A Contradictory Role of A1 Adenosine Receptor in Carbon Tetrachloride- and Bile Duct Ligation-Induced Liver Fibrosis in Mice
A Contradictory Role of A1 Adenosine Receptor in Carbon Tetrachloride- and Bile Duct Ligation-Induced Liver Fibrosis in Mice
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A1 腺苷受体在四氯化碳和胆管结扎诱导的小鼠肝纤维化中的矛盾作用
DOI：
10.1124/jpet.109.162727
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发表时间：
2010
影响因子：
3.5
通讯作者：
Jianfa Zhang
中科院分区：
文献类型：
--
作者：
Ping Yang;Zheyi Han;Peng Chen;Lin Zhu;Shiming Wang;Z. Hua;Jianfa Zhang
缺乏 A1 腺苷受体 (A1AR) 的小鼠被认为可以避免患上脂肪肝；然而，A1AR 对肝纤维化的贡献尚未被探索。在此我们发现，慢性四氯化碳（CCl4）诱导的纤维化肝中A1AR的表达减少，而胆管结扎（BDL）诱导的纤维化肝中A1AR的表达增加。因此，我们使用 A1AR 敲除小鼠在 CCl4 和 BDL 动物模型中检查了 A1AR 是否会导致肝纤维化。与野生型（WT）小鼠相比，A1AR（−/−）小鼠因慢性CCl4暴露而导致的肝纤维化减弱，胶原沉积显着减少，肝星状细胞活化减少，而胆管结扎的A1AR（−/−）小鼠则表现出肝纤维化显着增加。单次注射 CCl4 后，A1AR(−/−) 小鼠的肝细胞损伤减少，肝脏中 CYP2E1 和 UCP2 基因表达下调，导致肝脏对 CCl4 的敏感性受损。然而，BDL 导致 A1AR(−/−) 小鼠肝脏严重胆汁梗塞，与 WT 小鼠相比，胆汁酸水平显着升高。 CCl4 和 BDL 导致 A1AR(−/−) 小鼠中纤维形成相关基因的不同表达模式。这些结果表明A1AR以复杂的机制参与肝纤维化的发病机制，靶向腺苷及其受体预防肝纤维化的作用应谨慎评估。
Mice lacking A1 adenosine receptors (A1AR) were thought to be protected from developing fatty liver; however, the contribution of A1AR to hepatic fibrosis has not been explored. Here we found that the expression of A1AR was decreased in fibrotic liver induced by chronic carbon tetrachloride (CCl4) but increased in that induced by bile duct ligation (BDL). Therefore, we examined whether A1AR contributes to hepatic fibrosis in CCl4 and BDL animal models using A1AR knockout mice. Compared with wild-type (WT) mice, hepatic fibrosis resulting from chronic CCl4 exposure was attenuated in A1AR(−/−) mice with markedly decreased collagen deposition and reduced hepatic stellate cell activation, whereas bile duct-ligated A1AR(−/−) mice displayed a significant increase in hepatic fibrosis. Hepatocyte damage was reduced in A1AR(−/−) mice after a single injection of CCl4, with down-regulation of CYP2E1 and UCP2 gene expression in livers, which resulted in impaired liver sensitivity to CCl4. However, BDL caused severe bile infarcts in livers of A1AR(−/−) mice, with significantly elevated levels of bile acid compared with those in WT mice. CCl4 and BDL resulted in different expression patterns of genes involved in fibrogenesis in A1AR(−/−) mice. These results indicate that A1AR participates in the pathogenesis of hepatic fibrosis with a complex mechanism, and the effect of targeting adenosine and its receptors in the prevention of hepatic fibrosis should be cautiously evaluated.
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影响因子：
29.4
作者：
Miyoshi, H;Rust, C;Gores, GJ
通讯作者：
Gores, GJ
DOI：
--
发表时间：
2018
期刊：
--
影响因子：
--
作者：
Zhongsheng Peng;P. Borea;T. Wilder;H. Yee;L. Chiriboga;M. Blackburn;G. Azzena;G. Resta;B. Cronstein
通讯作者：
Zhongsheng Peng;P. Borea;T. Wilder;H. Yee;L. Chiriboga;M. Blackburn;G. Azzena;G. Resta;B. Cronstein
DOI：
10.1152/ajpgi.00208.2006
发表时间：
2007-01-01
影响因子：
4.5
作者：
Hashmi, Ardeshir Z.;Hakim, Wyel;Mehal, Wajahat Z.
通讯作者：
Mehal, Wajahat Z.
影响因子：
5
作者：
Guo, Y;Bolli, R;Auchampach, JA
通讯作者：
Auchampach, JA