Reversibility of liver fibrosis is dependent on etiological factors, process duration and type of fibrosis. Thioacetamide (TAA)-induced fibrosis is hardly reversible spontaneously, while pharmacological reversion can achieve. Thus, TAA-reversal serves as a good model to test potential antifibrotics. Here we studied whether pentoxyphylline (PTX), well known to slow down progression of fibrosis, and statins, simvastatin (SIM) and fluvastatin (FLU), which are promising antifibrotic drugs, are able to reverse advanced TAA-fibrosis in rat. Male Wistar rats (230-240g) received TAA (200 mg/kg, i.p.) twice a week for 12 weeks to establish advanced liver fibrosis/cirrhosis. After TAA was stopped, 6 groups of fibrotic rats were administered with PTX (10 and 20 mg/kg), SIM (5 and 10 mg/kg), FLU (10 mg/kg) or vehicle (placebo group) by daily oral gavage for the subsequent 8 weeks. The degree of fibrosis reversal was assessed by a morphometric evaluation of liver slides stained with Azan-Mallory, hydroxyproline (Hyp) determination. mRNA expression of procollagen 1α , collagenase MMP-13 and its inhibitor TIMP-1 were determined in total liver RNA by QRT-PCR using the TaqMan technique. Serum TNFα was monitored using ELISA. TAA treatment induced micronodular liver fibrosis with pronounced septa formation. The square of connective tissue stained by Azan-Mallory increased in these rats nearly 7-fold, relative liver Hyp content – more than 2.5-fold and serum TNFα content – more than 2-fold. The TAA withdrawal led to improvement in histology with relative decrease of liver connective tissue area, whereas Hyp content in the liver and serum TNFα concentration did not change in rats deprived of TAA. Both doses of PTX decreased the accumulation of connective tissue in the liver, whereas decrease in liver Hyp and serum TNFα levels was significant only in rats treated with high dose of PTX (20 mg/kg). Both doses of PTX similarly up-regulated mRNA expression of interstitial collagenase MMP-13, while procollagen 1α and TIMP-1 was not changed. Only treatment with high dose SIM (10 mg/kg) significantly decreased the square of liver connective tissue stained by Azan-Mallory compared to the vehicle-treated group, whereas no significant reversion was observe in rats treated with low dose SIM (5 mg/kg) and FLU (10mg/kg). The tested statins did not changed total and relative HYP content in the liver. Interestingly, both doses of SIM increased hepatic levels of interstitial collagenase (MMP-13) mRNA expression, while FLU did not. PTX (20 mg/kg) promotes partial reversal of TAA-induced liver fibrosis. Statins with similar lipid-lowering properties may have a different antifibrotic activity. SIM, but not FLU demonstrated a moderate antifibrotic effect in a model of TAA-induced liver fibrosis reversal. Our study suggests that the PTX and SIM may consider as antifibrotics in patients with advanced liver fibrosis.

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