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中药下瘀血汤抑制四氯化碳诱导的肝纤维化大鼠肝脏血管生成

[Chinese herbal medicine Xiayuxue Decoction inhibits liver angiogenesis in rats with carbon tetrachloride-induced liver fibrosis].

作者信息

Du Jin-xing, Liu Ping, Sun Ming-yu, Tao Qing, Zhang Li-jun, Chen Gao-feng, Hu Yi-yang, Liu Cheng-hai, Xu Lie-ming

机构信息

Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.

出版信息

Zhong Xi Yi Jie He Xue Bao. 2011 Aug;9(8):878-87. doi: 10.3736/jcim20110810.

Abstract

OBJECTIVE

To evaluate the effects of Xiayuxue Decoction, a compound traditional Chinese medicine, on liver angiogenesis in rats with carbon tetrachloride (CCl(4))-induced liver fibrosis.

METHODS

Liver cirrhosis was induced by intraperitoneal injection of 50% CCl(4)-olive oil solution at the dose of 1 mL/kg body weight, twice per week for 9 consecutive weeks. After 3- and 6-week injection, 6 rats in the normal group and 6 rats in the model group were randomly sacrificed for dynamic observation. The survival rats of model group were randomly divided into model group (n=15) and Xiayuxue Decoction group (n=11). Six normal rats were used as a normal control. Xiayuxue Decoction was administered orally starting from the 7th week for 3 weeks. At the end of the ninth week, animals were sacrificed and liver tissues were harvested to measure histological changes, activities of matrix metalloproteinase-2 (MMP-2) and MMP-9 and protein expressions of platelet endothelial cell adhesion molecule-1 (CD31), von Willebrand factor (vWF), vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor-2 (VEGFR2), complement decay-accelerating factor (DAF) and α-smooth muscle actin (α-SMA) in the liver tissues.

RESULTS

Compared with the normal group, liver injury, fatty degeneration and collagen deposition were evidently observed in the model group and protein expressions of CD31, vWF, VEGF, VEGFR2, DAF and α-SMA were gradually increased. In addition, the activities of MMP-2 and MMP-9 in liver tissues were enhanced in the model group (P<0.01). Compared with 9-week model group, liver injury, fatty degeneration and collagen deposition were markedly inhibited by Xiayuxue Decoction; protein expressions of CD31, vWF, VEGF, VEGFR2,α-SMA and DAF and activities of MMP-2 and MMP-9 in the liver tissues were decreased in the Xiayuxue Decoction group (P<0.01).

CONCLUSION

The angiogenesis is evident and aggravating gradually during the progression of liver cirrhosis induced by CCl(4). Xiayuxue Decoction inhibits the angiogenesis by decreasing the activities of MMP-2 and MMP-9, inhibiting the activation of hepatic stellate cells, and damaging the new vessel integrality.

摘要

目的

评价中药复方下瘀血汤对四氯化碳(CCl₄)诱导的大鼠肝纤维化肝脏血管生成的影响。

方法

采用腹腔注射50% CCl₄-橄榄油溶液,剂量为1 mL/kg体重,每周2次,连续9周诱导大鼠肝硬化。注射3周和6周后,分别随机处死正常组6只大鼠和模型组6只大鼠进行动态观察。将模型组存活大鼠随机分为模型组(n = 15)和下瘀血汤组(n = 11)。另取6只正常大鼠作为正常对照组。从第7周开始口服下瘀血汤,连续3周。在第9周结束时,处死动物,取肝脏组织,检测组织学变化、基质金属蛋白酶-2(MMP-2)和MMP-9活性以及肝脏组织中血小板内皮细胞黏附分子-1(CD31)、血管性血友病因子(vWF)、血管内皮生长因子(VEGF)、血管内皮生长因子受体-2(VEGFR2)、补体衰变加速因子(DAF)和α-平滑肌肌动蛋白(α-SMA)的蛋白表达。

结果

与正常组相比,模型组可见明显的肝损伤、脂肪变性和胶原沉积,CD31、vWF、VEGF、VEGFR2、DAF和α-SMA蛋白表达逐渐增加。此外,模型组肝脏组织中MMP-2和MMP-9活性增强(P < 0.01)。与9周模型组相比,下瘀血汤明显抑制肝损伤、脂肪变性和胶原沉积;下瘀血汤组肝脏组织中CD31、vWF、VEGF、VEGFR2、α-SMA和DAF蛋白表达以及MMP-2和MMP-9活性降低(P < 0.01)。

结论

CCl₄诱导的肝硬化进展过程中血管生成明显且逐渐加重。下瘀血汤通过降低MMP-2和MMP-9活性、抑制肝星状细胞活化及破坏新生血管完整性来抑制血管生成。

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