Effect of all-trans retinoic acid on liver fibrosis induced by common bile duct ligation in rats.
The aim of this study was to investigate the effect and possible mechanism of all-trans retinoic acid (ATRA) on liver fibrosis induced by common bile duct ligation (CBDL) in rats. Fifty-three female Wistar rats were randomly divided into 5 groups: sham operation group (group J, 5 animals) and groups A, B, C and D (12 animals in each group). The rats in groups A, B, C and D were subjected to CBDL to induce liver fibrosis, while those in group J to sham operation. From the 3rd week the rats in groups B, C and D respectively received daily administration of ATRA via gastric tube at three different doses [0.1, 1.5 and 7.5 mg/kg body weight (BW)]. Animals were sacrificed at 6th week. Rats' liver tissues were observed for pathologic changes under a light microscope. The protein levels of type I collagen (COL I), matrix metalloproteinase-2 (MMP2), MMP13 and tissue inhibitors of metalloproteinase-1 (TIMP-1) in liver tissues were determined by immunohistochemical techniques. The expression levels of TGF-beta1 and CTGF mRNA in liver tissues were detected by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR). The results showed that loss of normal hepatic architecture and formation of obvious fibrosis were observed in group A, while ATRA treatment for 4 weeks notably alleviated the pathological changes of hepatocytes. The expression of COL I and TIMP-1 proteins in group A was increased, while decreased in ATRA-treated CBDL groups (P<0.05). ATRA (1.5 and 7.5 mg/kg BW) reduced the expression levels of COL I protein more greatly than that of 0.1 mg/kg BW (P<0.05). ATRA treatment increased the protein levels of MMP2 and MMP13. The expression levels of TGF-beta1 and CTGF mRNA in group A were increased. In comparison with group A, the mRNA levels of TGF-beta1 and CTGF in ATRA-treated CBDL groups were significantly decreased (P<0.05). It was concluded that ATRA could inhibit CBDL-induced liver fibrosis in rats by suppressing the expression of TGF-beta1 and CTGF so as to diminish the inhibition of TIMP-1 on MMP2 and MMP13 and increase the activity of MMP2 and MMP13.
Wang
Hui
H
Department of Gastroenterology, Pu'ai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. lio20123wh@163.com
Dan
Zili
Z
Jiang
Haiyan
H
D000818:Animals; D003135:Common Bile Duct / Q000601:surgery; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism*; D005260:Female; D008026:Ligation; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000209:etiology; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology / Q000627:therapeutic use*
C526316:CCN2 protein, rat; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; D014212:Tretinoin; D053509:Matrix Metalloproteinase 13; C507083:Mmp13 protein, rat; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat