Sepsis involves endothelial cell dysfunction leading to the development of lung injury. Fatty acid synthesis contributes to the development of inflammatory injury in sepsis. However, the regulatory mechanisms of fatty acid synthesis-related endothelial activation remain unclear. In this study, we found that fatty acid synthesis in patients with sepsis was greatly disordered. Inhibition of fatty acid synthesis significantly alleviated sepsis-induced endothelial damage and lung injury both in vitro and in vivo. We further found that the release of mtDNA participated in fatty acid synthesis-related regulation of endothelial inflammatory and coagulation activation. Mechanistically, fatty acid synthesis promoted the oligomerization of voltage-dependent anion channel 1 (VDAC1) via ETS proto-oncogene 1 (ETS1)-mediated inhibition of VDAC1 ubiquitination, thereby leading to the increased release of mtDNA and subsequent activation of cGAS-STING signaling and pyroptosis in endothelial cells. Our findings revealed that fatty acid synthesis promoted endothelial dysfunction through mtDNA release, providing new insight into the therapeutic strategies for treating sepsis-associated lung injury.

Microcirculatory dysfunction is one of the main characteristics of sepsis. Shenfu Injection (SFI) as a traditional Chinese medicine is widely applied in clinical severe conditions. Recent studies have shown that SFI has the ability to ameliorate sepsis-induced inflammation and to improve microcirculation perfusion. This study aims to investigate the underlying mechanism of SFI for ameliorating sepsis-associated endothelial dysfunction and organ injury. Side-stream dark-field (SDF) imaging was used to monitor the sublingual microcirculation of septic patients treated with or without SFI. Septic mouse model was used to evaluate the effects of SFI in vivo. Metabolomics and transcriptomics were performed on endothelial cells to identify the underlying mechanism for SFI-related protective effect on endothelial cells. SFI effectively abolished the disturbance and loss of sublingual microcirculation in septic patients. Twenty septic shock patients with or without SFI administration were enrolled and the data showed that SFI significantly improved the levels of total vessel density (TVD), perfused vessel density (PVD), microvascular flow index (MFI), and the proportion of perfused vessels (PPV). The administration of SFI significantly decreased the elevated plasma levels of Angiopoietin-2 (Ang2) and Syndecan-1, which are biomarkers indicative of endothelial damage in sepsis patients. In the mouse septic model in vivo, SFI inhibited the upregulation of endothelial adhesion molecules and Ly6G + neutrophil infiltration while restored the expression of VE-Cadherin in the vasculature of the lung, kidney, and liver tissue. Additionally, SFI reduced the plasma levels of Ang2, Monocyte Chemoattractant Protein-1(MCP1), and Interleukin-6 (IL6), and alleviated liver and kidney injury in septic mice. Moreover, SFI significantly inhibited the inflammatory activation and increased permeability of endothelial cells induced by endotoxins in vitro. By performing metabolomics and transcriptomics, we identified the activation of PI3K/Akt-mediated glycolysis as the underlying mechanism for SFI-related protective effect on endothelial cells. Our findings revealed that SFI may improve microcirculation perfusion and endothelial function in sepsis via inhibiting PI3K/Akt-mediated glycolysis, providing theoretical evidence for the clinical application of SFI.

Polymyxins are the last line of defense against multidrug-resistant (MDR) Gram-negative bacterial infections. However, this last resort has been threatened by the emergence of superbugs carrying the mobile colistin resistance gene-1 (mcr-1). Given the high concentration of matrix metalloproteinase 3 (MMP-3) in bacterial pneumonia, limited plasma accumulation of colistin (CST) in the lung, and potential toxicity of ionic silver (Ag⁺), we designed a feasible clinical transformation platform, an MMP-3 high-performance lung-targeted bio-responsive delivery system, which we named "CST&Ag@CNMS". This system exhibited excellent lung-targeting ability (>80% in lungs), MMP-3 bio-responsive release property (95% release on demand), and synergistic bactericidal activity in vitro (2-4-fold minimum inhibitory concentration reduction). In the mcr-1⁺ CST-resistant murine pneumonia model, treatment with CST&Ag@CNMS improved survival rates (70% vs. 20%), reduced bacteria burden (2-3 log colony-forming unit [CFU]/g tissue), and considerably mitigated inflammatory response. In this study, CST&Ag@CNMS performed better than the combination of free CST and AgNO₃. We also demonstrated the superior biosafety and biodegradability of CST&Ag@CNMS both in vitro and in vivo. These findings indicate the clinical translational potential of CST&Ag@CNMS for the treatment of lung infections caused by CST-resistant bacteria carrying mcr-1.

To evaluate the effectiveness and safety of the Shenfu injection (SFI) combined with standard bundle treatment in septic patients with hypoperfusion. This study was a multi-center, randomized, open-label, controlled trial conducted in four teaching hospitals in China. The septic patients with hypoperfusion and traditional Chinese medicine (TCM) syndrome with Yang-Qi deficiency were enrolled from January 2019, through September 2020. Eligible patients were randomly allocated in a 1:1 ratio to either receive 60 mL of SFI infusion per day plus standard treatment (SFI group) or standard bundle treatment alone (control group). The primary outcome was 28-day all-cause mortality. Secondary outcomes were 90-day all-cause mortality time to weaning from mechanical ventilation, time to weaning from vasopressors, time to discharge from the ICU and hospital, and laboratory results after randomization. A total of 188 patients completed the trail. This study revealed that the results of the SFI group and the control groups were not statistically significant in 28-day all-cause mortality (10.6% vs. 20.2%, respectively; P=0.106). The infusion of SFI was associated with a significant reduction in the duration of vasopressor use (median=4.0 days, interquartile range [IQR]: 2.0 days–6.0 days vs. median=5.0 days, IQR: 3.0 days–8.0 days, respectively; P=0.043). Patients in the SFI group had statistically greater reductions in plasma lactate levels compared with those in the control group at the first 12 h (median=1.1 mmol/L, IQR: 0.3–2.0 mmol/L vs. median=0.0 mmol/L, IQR: −0.2 to 0.8 mmol/L, respectively; P <0.001) and 24 h (median=1.4 mmol/L, IQR: 0.3–2.2 mmol/L vs. median=0.4 mmol/L, IQR: −0.4 to 1.6 mmol/L, respectively; P=0.001). SFI plus standard therapy did not significantly decrease 28-day all-cause mortality for septic patients with hypoperfusion and TCM syndrome with Yang-Qi deficiency. Trial registration Chinese Clinical Trial Registry Identifier: ChiCTR1800020435