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目的:研究芍芪多苷(SQDG)对四氯化碳(CCl4)诱导的肝纤维化大鼠肝组织和转化生长因子β1(TGF-β1)刺激的肝星状细胞(HSC)基质金属蛋白酶13(MMP-13)、组织金属蛋白酶抑制因子1(TIMP-1)表达的影响,探讨SQDG抗肝纤维化作用的可能机制。方法:CCl4皮下注射建立大鼠肝纤维化模型,设立正常对照组、模型组、SQDG给药组(42.5,85,170 mg.kg-1)。放免法检测血清中I型胶原(C-I)水平;Masson染色对肝脏组织作病理检查;免疫组化法检测肝组织MMP-13,TIMP-1的表达。采用Western blot探讨SQDG体外对TGF-β1刺激的HSC MMP-13,TIMP-1及C-I表达的影响。结果:SQDG可显著降低纤维化大鼠血清中C-I含量;病理组织学检查发现,SQDG可降低化学性肝纤维化大鼠的纤维化程度,与模型组相比,纤维沉积、肝小叶的破坏等均有所减轻。免疫组化结果显示,SQDG(85,170 mg.kg-1)可显著升高肝纤维化大鼠肝脏局部MMP-13水平,降低TIMP-1水平。进一步研究发现,SQDG体外可明显抑制TGF-β1刺激的HSC-T6 TIMP-1表达,促进MMP-13的表达,同时降低C-I的表达水平。结论:SQDG可能通过调节肝纤维化大鼠肝组织MMP-13和TIMP-1的异常表达,促进HSCMMP-13的表达,抑制TIMP-1的表达,促进胶原降解而发挥抗肝纤维化的作用。
OBJECTIVE: To investigate the effect of SQDG on hepatic stellate cells (HSCs) and hepatic stellate cells (HSC) stimulated by transforming growth factor-β1 (TGF-β1) induced by carbon tetrachloride (CCl4) (MMP-13) and tissue inhibitor of metalloproteinase-1 (TIMP-1), and explore the possible mechanism of SQDG on hepatic fibrosis. Methods: The rat model of hepatic fibrosis was induced by CCl4 subcutaneously. The normal control group, model group and SQDG group (42.5, 85, 170 mg.kg-1) were established. Serum levels of type I collagen (C-I) were detected by radioimmunoassay; Masson staining was used to examine the liver tissue; immunohistochemistry was used to detect the expression of MMP-13 and TIMP-1 in liver tissues. Western blot was used to investigate the effect of SQDG on the expression of MMP-13, TIMP-1 and C-I in HSC stimulated by TGF-β1. Results: SQDG significantly reduced CI in serum of fibrotic rats. It was found by histopathological examination that SQDG reduced the degree of fibrosis in rats with chemical fibrosis. Compared with the model group, the deposition of fibrin and the destruction of hepatic lobules Are reduced. Immunohistochemical results showed that SQDG (85,170 mg.kg-1) could significantly increase the level of local MMP-13 and decrease the level of TIMP-1 in liver of rats with hepatic fibrosis. Further study found that, SQDG can significantly inhibit the TGF-β1-stimulated HSC-T6 TIMP-1 expression, promote MMP-13 expression, while reducing the expression of C-I. Conclusion: SQDG may play an anti-hepatic fibrosis effect by regulating the expression of MMP-13 and TIMP-1 in hepatic tissue of rats with hepatic fibrosis, promoting the expression of HSCMMP-13, inhibiting the expression of TIMP-1 and promoting collagen degradation.