Background: Sepsis is a syndrome with the disturbed host response to severe infection and is a major health problem worldwide. As the front line of infection defense and drug metabolism, the liver is vulnerable to infection- or drug-induced injury. Acute liver injury (ALI) is thus common in patients with sepsis and is significantly associated with poor prognosis. However, there are still few targeted drugs for the treatment of this syndrome in clinics. Recent studies have reported that mesenchymal stem cells (MSCs) show potential for the treatment of various diseases, while the molecular mechanisms remain incompletely characterized.Aims and Methods: Herein, we used cecal ligation puncture (CLP) and lipopolysaccharide (LPS) plus D-galactosamine (D-gal) as sepsis-induced ALI models to investigate the roles and mechanisms of mesenchymal stem cells (MSCs) in the treatment of ALI in sepsis.Results: We found that either MSCs or MSC-derived exosome significantly attenuated ALI and consequent death in sepsis. miR‐26a‐5p, a microRNA downregulated in septic mice, was replenished by MSC-derived exosome. Replenishment of miR‐26a‐5p protected against hepatocyte death and liver injury caused by sepsis through targeting Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1), a long non-coding RNA highly presented in hepatocyte and liver under sepsis and inhibiting anti-oxidant system.Conclusion: Taken together, the results of the current study revealed the beneficial effects of MSC, exosome or miR-26a-5p on ALI, and determined the potential mechanisms of ALI induced by sepsis. MALAT1 would be a novel target for drug development in the treatment of this syndrome.

Acute lung injury (ALI) is a common complication of critical illness that could frequently lead to acute respiratory distress syndrome and other serious clinical consequences. Sepsis is one of the major and most common inducements among all causes of ALI. Due to its high incidence and mortality rate and also the complexity in treatment, sepsis-related ALI has become an urgent clinical problem waiting to be solved effectively. At present, only the protective ventilation strategy, restrictive fluid management, and antibiotics application are measures that can improve the prognosis with evidence-based medical proof. No pharmacological treatment is currently available to protect or significantly reverse the prognosis. Seeking for effective interventions measures for sepsis-related ALI is one of the most necessitous research directions. In this research, a conspicuous discovery of treatment-related translational use for a 4-benzene-indol derivative was elaborated by screening a large number of chemical compounds. The results showed that 4-benzene-indol derivative could not only suppress the activation of NLRP3 inflammasome both in vitro and alleviate LPS-induced ALI in vivo but also suppress the NLRP3 inflammasome in human myeloid leukemia mononuclear cells (THP-1) cell lines. Mechanistically, 1,2-diol blocks the NLRP3 inflammasome activation by disrupting NLRP3–NEK7 interaction and the subsequent NLRP3 inflammasome assembly and activation. To summarize, this research indicated that the newly-discovered 4-benzene-indol derivative targets NLRP3 inflammasome signaling, which consequently alleviates sepsis-related ALI. Collectively, the 4-benzene-indol derivative may serve as a potential therapeutic drug and NLRP3 inflammasome signaling would be a novel pharmaceutical target for clinical treatment of sepsis-related ALI.

Metabolic syndrome (MetS) is characterized by chronic low-grade inflammation and immune dysregulation, which may increase susceptibility to sepsis. However, epidemiologic evidence remains limited. This study aimed to evaluate the association of MetS with the risk of sepsis and sepsis-related mortality. This study included 359,633 participants from the UK Biobank and 152,317 participants from the Kailuan Study. MetS was defined as the presence of ≥3 metabolic abnormalities. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of MetS with risk of sepsis and 28-day mortality following sepsis. Stratified analyses were conducted to assess potential effect modification. In the UK Biobank, we further evaluated the dose-response relationship between the number of MetS components and sepsis outcomes, explored potential mediation by inflammatory and immune biomarkers, and investigated the joint effect of MetS and lifestyle; in the Kailuan Study, we further investigated the impact of MetS evolution on sepsis risk. Sensitivity analyses were performed to evaluate the robustness of the results. During a median follow-up of 13.7 years, 11,040 sepsis cases were identified in the UK Biobank, whereas 5672 cases were documented in the Kailuan Study during a median follow-up of 16.4 years. After multivariable adjustment, MetS was associated with higher risks of sepsis (HR=1.55, 95% CI 1.49–1.61) and 28-day mortality following sepsis (HR=1.51, 95% CI 1.37–1.65) in the UK Biobank; corresponding HRs were 1.32 (95% CI 1.25–1.40) and 1.49 (95% CI 1.32–1.69) in the Kailuan Study, respectively (all P<0.001). These associations were generally consistent across stratified analyses. Moreover, the risk of sepsis outcomes increased with the number of MetS components and was partly mediated by inflammation. Compared with individuals free of MetS, individuals with MetS and an unfavorable lifestyle had substantially higher risks of sepsis (HR=1.91, 95% CI 1.81–2.00) and 28-day mortality following sepsis (HR=1.84, 95% CI 1.64–2.07), whereas those with MetS but a favorable lifestyle showed only a modestly increased risk of sepsis and no excess risk of 28-day mortality (HR=1.18, 95% CI 1.09–1.28 and HR=1.05, 95% CI 0.88–1.27, respectively). In analyses of MetS evolution, using individuals with persistently normal metabolic status as the reference, those with a persistent MetS demonstrated the highest risks of sepsis (HR=1.46, 95% CI 1.32–1.61) and 28-day mortality following sepsis (HR=1.88, 95% CI 1.50–2.35), followed by individuals with progressive MetS (HR=1.17, 95% CI 1.05–1.31 and HR=1.36, 95% CI 1.04–1.77, respectively), whereas those who recovered from MetS did not show a significantly increased risk (HR=1.09, 95% CI 0.96–1.25 and HR=1.19, 95% CI 0.87–1.61, respectively). Sensitivity analyses confirmed the robustness of the findings. This study demonstrated that MetS was associated with an increased risk of sepsis and sepsis-related mortality. These associations were partially mediated through inflammatory responses. The findings highlight the importance of maintaining metabolic health as well as promoting healthy lifestyles as strategies to reduce its burden.