Plasma levels of microRNA are altered with the development of shock in human sepsis: an observational study.
Plasma levels of microRNA are altered with the development of shock in human sepsis: an observational study.
复制标题
DOI：
10.1186/s13054-015-1162-8
复制
发表时间：
2015-12-18
期刊：
影响因子：
--
通讯作者：
Fan H
中科院分区：
文献类型：
--
作者：
Goodwin AJ;Guo C;Cook JA;Wolf B;Halushka PV;Fan H
内皮功能障碍在脓毒症相关器官衰竭的发展中起关键作用；然而，控制其发展的机制尚不完全清楚。内皮祖细胞（EPCs）通过调节血浆中microRNA （miRNA）的表达，减少实验性败血症中的血管泄漏和器官衰竭。MicroRNAs是一种小的、非编码的RNA片段，可以调节基因表达，并调节内皮细胞功能和炎症信号通路。我们假设miRNA可能在脓毒症的内皮功能障碍中起病因学作用，并且它们的细胞外表达水平在休克患者中会发生改变。通过文献检索和实时荧光定量PCR分析人epc衍生外泌体的内容，鉴定出13个mirna。从重症脓毒症患者（n = 62）和健康对照（n = 32）入院24小时内采集血浆样本，采用实时荧光定量PCR检测候选mirna的表达。使用Wilcoxon秩和检验比较13种候选miRNA在脓毒症患者（n = 29）和未（n = 33）休克中的表达水平，并使用logistic回归来确定miRNA表达与休克之间关联的曲线下面积。使用miRNA数据库进行生物信息学分析，以确定与败血症相关性休克潜在相关的差异表达miRNA的途径和基因靶点。休克组MiRNA-34a表达显著升高（p = 0.03）， miR-15a、miR-27a表达显著降低（p = 0.006、0.03）。这三种mirna的联合表达预测休克的曲线下面积为0.78 （95% CI 0.66-0.90）。计算机分析预测，这三种mirna可调控参与内皮细胞周期、凋亡、VEGF信号传导、lps刺激的MAPK信号传导和核因子κ B信号传导的基因。严重脓毒症并发休克患者的血浆miRNA水平发生改变，可能提供预后价值以及脓毒症中内皮功能障碍机制的见解。
Endothelial dysfunction plays a critical role in the development of sepsis-related organ failure; however, the mechanisms that govern its development are not fully understood. Endothelial progenitor cells (EPCs) reduce vascular leak and organ failure in experimental sepsis while modulating plasma expression of microRNA (miRNA). MicroRNAs are small, noncoding segments of RNA that regulate gene expression and are known to modulate endothelial cell function and inflammatory signaling pathways. We hypothesized that miRNA may play an etiologic role in the endothelial dysfunction of sepsis and that their extracellular expression levels would be altered in those with shock. Thirteen miRNAs were identified by literature search and analysis of the contents of human EPC-derived exosomes using real-time PCR. Plasma samples were obtained from patients within 24 hours of their admission to ICUs with severe sepsis (n = 62) and from healthy controls (n = 32) and real-time PCR was used to measure the expression of the candidate miRNAs. The Wilcoxon rank sum test was used to compare expression levels of the 13 candidate miRNAs in septic patients with (n = 29) and without (n = 33) shock while logistic regression was used to determine the area under the curve for associations between miRNA expression and shock. Bioinformatic analyses using miRNA databases were performed to identify pathways and gene targets of differentially expressed miRNA with potential relevance to sepsis-related shock. MiRNA-34a expression was significantly increased in the group who developed shock (p = 0.03) while miR-15a and miR-27a expressions were significantly decreased in this group (p = 0.006 and 0.03, respectively). The combined expression of these three miRNAs predicted shock with an area under the curve of 0.78 (95 % CI 0.66–0.90). In silico analyses predict that these three miRNAs regulate genes involved in endothelial cell cycle, apoptosis, VEGF signaling, LPS-stimulated MAPK signaling, and nuclear factor kappa B signaling. The plasma levels of miRNA are altered in patients with severe sepsis complicated by shock and may offer prognostic value as well as insights into the mechanisms of endothelial dysfunction in sepsis.