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中国应用生理学杂志 ›› 2016, Vol. 32 ›› Issue (4): 378-382.doi: 10.13459/j.cnki.cjap.2016.04.023

• 研究论文 • 上一篇    下一篇

吡非尼酮对四氯化碳诱导的小鼠肝纤维化的影响

肖敏, 屈小虎, 吕聚坪, 史杨, 李长西, 谢克俭   

  1. 温州医科大学检验医学与生命科学学院, 浙江 温州 325035
  • 收稿日期:2015-12-29 修回日期:2016-04-19 出版日期:2016-07-28 发布日期:2018-06-20
  • 通讯作者: 谢克俭,Tel:13705883181;E-mail:xkj@wmu.edu.cn E-mail:xkj@wmu.edu.cn
  • 基金资助:
    2015年度浙江省公益技术应用研究计划(实验动物)项目(2015C37099)

Effects of pirfenidone on hepatic fibrosis in mice induced by carbon tetrachloride

XIAO Min, QU Xiao-hu, LV Jv-ping, SHI Yang, LI Chang-xi, XIE Ke-jian   

  1. Department of Biology, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou 325035, China
  • Received:2015-12-29 Revised:2016-04-19 Online:2016-07-28 Published:2018-06-20
  • Supported by:
    2015年度浙江省公益技术应用研究计划(实验动物)项目(2015C37099)

摘要: 目的:研究吡非尼酮对四氯化碳诱导的小鼠肝纤维化的影响。方法:选用8周健康雄性SPF级ICR小鼠40只,随机分为4组(n=10):肝纤维化模型组(CCL4组)、吡非尼酮低剂量组(PFD-L组)、吡非尼酮高剂量组(PFD-H组)及正常对照组。CCL4肝纤维化模型采用0.4 ml/只10%的CCL4大豆油溶液进行小鼠腹腔注射制备,低剂量、高剂量吡非尼酮干预组在造模后采用120 mg/kg、240 mg/kg吡非尼酮(PFD)灌胃,正常对照组采用与前三组等量的生理盐水腹腔注射的方法。全自动生化仪检测血清中谷丙转氨酶(ALT)、谷草转氨酶(AST)、碱性磷酸酶(ALP);取肝脏组织HE染色观察组织的病理学变化;荧光定量PCR法测定肝脏中α-平滑肌肌动蛋白(α-SMA)相关基因的表达,酶联反应法检测肝纤维化指标透明质酸(HA)、层粘连蛋白(LN)、Ⅳ型胶原(IV-C)。结果:与正常组相比,CCL4组小鼠肝小叶结构明显破坏,胶原纤维沉积明显,可见假小叶形成;血清ALT、AST、ALP均显著升高(P<0.05);血清肝纤维化指标HA、LN、IV-C均显著升高(P<0.05);α-SMA基因的表达水平也显著升高(P<0.05)。PFD-L组和PFD-H组小鼠AST、ALT、ALP相较于CCL4组明显降低,PFD-L组和PFD-H组小鼠血清肝纤维化指标HA、LN、IV-C相较于CCL4组明显降低,α-SMA基因的表达也受到抑制(P<0.05)。病理学观察发现,PFD-L组小鼠的肝纤维化程度减轻,胶原纤维减少,仅见少量假小叶;PFD-H组小鼠细胞排列恢复,小叶结构轻度紊乱,未见明显假小叶,恢复效果比PFD-L组好。结论:吡非尼酮对于肝纤维化有一定的治疗作用,其可成为肝纤维化早期干预的新药物。

关键词: 吡非尼酮, 四氯化碳, 肝纤维化, 肝星状细胞, 小鼠

Abstract: Objective:To investigate the effects of pirfenidone on CCl4-induced liver fibrosis in mice. Methods:After 8-week feeding, 40 healthy male SPF ICR mice were randomly divided into 4 groups:liver fibrosis group (CCL4 group), low doses of Pirfenidone group (PFD-L group), high doses of Pirfenidone group (PFD-H group) and control group. The mice in CCL4 group, low doses of Pirfenidone group (PFD-L group), high doses of Pirfenidone group (PFD-H group) were injected intraperitoneally with 0.4 ml 10% CCL4 solution dissolved in soybean oil. Then the PFD-L and PFD-H groups were treated with 120 mg and 240 mg PFD via gastric gavage, respectively. Control group was injected with same volume of saline. Alanine aminotransferase(ALT), aspartate aminotransferase(AST), alkaline phosphatase(ALP) in serum were tested with automatic biochemistry analyzer and the pathologic changes of liver tissue were examined by HE staining. Furthermore, we identi-fied hyaluronic acids(HA), laminin(LN), collagentype IV(IV-C) in serum using radioimmunoassay and the expression of smooth muscle acti-nalpha(α-SMA) related gene in liver was tested by real-time fluorescence quantitative PCR. Results:Compared with control group, hepatic lobules in CCL4 mice were damaged significantly, collagenous fiber was deposited obviously, and counterfeit hepatic lobules formed. The serum levels of ALT, AST, ALP were increased obviously (P<0.05) with the enhancement of HA, LN, IV-C in serum (P<0.05) and the ex-pression of α-SMA related gene (P<0.05). Compared to CCL4-treated mice, the serum levels of ALT, AST, ALP in PFD-L and PFD-H groups were decreased, HA, LN, IV-C in PFD-L and PFD-H mice went down obviously,and the expression of α-SMA related gene was con-trolled (P<0.05). From pathological observation, we found the degree of liver fibrosis in PFD-L mice was reduced and collagenous fiber was decreased, only a little counterfeit hepatic lobule could be found. Cell arrangement in PFD-H mice recovered, the structural of hepatic lobules disordered and no obvious counterfeit hepatic lobules were found. Therefore, the recovery of PFD-H group was better than PFD-L group.Conclusion:Pirfenidone has a protective role in improving the outcome of the liver fibrosis and it may become a new direction of early intervention in liver fibrosis.

Key words: pirfenidone, carbon tetrachloride, hepatic fibrosis, hepatic stellate cells, mice

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