Evidence-Based Medicine
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World J Gastroenterol. Jun 21, 2014; 20(23): 7452-7460
Published online Jun 21, 2014. doi: 10.3748/wjg.v20.i23.7452
Inhibitory effects of rapamycin on the different stages of hepatic fibrosis
Yun Jeung Kim, Eaum Seok Lee, Seok Hyun Kim, Heon Young Lee, Seung Moo Noh, Dae Young Kang, Byung Seok Lee
Yun Jeung Kim, Eaum Seok Lee, Seok Hyun Kim, Heon Young Lee, Byung Seok Lee, Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon 301-721, South Korea
Seung Moo Noh, Department of Surgery, Chungnam National University School of Medicine, Daejeon 301-721, South Korea
Dae Young Kang, Department of Pathology, Chungnam National University School of Medicine, Daejeon 301-721, South Korea
Author contributions: Kim YJ wrote the manuscript; Lee ES, Kim SH advised intellectual content; Lee HY, Noh SM, Kang DY and Lee BS critically reviewed the work.
Supported by Grants from YUHAN Cooperation
Correspondence to: Byung Seok Lee, Associate Professor, Department of Internal Medicine, Chungnam National University School of Medicine, 640 Daesa-Dong, Jung-Gu, Daejeon 301-721, South Korea. gie001@cnuh.co.kr
Telephone: +82-42-2807163 Fax: +82-42-2575753
Received: October 10, 2013
Revised: February 24, 2014
Accepted: April 2, 2014
Published online: June 21, 2014
Processing time: 253 Days and 18.9 Hours
Abstract

AIM: To investigate and compare the inhibitory effects of rapamycin in the different stages of liver fibrosis.

METHODS: We performed bile duct ligation (BDL) in male Wistar rats (n = 24). The experimental rats were classified into four groups: the BDL+/Rapa- group (un-treated control, n = 4), the BDL+/Rapa+ group (treated 14 d after BDL, n = 8), the BDL+/Rapa++ group (treated on the day after BDL, n = 8), and the BDL-/Rapa- group (un-treated, sham -operated control, n = 4). The BDL+/Rapa+ and BDL+/Rapa++ groups were administered rapamycin (2 mg/kg) for 28 d. The liver tissues were tested by immunohistochemical staining for α-smooth muscle actin (α-SMA) and cytokeratin.

RESULTS: The liver mRNA levels of transforming growth factor (TGF)-β1 and platelet-derived growth factor (PDGF) were measured using the polymerase chain reaction. The protein levels of liver p70s6K and p-p70s6k were determined using Western blotting. α-SMA expression was lowest in the BDL+/Rapa++group. TGF-β1 and PDGF expression levels in the rapamycin-treated group were lower than those in the un-treated group and higher than those in the control groups (TGF-β1: 0.23 ± 0.00 vs 0.34 ± 0.01, 0.23 ± 0.0 vs 0.09 ± 0.00, P < 0.0001; PDGF: 0.21 ± 0.00 vs 0.34 ± 0.01, 0.21 ± 0.0 vs 0.09 ± 0.00, P < 0.0001). The p70s6k and p-p70s6k levels decreased in the treated groups and were lowest in the BDL+/Rapa++group (p70s6k: 1.05 ± 0.17 vs 1.30 ± 0.56, 0.40 ± 0.01 vs 1.30 ± 0.56, P < 0.0001; p-p70s6k: 1.40 ± 0.5 vs 1.67 ± 0.12, 0.70 ± 0.01 vs 1.67 ± 0.12, P < 0.0001).

CONCLUSION: The results of our study indicate that rapamycin has inhibitory effects on liver fibrosis, and the treatment is most effective in the early stages of fibrosis.

Keywords: Liver cirrhosis; Sirolimus; Transforming growth factor beta; Platelet-derived growth factor; Ribosomal protein S6 kinases

Core tip: Liver cirrhosis is a serious disease causing significant mortality, but a curative treatment has not yet been developed. Therefore, there is great interest within the field of drug development in developing agents capable of inhibiting the progression of hepatic fibrosis. Rapamycin is an immunosuppressive agent that is also expected to attenuate the progression of liver fibrosis. We therefore aimed to investigate the inhibitory effects of rapamycin in the early and late stages of fibrosis, with the goal of contributing to the development of novel fibrosis treatments.