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DOI: 10.1055/s-0031-1295789
Evidence for differential modulation of liver fibrogenesis by selective inhibition of the chemokine receptor CCR1 in a toxic model but not Abcb4-/- mice
Aims: Recently recruitment of peripheral blood monocytes via CCR2 stimulation has been shown to induce liver fibrosis in a toxic mouse model of liver fibrosis. In humans, monocyte recruitment is also influenced by CCR1 signalling. Inhibition of CCR1 signalling by a specific non-peptide inhibitor (BX471) reduces kidney fibrosis after unilateral ureteral obstruction. However, currently it remains unclear whether selective CCR1 inhibition may also influence liver fibrogenesis. We therefore aimed to study the effect of CCR1 inhibition on liver fibrosis in a toxic mouse model and Abcb4-/- mice, which develop biliary fibrosis.
Methods: We induced fibrosis in mice (N=32) by intra-peritoneal injection of 0.7ml/kg CCl4 over 6 weeks. The verum group was treated with subcutaneous injections of 50mg/kg BX471 bid, while controls received vehicle only. Collagen contents in liver were determined by enzymatic hydroxyproline (Hyp) assays, and liver histopathology was assessed by specific stains. In addition, we injected BX471 in 24 Abcb4-/- deficient mice from week 10 to week 16.
Results: Significant differences were neither observed in ALT levels after 6 weeks of treatment between the two groups in the CCL4 treated mice nor in Abcb4-/- mice. Interestingly, hepatic collagen contents were significantly (p=0.03) higher in mice treated with BX471 as compared to controls (302.3±41.3µg Hyp/g vs. 395.4±150.0µg Hyp/g) but histological staging of liver fibrosis did not differ between the two groups. Interestingly, we observed no effects on liver fibrogenesis in the non-toxic model of liver fibrosis.
Conclusions: Our data suggest a protective effect of CCR1 on liver fibrogenesis in CCl4 treated mice but not in the cholestatic Abcb4-/- model of liver fibrosis. Selective stimulation of CCR1 may have beneficial effects during liver injury and represent a potential anti-fibrotic strategy for toxic liver diseases but not for cholestatic liver diseases.