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扶正化瘀方对非酒精性脂肪性肝病大鼠肝纤维化及ACE-Ang Ⅱ-AT1R轴的影响
作者:霍苗苗 程变巧 林伟国 吴旭玮 
单位:350007  福州  厦门大学附属福州第二医院肝内科(霍苗苗、程变巧、林伟国) 350025  福州  福建医科大学孟超肝胆 医院肝病消化科(吴旭玮) 
关键词:非酒精性脂肪性肝病 肝纤维化 扶正化瘀方 肾素-血管紧张素系统 
分类号:R575.5
出版年,卷(期):页码:2018,43(2):114-119
摘要:

[摘要]  目的  探讨扶正化瘀方对非酒精性脂肪性肝病大鼠肝纤维化及肾素血管紧张素转换酶-血管紧张素Ⅱ-血管紧张素Ⅱ1型受体(ACE-Ang-AT1R)轴的影响。方法 40只雄性SD大鼠随机分为正常对照组、模型组、扶正化瘀方低剂量干预组(低剂量组)和扶正化瘀方高剂量干预组(高剂量组)。除正常对照组外,其余3组经高脂饲料喂养24周后,低、高剂量组分别给予0.751.5g/kg扶正化瘀方灌胃,1/d6/周,共6周。测定血清总胆固醇(TC)、甘油三酯(TG)、丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)等生化指标;放射免疫法检测血浆及肝组织中Ang水平;采用HE染色及Masson染色观察肝脏病理形态学变化;免疫组化法检测肝组织α-平滑肌肌动蛋白(α-SMA)ACEAT1R的表达;RT-qPCR测定α-SMAACEAT1R mRNA水平。结果 与模型组比较,低剂量组及高剂量组ALTAST水平均明显降低,且高剂量组降低更明显,差异有统计学意义(P<0.05)3组间TCTG差异无统计学意义(P>0.05)。与正常对照组比较,其余3组血浆及肝组织中Ang均明显升高;3组间血浆Ang水平差异无统计学意义(P>0.05);而高、低剂量组肝组织Ang表达与模型组比较均明显下降,差异均有统计学意义(P<0.05)HE染色及Masson染色结果显示,与模型组比较,低剂量组和高剂量组肝细胞脂肪变性、炎性反应及肝纤维化程度均减轻,其中高剂量组效果更为明显。免疫组化分析显示,低剂量组和高剂量组α-SMAACEAT1R等蛋白表达均较模型组明显降低,其中高剂量组表达最低,差异均有统计学意义(P<0.05)RT-qPCR结果显示,α-SMAACEAT1RmRNA水平显示出与蛋白表达相同的变化规律。结论 扶正化瘀方能有效延缓非酒精性脂肪性肝纤维化的发生和发展,该机制可能与抑制ACE-Ang-AT1R轴活性,从而有效抑制肝星状细胞的进展密切相关。

[Abstract]  Objective  To evaluate the influence of Fuzhenghuayu decoction on fibrotic liver tissue and angiotensin- converting enzyme- angiotensin - angiotensin 1 receptor (ACE-Ang -AT1R) axis using a nonalcoholic fatty liver fibrosis rat model system. Methods  Forty male Sprague-Dawley (SD) rats were randomly divided into the following groups: normal control group, liver fibrosis model group, and liver fibrosis model Fuzhenghuayu drug intervention at low-dose [0.75g/(kg.d)] group and high-dose [1.5g/(kg.d)] group. Except the normal control group, the other three groups were fed high-fat diet for 24 weeks to induce nonalcoholic hepatic fibrosis model. The drug intervention was administered via oral-gastric irrigation once daily for 6 times per week over a 6-week period. The rats were sacrificed at the end of 6 weeks for serum and liver tissue collection. The levels of serum total cholesterol (TC), triglycerides (TG), alanine aminotransferase (ALT), aspartate aminotransferase (AST) were measured by standard biochemical assays. The Ang contents of plasma and liver tissue were surveyed and evaluated by the radioimmunoassay method. Liver pathology was detected using HE staining and Masson trichrome staining. The mRNA and protein expressions of ACE, AT1R, α-smooth muscle actin (α-SMA) in the liver tissue were evaluated with real time-PCR, immunohistochemical staining, respectively. Results  Compared with the model group, the levels of serum ALT and AST in the low-dose group and high-dose group decreased conspicuously, especially in the high-dose group, with a statistically significant difference (P<0.05); While the difference in the levels of serum TC and TG between the three groups was not statistically significant. Compared with the normal control group, Ang levels in plasma and liver tissue significantly increased in the other three groups; Further more, there was no significant difference in the plasma Ang level between the three groups (P>0.05); While the level of liver tissue Ang decreased significantly in the low-dose group and high-dose group than that in model group (P<0.05). Compared with the model group, the extent of pathological changes in hepatic tissues ameliorated after Fuzhenghuayu intervention according to HE and Masson staining, especially in the high-dose group. According to real time-PCR and immunohistochemical staining, the mRNA and protein expressions of ACE, α-SMA and AT1R decreased significantly in low-dose group and high-dose group than that in model group (P<0.05), and the high-dose group showed the most robust decrease. Conclusions  The Fuzhenghuayu decoction reduces nonalcoholic fatty hepatic fibrosis effectively, thereby leading to down-regulated the expressions of ACE-Ang -AT1R axis. These effects may represent the mechanism by which this drug suppresses hepatic fibrosis.

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