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Pentoxifylline Downregulates Profibrogenic Cytokines and Procollagen I Expression in Rat Secondary Biliary Fibrosis

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Pentoxifylline Downregulates Profibrogenic Cytokines and Procollagen I Expression in Rat Secondary Biliary Fibrosis

C Raetsch et al. Gut.

Abstract

Background: The trisubstituted methylxanthine derivative pentoxifylline inhibits hepatic stellate cell proliferation and collagen synthesis in vitro. The antifibrotic effect of pentoxifylline in a suitable in vivo model of chronic liver fibrogenesis remains to be tested.

Methods: Groups of adult rats (n=20-23) received oral pentoxifylline at a dose of 8 mg/kg/day from week 1 to week 6, and 16 mg/kg/day from week 1 to week 6 or week 4 to week 6 after complete bile duct occlusion. Animals who underwent sham operation that received 16 mg/kg/day pentoxifylline and untreated rats with bile duct occlusion alone served as controls. After six weeks, animals were sacrificed and parameters of fibrogenesis determined.

Results: Bile duct occlusion caused portal cirrhosis with a 10-fold increased hepatic collagen content in the absence of inflammation or necrosis. This was accompanied by an 11-fold elevated serum aminoterminal procollagen III peptide (PIIINP). The drug induced a dramatic eightfold downregulation of procollagen I mRNA, and suppression of the fibrogenic factors transforming growth factor beta1 and connective tissue growth factor by 60-70%. However, profibrogenic tissue inhibitor of metalloproteinase 1 (TIMP-1) mRNA was increased twofold, resulting in only a moderate decrease in liver collagen, fibrosis score, and PIIINP.

Conclusions: We conclude that targeting pentoxifylline to the fibrogenic cells, thereby avoiding upregulation of TIMP-1, could become a potent antifibrogenic tool in chronic liver disease.

Figures

Figure 1
Figure 1
Study design. BDO, bile duct occlusion; BDO/PTX low, BDO/PTX high, BDO/PTX late, rats with BDO treated with pentoxifylline (PTX) at 8 mg/kg/day from week 1 to 6, at 16 mg/kg/day from week 1 to week 6, or with PTX at 16 mg/kg/day from week 4 to week 6, respectively. Rats who underwent sham operation and daily treatment with PTX at 16 mg/kg/day from week 1 to week 6 (sham PTX) served as controls.
Figure 2
Figure 2
Effect of pentoxifylline (PTX) on parameters of liver fibrosis of normal and bile duct occluded (BDO) rats. (A) Total liver collagen expressed as total hydroxyproline. (B) Relative content of collagen, as hydroxyproline per gram of wet liver weight. (C) Modified histo score. (D) Serum aminoterminal procollagen type III peptide (PIIINP). Sham 16 w1–6, sham operation and PTX at 16 mg/kg/day for six weeks; BDO w1–6, bile duct occlusion for six weeks; BDO 16 w1–6, bile duct occlusion and PTX at 16 mg/kg/day for six weeks; BDO 8 w1–6, bile duct occlusion and PTX at 8 mg/kg/day for six weeks; BDO 16 w4–6, bile duct occlusion for six weeks and PTX at 16 mg/kg/day from week 4 to week 6. Significant differences were calculated using the Mann-Whitney rank sum test, and data are presented as box plots, with medians and boxes representing the 25th and 75th percentiles. *p<0.05, **p<0.01 versus the untreated group (BDO alone).
Figure 3
Figure 3
Modulation of hepatic procollagen α1(I) (Pro α1 (I)), tissue inhibitor of metalloproteinase 1 (TIMP-1), transforming growth factor β (TGF-β1), and connective tissue growth factor (CTGF) mRNA expression by pentoxifylline (PTX) treatment. RNA from livers of five rats in each experimental group was extracted and analysed for pro α1 (I), TIMP1, TGF-β1, CTGF and GAPDH mRNA content by multiprobe RNAse protection assay, followed by densitometry of protected bands. (A) Representative autoradiographs. (B) Results of the densitometrical analysis normalised to GAPDH. Sham/PTX, sham operation and PTX (high) for six weeks; BDO, bile duct occlusion alone for six weeks; BDO/PTX, bile duct occlusion and PTX (high) for six weeks. Data are mean (SD). *p<0.05, **p< 0.001 versus untreated group (BDO alone).
Figure 4
Figure 4
Correlations between total liver collagen, aminoterminal propeptide of procollagen type III (PIIINP), and the histo score. Correlations were calculated using the Spearman rank order correlation, as described in the methods.

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