Selective inhibition of the chemokine receptor CCR1 by the non-peptide antagonist BX471 provides evidence for anti-fibrotic effects of CCR1 in liver

Induction: Progression and resolution of liver fibrosis are influenced by multiple chemokines. Recently, recruitment of peripheral blood monocytes via CCR2 stimulation has been shown to induce liver fibrosis in a toxic mouse model of liver fibrosis (Karlmark et al. Hepatology 2008;48:436A). In humans, monocyte recruitment is also influenced by CCR1 signalling (Heydtman & Adams. Hepatology 2009;49:676–88). Inhibition of CCR1 signalling by a specific non-peptide inhibitor (BX471) reduces kidney fibrosis after unilateral ureteral obstruction by suppression of leukocyte recruitment. However, currently it remains unclear whether selective CCR1 inhibition may also have an influence on liver fibrogenesis. We therefore aimed to study the effect of CCR1 inhibition on liver fibrosis in a toxic mouse model.

Methods: We induced fibrosis in susceptible BALB/c 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.

Results: BX471 injections were tolerated moderately well by all mice, and all mice developed portoseptal liver fibrosis; two mice of the verum group died. No significant differences were observed in ALT levels after 6 weeks of treatment between the two groups. Interestingly, hepatic collagen contents were significantly higher in mice treated with BX471 compared to controls (302.3±41.3mg Hyp/g vs. 395.4±150.0mg Hyp/g; p=0.03). Although histological staging of liver fibrosis did not differ between the two groups, relative liver weights were significantly lower in BX471 treated mice as compared to controls (8.7% vs. 9.6%; p=0.026).

Conclusions: Our data suggests a protective effect of CCR1 on liver fibrogenesis in CCl₄ treated mice. However, whether this holds true for other non-toxic liver fibrosis models needs to be evaluated in further studies. Selective stimulation of CCR1 may have beneficial effects during liver injury and represent a potential anti-fibrotic strategy.