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中国应用生理学杂志 ›› 2020, Vol. 36 ›› Issue (2): 152-156.doi: 10.12047/j.cjap.5903.2020.034

• 研究论文 • 上一篇    下一篇

α-荼异硫氰酸酯诱导小鼠胆汁淤积性肝纤维化及其炎症通路*

罗怡爽, 郑秀婷, 章浩月, 徐丽萍, 裘加鹏, 徐港铭, 刘爱明   

  1. 宁波大学医学院, 浙江 宁波 315211
  • 出版日期:2020-03-28 发布日期:2020-07-31
  • 通讯作者: Tel: 13819880589; E-mail: liuaiming@nbu.edu.cn
  • 基金资助:
    *宁波市自然科学基金(2018A610253, 2018A610384);浙江省基础公益技术研究计划(LGD19H070001, LY20H030001);宁波大学研究生科研创新基金(G19130)

The cholestatic fibrosis induced by α-naphthylisothiocyanate in mice and the inflammation pathway

LUO Yi-shuang, ZHENG Xiu-ting, ZHANG Hao-yue, XU Li-ping, QIU Jia-peng, XU Gang-ming, LIU Ai-ming   

  1. Medical School of Ningbo University, Ningbo 315211, China
  • Online:2020-03-28 Published:2020-07-31

摘要: 目的: 探讨α-荼异硫氰酸酯(ANIT)诱导的胆汁淤积性肝纤维化的发展及其炎症通路。方法: 将15只体重为(23±2) g的129/Sv小鼠随机分为对照组(n=5)和实验组(n=10)。对照组常规饲料喂养,实验组小鼠给予0.05% ANIT饲料食饲。实验组分别在14 d和28 d各处死5只小鼠,收集胆囊、血清、肝脏等标本。按试剂盒程序检测胆汁淤积生化指标,组织病理学评估肝细胞损伤程度,Q-PCR和WB分析肝纤维化、炎症反应等水平。结果: 与对照组相比,造模第2周ANIT -14 d组(A-D14)中的主要胆汁淤积指标总胆汁酸(TBA)从(3.2±0.9) μmol/L显著增加至(31.6±4.3) μmol/L,肝损伤指标谷草转氨酶(AST)和谷丙转氨酶(ALT)也显著升高(P<0.05);纤维化因子金属蛋白酶组织抑制因子1(TIMP-1)、单核细胞趋化因子(MCP-1)、I型胶原蛋白(Collagen I)表达高于对照组(P<0.05);Collagen I和α-SMA纤维化蛋白表达均上调;肝脏胶原纤维大量沉积,纤维化已产生(P<0.05)。炎症因子表达高于对照组,JNK、c-Jun、STAT3等均被激活(P<0.05)。ANIT-28 d组(A-D28)中除AST、基质金属蛋白酶2(MMP-2),Collagen I指标稍有降低外,其余胆汁淤积、肝损伤、肝纤维化、炎症等指标继续上调或保持稳定(P< 0.05)。结论: 0.05%的ANIT饲料干预14 d,小鼠即发生明显的胆汁淤积性肝纤维化;28 d后,胆汁淤积性肝纤维化趋于稳定;JNK炎症通路在肝纤维化的发生发展中起着至关重要的作用。

关键词: α-荼异硫氰酸酯, 胆汁淤积, 肝纤维化, JNK通路, 小鼠

Abstract: Objective: To explore the development of cholestatic fibrosis induced by α-naphthylisothiocyanate (ANIT) and the inflammation pathways. Methods: Fifteen 129/Sv mice weighing (23±2) g were randomly divided into 2 groups: control group (n=5) and experiment group (n=10). The control group was fed commercial chow diet and the experiment group was fed the same diet supplemented with 0. 05% ANIT. Five mice in the experiment group were sacrificed on day 14 and 28 respectively. The gallbladder, serum and liver samples were collected. Biochemical indicators of cholestasis were detected following the procedures in the kit. Liver injury was evaluated by histopathological. Hepatic fibrosis and inflammatory response were analyzed by Q-PCR and WB. Results: Compared with the control group, total bile acid (TBA), the main cholestasis biomarker, was increased from (3. 2±0. 9) μmol/L to (31. 6±4. 3) μmol/L in A-D14 group. AST and ALT, the biomarkers of liver injury, were also increased significantly (P<0. 05). The expression levels of fibrotic factor tissue inhibitors of metalloproteinases 1 (TIMP-1), monocyte chemoattractant protein 1 (MCP-1) and collagen protein I (Collagen I) were higher than those of control group (P<0. 05). The expressions of fibrosis protein Collagen I and α-SMA were also up-regulated. The collagen fibers of the liver were largely deposited and the liver fibrosis occurred (P<0. 05). The expression of inflammatory factors was higher than the control group, JNK, c-Jun and STAT3 were activated (P<0. 05). In A-D28 group, except AST, matrix metalloproteinases 2 (MMP-2) and Collagen I indicators were slightly decreased, other indicators of cholestasis, liver injury, liver fibrosis and inflammation continued to be up-regulated or stable (P<0. 05). Conclusion: After 14-day treatment with 0. 05% ANIT diet, significant cholestatic liver fibrosis occurred in mice. After 28 days of treatment, cholestasis liver fibrosis kept stable. The JNK inflammatory pathway played a crucial role in the development of liver fibrosis.

Key words: ANIT, cholestatic, liver fibrosis, jnk pathway, mice

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