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Novel mouse model for cholestasis‐induced liver fibrosis resolution by cholecystojejunostomy
Author(s) -
Yoshino Kenji,
Taura Kojiro,
Iwaisako Keiko,
Masano Yuki,
Uemoto Yusuke,
Kimura Yusuke,
Nam Nguyen Hai,
Nishino Hiroto,
Ikeno Yoshinobu,
Okuda Yukihiro,
Nishio Takahiro,
Yamamoto Gen,
Seo Satoru,
Uemoto Shinji
Publication year - 2021
Publication title -
journal of gastroenterology and hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.214
H-Index - 130
eISSN - 1440-1746
pISSN - 0815-9319
DOI - 10.1111/jgh.15406
Subject(s) - cholestasis , medicine , fibrosis , anastomosis , bile duct , pathology , gastroenterology , surgery
Background and Aim Studies on the resolution of liver fibrosis are becoming more important in this era of etiologic eradication. In contrast to the extensive research on the recovery of liver fibrosis induced by hepatotoxic injuries, regression of cholestatic liver fibrosis has been insufficiently examined owing to the limited availability of animal models. Methods We examined our novel recanalization mice model of biliary obstruction, involving anastomosis between the gallbladder and jejunum (G–J anastomosis) by invagination. Transgenic mice expressing green fluorescent protein (GFP) under the collagen 1(α)1 promoter underwent G–J anastomosis 14 days after bile duct ligation (BDL) and were sacrificed 14 days later. Results Transaminase and total bilirubin levels decreased to almost normal values on day 14 after G–J anastomosis. G–J anastomosis resulted in dramatic reversal of liver fibrosis induced by BDL. Activated portal fibroblasts (PFs) double‐positive for GFP and Thy‐1 on immunofluorescence in the liver of BDL‐injured mice became less noticeable following G–J anastomosis. Messenger RNA expression of markers for activated PFs in the liver was downregulated after anastomosis. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) were induced by BDL. After anastomosis, expressions of MMP‐3, 8 as well as hepatocyte growth factor were further upregulated, whereas those of TIMP‐1 and TIMP‐3 were markedly downregulated. Conclusions Our established G–J anastomosis model is associated with fibrosis resolution and reduced PF activation through reopening of bile duct obstruction and will be valuable for studying the recovery process of cholestatic liver fibrosis.