Cao Xinyue, Ma Ruihua, Wang Yirui, Huang Yuran, You Keyuan, Zhang Lijie, Li Haidong, Feng Guize, Chen Tongqing, Wang Dong, Sun Keyu, Fang Hao, Shen Xiaoyan
Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, PR China.
Department of Anesthesiology, The Fourth Affiliated Hospital of Soochow University, Suzhou, Jiangsu, PR China, 215125.
Phytomedicine. 2025 Mar;138:156384. doi: 10.1016/j.phymed.2025.156384. Epub 2025 Jan 12.
Sepsis is a life-threatening condition characterized by organ dysfunction resulting from the body's aberrant response to infection. A primary indicator of early sepsis is vascular leakage due to endothelial injury. The immunomodulatory effects of paeoniflorin are well established. However, its effect on vascular endothelial injury in sepsis remains to be verified.
The sepsis model was established by cecal ligation and puncture (CLP), along with simultaneous administration of paeoniflorin. The therapeutic effectiveness of paeoniflorin was evaluated by assessing the survival rate, the bacterial load in blood and the histopathological lung tissue injury. The pulmonary vascular endothelial barrier integrity was assessed using immunofluorescence, western blot, Evans blue dye, and qPCR. Human umbilical vein endothelial cells (HUVECs) were used for in vitro validation and exploration of the underlying mechanisms.
The CLP mice exhibited significant damage to pulmonary tissue and breakdown of endothelial barrier. Administration of paeoniflorin markedly improved survival rates, mitigated lung injury, and preserved the integrity of the pulmonary vascular endothelial barrier in CLP mice which was confirmed by in vitro experiments. Pharmacological mechanism studies showed that the protective effects of paeoniflorin on the vascular endothelium was achieved through activation of RXRα signaling, which could be reversed by RXRα knockdown.
Our experiments demonstrates the protective effect of paeoniflorin on the vascular endothelial barrier through activation of the RXRα, thereby offering potential therapeutic options for sepsis treatment. We also identified RXRα as a novel transcription factor for VE-cadherin, providing a potential new intervention target for vascular endothelial barrier damage in sepsis.
脓毒症是一种危及生命的病症，其特征是机体对感染的异常反应导致器官功能障碍。早期脓毒症的一个主要指标是由于内皮损伤引起的血管渗漏。芍药苷的免疫调节作用已得到充分证实。然而，其对脓毒症血管内皮损伤的影响仍有待验证。
通过盲肠结扎和穿刺（CLP）建立脓毒症模型，并同时给予芍药苷。通过评估生存率、血液中的细菌载量和肺组织病理损伤来评价芍药苷的治疗效果。使用免疫荧光、蛋白质免疫印迹、伊文思蓝染料和定量聚合酶链反应评估肺血管内皮屏障的完整性。用人脐静脉内皮细胞（HUVECs）进行体外验证并探索潜在机制。
CLP小鼠表现出明显的肺组织损伤和内皮屏障破坏。给予芍药苷可显著提高生存率，减轻肺损伤，并维持CLP小鼠肺血管内皮屏障的完整性，体外实验也证实了这一点。药理机制研究表明，芍药苷对血管内皮的保护作用是通过激活RXRα信号实现的，RXRα基因敲低可逆转这种作用。
我们的实验证明了芍药苷通过激活RXRα对血管内皮屏障具有保护作用，从而为脓毒症治疗提供了潜在的治疗选择。我们还确定RXRα是血管内皮钙黏蛋白的一种新型转录因子，为脓毒症血管内皮屏障损伤提供了一个潜在的新干预靶点。
