早死亡有关;在美国，PM是 每年有20万人死亡，其中大部分是由于心血管疾病（CVD）。 然而，PM暴露诱导心血管损伤的机制仍不清楚。 了解这些机制对于开发PM诱导的生物标志物是重要的。 亚临床损伤，并制定有效的治疗干预措施。在轻度糖尿病患者中的机制研究 中度CVD风险涉及内皮功能障碍和炎症作为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恶化， 下午.我们发现，在年轻的健康个体中，暴露于高水平的细颗粒物（PM2.5）抑制了 内皮祖细胞（EPCs）的循环水平。EPCs的慢性抑制表明早期 内皮损伤，并且在前瞻性研究中预测CVD死亡率。然而， PM2.5抑制EPC水平仍然不清楚，目前还不清楚PM2.5是否影响EPC功能， 它们促进组织修复和血管生成的能力。我们的初步数据显示， 高浓度的PM2.5降低了EPCs的代谢活性，并降低了它们修复血管组织的能力。 我们还发现，PM2.5的影响是减弱过表达细胞外超氧化物 歧化酶基于这些观察结果，我们提出，在吸入PM2.5后， 超氧化物的产生损害了EPC信号传导和代谢，这损害了它们维持一个细胞周期的能力。 健康内皮和促进血管生成。为了验证这一假设，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;并阐明 PM2.5暴露诱导EPCs代谢和功能变化的机制。完成本 一个项目不仅将导致更好地了解PM如何导致EPC功能障碍，而且还可以识别 选择性，特异性和机械验证的PM2.5诱导的心血管损伤的生物标志物。总的来说， 我们的研究结果将进一步提出一个新的概念-PM2.5引起的心血管损伤是由于缺陷的EPC 代谢-并可能导致开发一种新的方法，可以在未来进行测试 减少PM2.5引起的CVD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.