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, 11 (32), 4931-8

Thiazolidinedione Treatment Inhibits Bile Duct Proliferation and Fibrosis in a Rat Model of Chronic Cholestasis

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Thiazolidinedione Treatment Inhibits Bile Duct Proliferation and Fibrosis in a Rat Model of Chronic Cholestasis

Fabio Marra et al. World J Gastroenterol.

Abstract

Aim: To investigate the effects of troglitazone (TGZ), an anti-diabetic drug which activates peroxisome proliferator-activated receptor-gamma (PPAR-gamma), for liver tissue repair, and the development of ductular reaction, following common bile duct ligation (BDL) in rats.

Methods: Rats were supplemented with TGZ (0.2% w/w in the pelleted food) for 1 wk before BDL or sham operation. Animals were killed at 1, 2, or 4 wk after surgery.

Results: The development of liver fibrosis was reduced in rats receiving TGZ, as indicated by significant decreases of procollagen type I gene expression and liver hydroxy-proline levels. Accumulation of alpha-smooth-muscle actin (SMA)-expressing cells surrounding newly formed bile ducts following BDL, as well as total hepatic levels of SMA were partially inhibited by TGZ treatment, indicating the presence of a reduced number and/or activation of hepatic stellate cells (HSC) and myofibroblasts. Development of the ductular reaction was inhibited by TGZ, as indicated by histochemical evaluation and hepatic activity of gamma-glutamyl-transferase (GGT).

Conclusion: Treatment with thiazolidinedione reduces ductular proliferation and fibrosis in a model of chronic cholestasis, and suggests that limiting cholangiocyte proliferation may contribute to the lower development of scarring in this system.

Figures

Figure 1
Figure 1
Effects of oral supplementation with TGZ on liver pathology in control rats (A and B) and bile duct-ligated rats (C-J). Animals received sham operation (A and B) or were subjected to BDL for 2 wk (C-F) or for 4 wk (G-J).
Figure 2
Figure 2
Effects of TGZ on type I procollagen expression in bile duct-ligated rats.
Figure 3
Figure 3
TGZ inhibits collagen accumulation in bile duct-ligated rats in different experimental groups. aP<0.05 vs Sham, cP<0.05 vs BDL.
Figure 4
Figure 4
TGZ reduces accumulation of SMA-positive cells after BDL in different experimental groups. A: Sham; B: TGZ; C: BDL; D: BDL/TGZ.
Figure 5
Figure 5
Effects of TGZ on SMA expression in rats undergoing BDL. aP<0.05 vs Sham, cP<0.05 vs BDL.
Figure 6
Figure 6
Development of ductular reaction is inhibited in bile duct ligated and TGZ-treated rats in different experimental groups. (A: Sham; B: TGZ; C, E and G: BDL; D, F, and H: BDL/TGZ) for different periods of time (C and D: 1 wk; E and F: 2 wk; A, B, G, and H: 4 wk).
Figure 7
Figure 7
Effects of TGZ on liver GGT activity in bile duct-ligated rats. aP<0.05 vs Sham, cP<0.05 vs BDL.

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