Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, China.
J Ethnopharmacol. 2024 Dec 5;335:118634. doi: 10.1016/j.jep.2024.118634. Epub 2024 Jul 30.
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.
微循环功能障碍是脓毒症的主要特征之一。参附注射液（SFI）作为一种中药，广泛应用于临床重症。最近的研究表明，SFI 具有改善脓毒症引起的炎症和改善微循环灌注的能力。
本研究旨在探讨 SFI 改善脓毒症相关内皮功能障碍和器官损伤的潜在机制。
采用边流暗场（SDF）成像技术监测接受或未接受 SFI 治疗的脓毒症患者的舌下微循环。采用脓毒症小鼠模型评价 SFI 的体内作用。对内皮细胞进行代谢组学和转录组学分析，以确定 SFI 相关保护作用在内皮细胞中的潜在机制。
SFI 能有效消除脓毒症患者舌下微循环的紊乱和丧失。共纳入 20 例接受或未接受 SFI 治疗的脓毒性休克患者，数据显示 SFI 显著提高了总血管密度（TVD）、灌注血管密度（PVD）、微血管血流指数（MFI）和灌注血管比例（PPV）水平。SFI 给药显著降低了脓毒症患者血浆中升高的血管生成素-2（Ang2）和 syndecan-1 水平，这是内皮损伤的生物标志物。在体内脓毒症小鼠模型中，SFI 抑制了内皮黏附分子的上调和 Ly6G+中性粒细胞浸润，同时恢复了肺、肾和肝组织血管中 VE-Cadherin 的表达。此外，SFI 降低了脓毒症小鼠血浆中 Ang2、单核细胞趋化蛋白-1（MCP1）和白细胞介素-6（IL6）的水平，并减轻了肝、肾损伤。此外，SFI 还显著抑制了内皮细胞在体外受内毒素刺激后的炎症激活和通透性增加。通过进行代谢组学和转录组学分析，我们确定了 PI3K/Akt 介导的糖酵解激活是 SFI 相关保护作用在内皮细胞中的潜在机制。
我们的研究结果表明，SFI 通过抑制 PI3K/Akt 介导的糖酵解改善脓毒症患者的微循环灌注和内皮功能，为 SFI 的临床应用提供了理论依据。
