Preventive effects of ME3738 on hepatic fibrosis induced by bile duct ligation in rats.
OBJECTIVE
The aim of this study was to examine the preventive effects of ME3738 on hepatic fibrosis induced by bile duct ligation (BDL) in rats.


METHODS
ME3738 (20 mg/day) was administered orally for 21 days immediately after BDL. Fibrosis was assessed by measuring hepatic hydroxyproline (Hyp) content. Activated hepatic stellate cells (HSCs) were assessed by alpha-smooth muscle actin (alpha-SMA) immunostaining. Hepatic thiobarbituric acid-reactive substance (TBARS), 4-hydroxy-2-nonenal (4-HNE) and 8-hydroxy-2-deoxyguanosine (8-OHdG) immunostaining were used to analyze oxidative stress. The gene expressions of collagen-I, transforming growth factor-beta1 (TGF-beta1), tissue inhibitor of metalloproteinases-1 (TIMP-1), interleukin-6 (IL-6) and heme oxygenase-1 (HO-1) in the liver were examined by real-time reverse transcriptase polymerase chain reaction (RT-PCR).


RESULTS
Hepatic Hyp content and the area of hepatic fibrosis in BDL rats treated with ME3738 were reduced by 24% and 39% compared with non-treated BDL rats (hepatic Hyp, 9.40 +/- 2.85 vs. 12.39 +/- 3.91 mg/liver; P = 0.036; area of hepatic fibrosis, 13.1 +/- 3.8 vs. 21.5 +/- 10.9; P = 0.045). Furthermore, alpha-SMA-positive cells were significantly reduced by 40% (22.3 +/- 14.8 vs. 37.6 +/- 14.2; P = 0.011), collagen-I mRNA by 83% (6.5 +/- 2.2 vs. 38.3 +/- 9.1; P = 0.002), HO-1 mRNA by 58% (4.13 +/- 1.22 vs. 9.73 +/- 1.80; P = 0.018) and hepatic HO-1 content by 26% (2.13 +/- 0.80 vs. 2.87 +/- 0.19; P = 0.01) following ME3738 treatment. The hepatic expression of TBARS, 4-HNE, 8-OHdG and mRNA levels of TGF-beta1, TIMP-1 and IL-6 in the liver were unchanged by ME3738 treatment.


CONCLUSIONS
Oral ME3738 administration may prevent the progression of hepatic fibrosis in BDL rats through suppression of the activation and collagen synthesis of HSC and, in part, oxidative stress. ME3738 has potential as a therapeutic drug for cholestatic liver fibrosis.
Maeda
Kazunori
K
Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, Yonago, Japan.
Koda
Masahiko
M
Matono
Tomomitsu
T
Sugihara
Takaaki
T
Yamamoto
Satoru
S
Ueki
Masaru
M
Murawaki
Yoshikazu
Y
Yamashita
Nobuyuki
N
Nishiyama
Shoji
S