五灵胶囊通过抑制 TLR4-NF-κB 信号通路调节巨噬细胞极化，从而缓解肝纤维化。
Wuling capsule modulates macrophage polarization by inhibiting the TLR4-NF-κB signaling pathway to relieve liver fibrosis.
机构信息
Co-Construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi and Education Ministry, Shaanxi Innovative Drug Research Center, State Key Laboratory of Research and Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi University of Chinese Medicine, Xianyang 712000, China.
Co-Construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi and Education Ministry, Shaanxi Innovative Drug Research Center, State Key Laboratory of Research and Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi University of Chinese Medicine, Xianyang 712000, China.
出版信息
Int Immunopharmacol. 2024 Mar 10;129:111598. doi: 10.1016/j.intimp.2024.111598. Epub 2024 Feb 3.
BACKGROUND AND PURPOSE
Wuling capsule (WL) has good efficacy in the clinical treatment of chronic hepatitis B and liver injury. Liver fibrosis is a common pathological feature of chronic liver disease and may progress to irreversible cirrhosis and liver cancer. Accumulating evidence reveals that modulating macrophage polarization contribute to the therapy of liver fibrosis. However, the effects of WL on modulating macrophage polarization to relive liver fibrosis remain unclear. This study investigated the anti-liver fibrosis effects of WL in carbon tetrachloride (CCl)-induced liver fibrosis in rats, and the modulation effects and underlying molecular mechanism on macrophage polarization.
METHODS
A rat liver fibrosis model was constructed by intraperitoneal injection of 40 % CCl olive oil mixture. At 2, 4, 6, and 8 weeks, the histopathological status of the liver was assessed by hematoxylin-eosin (HE) and Masson staining; the liver biochemical indexes were measured in rat liver tissue. The expression levels of inflammatory cytokines in liver tissue were detected by ELISA. The mRNA levels and proteins expression of macrophage markers of different phenotypes, TLR4-NF-κB signaling pathway indicators were detected independently by ELISA, immunofluorescence, RT-PCR and western blotting.
RESULTS
In vivo, WL treatment attenuated abnormal changes in weight, organ indices and biochemical indices, alleviated pathological changes, and reduced collagen fiber deposition as well as the expression of α-SMA in liver tissues. Further studies revealed that WL decreased the expression of the macrophage M1 polarization markers inducible nitric oxide synthase (iNOS), TNF-α, IL-6, and CD86, promoted the expression of the M2 macrophage polarization markers IL-10, CD206, and arginase-1 (Arg-1), and inhibited the activation of the TLR4-NF-κB signaling pathway via several key signaling proteins. In vitro, WL significantly suppressed macrophage M1 polarization, and promoted M2 polarization while boosted M1 polarization transform to M2 polarization in LPS-activated RAW264.7 cells.
CONCLUSIONS
This study demonstrated that WL modulated macrophage polarization against liver fibrosis mainly by inhibiting the activation of the TLR4-NF-κB signaling pathway.
背景与目的
五苓胶囊（WL）在慢性乙型肝炎和肝损伤的临床治疗中具有良好的疗效。肝纤维化是慢性肝病的常见病理特征，可能进展为不可逆的肝硬化和肝癌。越来越多的证据表明，调节巨噬细胞极化有助于肝纤维化的治疗。然而，WL 调节巨噬细胞极化缓解肝纤维化的效果尚不清楚。本研究探讨了 WL 在四氯化碳（CCl）诱导的大鼠肝纤维化中的抗肝纤维化作用，以及对巨噬细胞极化的调节作用及其潜在的分子机制。
方法
采用腹腔注射 40% CCl 橄榄油混合物构建大鼠肝纤维化模型。在 2、4、6 和 8 周时，通过苏木精-伊红（HE）和 Masson 染色评估肝组织的组织病理学状态；测量大鼠肝组织中的肝生化指标。通过 ELISA 检测肝组织中炎症细胞因子的表达水平。通过 ELISA、免疫荧光、RT-PCR 和 Western blot 分别检测不同表型巨噬细胞标志物、TLR4-NF-κB 信号通路指标的 mRNA 水平和蛋白表达。
结果
在体内，WL 治疗可减轻体重、器官指数和生化指标的异常变化，缓解病理变化，减少胶原纤维沉积以及肝组织中 α-SMA 的表达。进一步的研究表明，WL 降低了巨噬细胞 M1 极化标志物诱导型一氧化氮合酶（iNOS）、TNF-α、IL-6 和 CD86 的表达，促进了 M2 巨噬细胞极化标志物 IL-10、CD206 和精氨酸酶-1（Arg-1）的表达，并通过几个关键信号蛋白抑制 TLR4-NF-κB 信号通路的激活。在体外，WL 显著抑制巨噬细胞 M1 极化，促进 M2 极化，并促进 LPS 激活的 RAW264.7 细胞中 M1 极化向 M2 极化的转化。
结论
本研究表明，WL 通过抑制 TLR4-NF-κB 信号通路的激活来调节巨噬细胞极化以对抗肝纤维化。
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