ABSTRACT
BACKGROUND: Blood-brain barrier (BBB) impairment plays a significant role in the pathogenesis of sepsis-associated encephalopathy (SAE). However, the molecular mechanisms are poorly understood. In the present study, we aimed to investigate the regulatory relationship between the Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway, microRNA (miR)-181b and its target genes in sepsis in vivo and in vitro. METHODS: Four rat models (sham, sepsis, sepsis plus STAT3 inhibitor (Stattic), and sepsis plus miR-181b inhibitor [sepsis + anta-miR-181b]) were established. For the in vitro experiments, rat brain microvascular endothelial cells (rBMECs) and rat brain astrocytes (rAstrocytes) were cultured with 10% serum harvested from sham, sepsis, and sepsis + anta-miR-181b rats. Chromatin immunoprecipitation-quantitative polymerase chain reaction (ChIP-QPCR) analysis was carried out to detect the binding and enrichment of the JAK/STAT3 signal core transcription complex in the miR-181b promoter region. Dual-luciferase reporter gene assay was conducted to test miR-181b and its target genes. The cell adhesion rate of rBMECs was also measured. RESULTS: During our investigations, the expression levels of miR-181b, p-JAK2, p-STAT3, and C/EBPß were found to be significantly increased in the septic rats compared with the sham rats. STAT3 inhibitor halted BBB damage by downregulating the expression of miR-181b. In addition, miR-181b targeted sphingosine-1-phosphate receptor 1 (S1PR1) and neurocalcin delta (NCALD). The up-regulated miR-181b significantly decreased the cell adhesion rate of rBMECs. The administration of miR-181b inhibitor reduced damage to the BBB through increasing the expression of S1PR1 and NCALD, which again proved that miR-181b negatively regulates SIPR1 and NCALD to induce BBB damage. CONCLUSIONS: Our study demonstrated that JAK2/STAT3 signaling pathway induced expression of miR-181b, which promoted BBB impairment in rats with sepsis by downregulating S1PR1 and decreasing BBB cell adhesion. These findings strongly suggest JAK2/STAT3/miR-181b axis as therapeutic target in protecting against sepsis-induced BBB damage.
ABSTRACT
Background: Early recognition of septic patients with poor prognosis is important for clinicians to prescribe personalized therapies which include timely fluid resuscitation therapy and appropriate antimicrobial therapy. We aimed to evaluate the effect of the presepsin level on predicting the prognosis of patients with sepsis under the sepsis-3 criteria. Methods: Patients who were diagnosed as sepsis under the sepsis-3 criteria were recruited and assigned to the survivor group and the non-survivor group according to their in-hospital mortality. The two groups' baseline characteristics were analyzed with Pearson's chi-square (χ 2) test or Kruskal-Wallis test. Binary logistic regression analysis was performed to determine the independent predictors of in-hospital mortality from sepsis. Receiver operating characteristic analysis was conducted to evaluate the efficacy of presepsin in predicting patients' in-hospital mortality from sepsis. The correlation between presepsin and the Sequential Organ Failure Assessment (SOFA) score was measured with Spearman's rank correlation coefficient. P-values of less than 0.05 were considered to indicate statistical significance. Results: Overall, 138 patients were included in this study. The presepsin level of the non-survivor group was significantly higher than that of the other group (P=0.000). Binary logistic regression showed that the presepsin level was an independent risk factor of patients' in-hospital mortality from sepsis (OR =1.221 P=0.026). The presepsin level was positively associated with the SOFA score (ρ=0.396, P=0.000). ROC curve analysis revealed the presepsin level was highly accurate in predicting patients' in-hospital mortality from sepsis (AUC =0.703, P=0.000). The AUC value of a combination of presepsin and the SOFA score was significantly larger than that of the SOFA score alone (AUC: 0.817 vs 0.793, P=0.041). Conclusions: Presepsin is a prognostic biomarker with high accuracy in predicting the prognosis of sepsis under the sepsis-3 criteria.
