RESUMEN
BACKGROUND: Sepsis-induced liver injury is a fatal complication of sepsis. Trichostatin A (TSA) regulates inflammation and autophagy in some human diseases, and forkhead box O3a (FoxO3a) has been shown to regulate autophagy. The present study aims to investigate whether TSA exerts its effects on septic liver injury through the FoxO3a/autophagy signaling pathway. METHODS: A sepsis mouse model was constructed by the cecal ligation and puncture (CLP) method, and AML12 cells were pretreated with lipopolysaccharide (LPS) (1 µg/mL) to establish a sepsis cell model. Forty mice were divided into four groups, namely control group, TSA group, CLP group, and CLP+TSA group, with 10 mice in each group. Cells were divided into control group, TSA group, LPS group, and LPS+TSA group. Hematoxylin-eosin (H&E) staining and biochemical methods were used to evaluate liver tissue injury. Enzyme-linked immunosorbent assay (ELISA) was applied to detect the expression of proinflammatory cytokines, and Western blotting and immunofluorescence were used to measure autophagy-related protein expression. RESULTS: Compared with the CLP group (mice), the proinflammatory cytokines (interleukin-ß [IL-ß] 2,665.27±324.90 pg/mL to 2,080.26±373.66 pg/mL; interleukin-6 [IL-6] 399.01±60.98 pg/mL to 221.90±46.89 pg/mL) and the hepatocyte injury markers (aspartate transaminase [AST] from 198.18±27.07 U/L to 128.42±20.55 U/L; alanine aminotransferase [ALT] from 634.98±74.10 U/L to 478.60±32.56 U/L) were notably decreased after TSA intervention. Moreover, LC3 II and FoxO3a showed an obvious increase and P62 showed an obvious decrease in the CLP+TSA group. Cell experiment results showed the similar trend. After FoxO3a gene was knocked down in AML12 cells, the promotion of autophagy and the improvement of liver enzyme index and inflammation by TSA were weakened. CONCLUSION: TSA may improve the inflammatory response and liver injury in septic mice through FoxO3a/autophagy.
RESUMEN
Background: The incidence and mortality of sepsis are increasing year by year, and there is still a lack of specific biomarkers to predict its prognosis. Prognostic value of vascular endothelial growth factor (VEGF) in predicting the severity and mortality of sepsis has been gradually discovered. Methods: Literature was searched through Embase, PubMed, Web of Science, China National Knowledge Infrastructure(CNKI) and Cochrane Library databases in March 2022. Observational studies, evaluating the impact of VEGF in sepsis outcomes (mortality and severity) are included in this meta-analysis. Risk of bias was assessed with the Newcastle-Ottawa Scale (NOS). Sensitivity and publication bias analyses were also assessed. Meta-regression analysis were performed to identify the potential sources of heterogeneity. Result: A total of 1,574 articles were retrieved from the systematic literature search. We included 20 studies for qualitative and quantitative analysis. Deceased and critically ill patients had higher baseline VEGF levels than survivors and non-severe patients. The pooled sensitivity and specificity for VEGF predicts sepsis mortality were 0.79and 0.76, respectively. the area under the SROC curve was 0.83. Conclusion: High VEGF are associated with poor clinical outcomes for patients diagnosed with sepsis. This study was recorded on PROSPERO, under the registration ID: CRD42022323079.
RESUMEN
Inflammatory injury is a hallmark of sepsis-induced acute respiratory distress syndrome (ARDS)/acute lung injury (ALI). However, the mechanisms underlying inflammatory injury remain obscure. Here, we developed the novel strategy to suppress lung inflammation through maintaining microvascular endothelial barrier integrity. VE-cadherin is the main adherens junction protein that interacts with ß-catenin and forms a complex. We found that lung inflammation was accompanied by decreased VE-cadherin expression and increased ß-catenin activity in animal models and human pulmonary microvascular endothelial cells (HPMECs), illuminating the relationship among VE-cadherin/ß-catenin complex, microvascular endothelial barrier integrity, and inflammation. Furthermore, we showed that the VE-cadherin/ß-catenin complex dissociated upon lung inflammation, while Sirt3 promoted the stability of such a complex. Sirt3 was decreased during lung inflammation in vivo and in vitro. Sirt3 deficiency not only led to the downregulation of VE-cadherin but also enhanced the transcriptional activity of ß-catenin that further increased ß-catenin target gene MMP-7 expression, thereby promoting inflammatory factor COX-2 expression. Sirt3 overexpression promoted VE-cadherin expression, inhibited ß-catenin transcriptional activity, strengthened the stability of the VE-cadherin/ß-catenin complex, and suppressed inflammation in HPMECs. Notably, Sirt3 deficiency significantly damaged microvascular endothelial barrier integrity and intensified lung inflammation in animal model. These results demonstrated the role of Sirt3 in modulating microvascular endothelial barrier integrity to inhibit inflammation. Therefore, strategies that aim at enhancing the stability of endothelial VE-cadherin/ß-catenin complex are potentially beneficial for preventing sepsis-induced lung inflammation.