title: Plasma levels of microRNA are altered with the development of shock in human sepsis: an observational study.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC, 29425, USA. goodwian@musc.edu.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Goodwin
authors.affiliation: Department of Neurosciences, Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC, 29425, USA. guo@musc.edu.
authors.forename: Changrun
authors.initials: C
authors.lastname: Guo
authors.affiliation: Department of Neurosciences, Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC, 29425, USA. cookja@musc.edu.
authors.forename: James A
authors.initials: JA
authors.lastname: Cook
authors.affiliation: Department of Public Health Sciences, Medical University of South Carolina, 135 Cannon Street, Charleston, SC, 29425, USA. wolfb@musc.edu.
authors.forename: Bethany
authors.initials: B
authors.lastname: Wolf
authors.affiliation: Departments of Pharmacology and Medicine, Medical University of South Carolina, 68 President Street, Charleston, SC, 29425, USA. halushpv@musc.edu.
authors.forename: Perry V
authors.initials: PV
authors.lastname: Halushka
authors.affiliation: Department of Neurosciences, Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC, 29425, USA. fanhong@musc.edu.
authors.forename: Hongkuan
authors.initials: H
authors.lastname: Fan
mesh_terms: D000328:Adult; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000032:analysis* / Q000097:blood; D008875:Middle Aged; D010949:Plasma / Q000378:metabolism; D011379:Prognosis; D012772:Shock, Septic / Q000150:complications / Q000209:etiology / Q000378:metabolism / Q000473:pathology*
chemical_list: D035683:MicroRNAs