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 广泛的证据表明，暴露于环境特定问题（PM）有助于全球负担 疾病。在全球范围内，空气污染与700万个早期死亡有关。在美国，下午是 与每年200,000例死亡有关，其中大多数是由于心血管疾病（CVD）。 然而，PM暴露引起心血管损伤的机制尚不清楚。 了解这种机制对于开发PM诱导的机械验证的生物标志物很重要 亚临床损伤并发展有效的治疗干预措施。中等的个体的机械研究 在中度的CVD风险中，已经实施了内皮功能障碍和注射，作为PM-的关键介体 诱发伤害；但是，由于这些调解员也是CVD的关键特征，因此尚不清楚PM是否 直接影响内皮功能，或这些更改是继发于CVD加剧的次要的 下午。我们发现，在年轻，健康的个体中，暴露于较高水平的良好PM（PM2.5）会抑制 内皮祖细胞（EPC）的循环水平。慢性抑制EPC是早期的 内皮损伤，并且在前瞻性研究中，可预测CVD死亡率。然而，这些机制通过 哪些pM2.5抑制EPC水平仍然晦涩，尚不清楚PM2.5是否影响EPC功能和 它们促进组织修复和血管生成的能力。我们的初步数据表明暴露于 浓缩PM2.5降低了EPC的代谢活性，并降低了其修复血管组织的能力。 我们还发现，PM2.5的影响通过过表达细胞外超氧化物而衰减 肺中的歧化酶。基于这些观察结果，我们建议在PM2.5吸入后，肺部 产生超氧化 健康的内皮并促进血管生成。为了检验这一假设，我们将确定 PM2.5 EPC代谢的暴露；评估PM2.5暴露对EPC功能的影响；并阐明 PM2.5暴露会诱导EPC的代谢和功能变化的机制。完成此操作 项目不仅会更好地了解PM如何引起EPC功能障碍，还可以识别 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志物。全面的， 我们的结果将进一步一个新的概念 - PM2.5引起的心血管损伤是由于EPC缺陷所致 新陈代谢 - 可能导致一种新颖的方法的发展 临床研究以减弱PM2.5诱导的CVD死亡率和发病率。