Plasma levels of microRNA are altered with the development of shock in human sepsis: an observational study

Abstract

BackgroundEndothelial 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.MethodsThirteen 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.ResultsMiRNA-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.ConclusionsThe 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.

The Expression of Nuclear Transcription Factor Kappa B (NF-κB) in the Case of Critically Ill Polytrauma Patients with Sepsis and Its Interactions with microRNAs

“…In this study, he analysed the blood plasma samples of 62 patients with sepsis. Finally, his study documented that in patients with sepsis, there exists an rise in microRNA34a expression and a drop in microRNA-15a as well as in microRNA-27a expression (Goodwin et al 2015) (Fig. 3).…”

The involvement of regulatory non-coding RNAs in sepsis: a systematic review

“…Analysis of peripheral blood by quantitative RT-PCR and miRNA microarrays has been widely used for expression profiling of miRNA in septic patients [15, 16, 49, 50]. Notably, several miRNA species, including miR-126, miR-21, miR-16, and miR-27a, increased more than 30-fold in sepsis [15]. Single-candidate miRNA studies have established the association of miR-146a, miR-25, and miR-15a/16 with sepsis [17, 51–54].…”

“…Microarray analyses, next-generation sequencing, and quantitative RT-PCR are important tools in developing biomarkers [15–21, 50, 51, 53, 57, 71, 97, 107, 119–131]. To date, candidate regulatory RNAs are limited to miRNAs.…”

“…Notably, miRNAs are essential for the production of proinflammatory tumor necrosis factor (TNF)-α and interleukin (IL)-1β via p38 mitogen-activated protein kinase (MAPK) and MAPK phosphatase 1 (MKP-1) pathways [6–9, 12–14]. In case-control studies, differential expression of miRNAs was detected in patients with sepsis compared to controls, suggesting that miRNAs may be used as biomarkers for diagnosis and prognostic stratification or as therapeutic targets [8, 12, 15–21]. …”

Patients After Splenectomy: Old Risks and New Perspectives

“…Firstly, numerous research groups studied the levels of cellular and in-plasma circulating miRNAs, as potential biomarkers, for sepsis (49,50). Our group observed in plasma of septic patients, that miR-150 is significantly downregulated and that its value correlates with the aggressiveness of the disease.…”