MicroRNA-203 Acts as a Potent Suppressor in Septic Shock by Alleviating Lung Injury via Inhibition of VNN1.

BACKGROUND: Septic shock, the most serious complication of sepsis, is a life-threatening disease that is mainly characterized by hypoperfusion and multiple organ failure. Various aberrantly expressed microRNAs (miRNAs) have been reported to be related to septic shock. We explored the regulatory effect of microRNA-203 (miR-203) on lung injury in septic shock mice. METHODS: Microarray-based gene expression profiling related to septic shock identified the differentially expressed gene vanin-1 (VNN1) and potential regulatory miR-203. miR-203 was predicted to mediate VNN1 expression, thus affecting septic shock, which was investigated by treatment with miR-203 mimic, miR-203 inhibitor, and siRNA-VNN1 in septic shock mouse models. Polymorphonuclear neutrophils (PMNs) and pulmonary alveolar macrophages in bronchoalveolar lavage fluid (BALF) as well as the wet/dry ratio of the lung were also measured to assess lung injury. Additionally, the effects of miR-203 on inflammatory cytokines, oxidative stress indexes, blood biochemical indexes, serine-threonine protein kinase (AKT) signaling pathway-related factors, and apoptosis-related factors were determined. RESULTS: VNN1 was verified to be targeted and negatively regulated by miR-203. In mouse models of septic shock, weak expression of miR-203, high expression of VNN1, and inhibition of AKT signaling pathway were identified. In response to miR-203 mimic and VNN1 gene silencing, mouse models of septic shock displayed reduced apoptosis, MDA, ALT, and AST in lung tissues, decreased levels of TNF-α, IL-1ß, IFN-γ, IL-10, and IL-6, in serum, and reduced PMN and PAM levels in BALF, in addition to elevated SOD activity. Notably, the presence of miR-203 mimic led to AKT signaling pathway activation. CONCLUSION: This study shows that upregulating miR-203 can alleviate lung injury through activation of the AKT signaling pathway by downregulating VNN1 in septic shock.

Intestinal microcirculation dysfunction in sepsis: pathophysiology, clinical monitoring, and therapeutic interventions.

BACKGROUND: Intestinal microcirculation dysfunction is an important factor that causes poor prognosis in sepsis patients and is an important pathophysiological basis for the occurrence and development of sepsis. DATA RESOURCES: PubMed, Web of Science, and China National Knowledge Infrastructure (CNKI) were searched from inception to August 1, 2021. The search was limited to the English language only. Two reviewers independently identified studies related to intestinal microcirculation dysfunction in sepsis. Exclusion criteria were duplicate articles according to multiple search criteria. RESULTS: Fifty articles were included, and most of them were animal studies. These studies reported pathogenesis, including endothelial dysfunction, leukocyte recruitment and adhesion, microthrombus formation, microcirculation hypoperfusion, and redistribution of intestinal wall blood flow. The monitoring methods of intestinal microcirculation were also diverse, including handheld microscopes, intravital microscopy (IVM), laser Doppler blood flow instruments, laser speckle contrast imaging, tissue reflectance spectrophotometry, biochemical markers of intestinal ischemia, and histopathological examination. In view of the related pathogenesis of intestinal microcirculation disorder in sepsis, existing studies also have different opinions on its treatment. CONCLUSIONS: Limited by monitoring, there are few clinical studies on intestinal microcirculation dysfunction in sepsis. Related research mainly focuses on basic research, but some progress has also been made. Therefore, this review may provide a reference for future research on intestinal microcirculation dysfunction in sepsis.

Trichostatin A improves the inflammatory response and liver injury in septic mice through the FoxO3a/autophagy signaling pathway.

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.

The circular RNA hsa_circ_0003091 regulates sepsis-induced lung injury by sponging the miR-149/Smad2 axis.

Sepsis-induced acute lung injury (ALI) is a severe cause of death. Increasing evidence has identified circular RNAs (circRNAs) acting as critical regulators of human diseases. However, their expression pattern and underlying mechanisms in ALI remain unclear. Herein, we screened the circRNAs of ALI patients and constructed a lung injury murine model using lipopolysaccharides (LPS) induction. Functional analyses of targeted circRNA were performed in vivo and in vitro. Then, the downstream miRNA and mRNA of specific circRNAs were identified. Compared to healthy subjects, 35 circRNAs were upregulated and 9 circRNAs were downregulated in sepsis patients. The top 10 differentially expressed circRNAs were selected for validation and has_circ_0003091 was selected. The ALI mice presented significantly elevated has_circ_0003091 (mmu_circ_0015268). The functional analysis revealed that mmu_circ_0015268 contributed to the pulmonary injury, cell apoptosis, inflammatory responses, and endothelial activation in the ALI murine model. On the other hand, silencing mmu_circ_0015268 showed protective effects in LPS-treated mice and PMVECs. Furthermore, mmu_circ_0015268 sponged miR-149 to upregulate the expression of its target Smad2. In summary, we demonstrated that has_circ_0003091 might be a novel target for the management and treatment of sepsis-induced ALI.

Prognostic role of elevated VEGF in sepsis: A systematic review and meta-analysis.

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.

Sirt3 Maintains Microvascular Endothelial Adherens Junction Integrity to Alleviate Sepsis-Induced Lung Inflammation by Modulating the Interaction of VE-Cadherin and ß-Catenin.

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.

HDAC6 promotes sepsis development by impairing PHB1-mediated mitochondrial respiratory chain function.

OBJECTIVE: This study was aimed at investigating the regulation of mitochondrial function by histone deacetylase 6 (HDAC6) and the role of HDAC6 in the development and progression of sepsis. RESULTS: HDAC6 downregulated PHB1 and subsequently promoted the development of CLP-induced sepsis. Inhibition of HDAC6 significantly attenuated CLP-induced sepsis through inhibition of mitochondrial dysfunction and reduced oxidant production, thus protecting the rats from oxidative injury. CONCLUSIONS: In this sepsis model, HDAC6 inhibits the expression and function of PHB1 and alters the function of the mitochondrial respiratory chain mediated by PHB1, thus enhancing the production of oxidants and increasing oxidative stress and thereby leading to severe oxidative injury in multiple organs. METHODS: The expression of HDAC6 and prohibitin 1 (PHB1) in humans and in a rat model of sepsis was measured by quantitative reverse-transcription PCR and western blotting. Sepsis induction by cecal ligation and puncture (CLP) was confirmed by histological analysis. Concentrations of different sepsis markers were measured by an enzyme-linked immunosorbent assay, and mitochondrial function was assessed via the mitochondrial respiratory control rate.