Z Gastroenterol 2011; 49 - P458
DOI: 10.1055/s-0031-1285729

Effect of complement 5a receptor (C5R1) deficiency on liver fibrosis in mice

K Hochrath 1, SN Weber 1, S Hillebrandt 2, U Pieper-Fürst 2, V Schmitz 2, S Huss 3, HP Fischer 3
  • 1Department of Medicine II, Saarland University Hospital, Homburg, Germany
  • 2Department of Medicine I, University Hospital Bonn, Bonn, Germany
  • 3Institute of Pathology, University Hospital Cologne, Cologne, Germany

Background: Previously we refined a quantitative trait locus that confers susceptibility to hepatic fibrosis in inbred mice and showed, that the gene encoding complement factor C5 underlies this fibrogenic locus in mice (Nat Genet 2005). C5R1 is a G protein-coupled receptor that specifically binds C5a, the potent proinflammatory fragment of C5. Our aim now was to dissect whether the profibrogenic effects of C5 are mediated via C5R1.

Methods: We analysed C5R1 knockout mice (C5R1-/- ) and C57BL/6J wild-type controls (N=10 per genotype) after fibrosis induction by CCl4 (12 x i.p., 0.7mg/kg). Liver enzyme activities (ALT, AP) were measured in plasma by standard assays. Hepatic collagen contents were determined by measurement of hydroxyproline. Histological stages of fibrosis (F-score) and relative collagen areas were assessed in a central pathology platform by a pathologist blinded to the study protocol, using Delphi-based image morphometry software.

Results: Liver fibrosis progresses from perivenular fibrosis to the maximum score F2 after toxic challenge of C5R1-/- and control mice. Fibrosis stages are markedly lower in C5R1-/- mice (1.27±0.27) as compared to controls (1.89±0.11; p=0.07). This difference is reflected by significantly lower relative collagen areas in male mice (1.0±0.4 vs. 2.2±0.2%; p=0.02), but hydroxyproline contents did not differ. Whereas 89% of C5R1+/+ mice develop circumferential venular fibrosis and incomplete fibrotic septae, only 55% of C5R1-/- mice display this phenotype corresponding to stage F2. C5R1-/- mice show higher ALT (248±40 vs. 100±5 U/L; p=0.004) but decreased AP activities (249±40 vs. 80±7 U/L; p=0.002) compared to wild-type animals. Inflammatory infiltrates but no necrosis were present in livers from both strains.

Conclusions: C5R1-/- mice display a moderate reduction of hepatic fibrosis, which is in line with the consistent but small antifibrotic effects we observed previously in C5-/- mice and mice treated with small peptidic inhibitors of C5R1. These findings indicate that the profibrogenic effects of C5 are mediated, at least in part, via C5a and C5R1. However, other C5-dependent mechanisms potentially modulating hepatic fibrosis such as the second C5 receptor, C5L2, are to be investigated in corresponding models.