title: Complement factor C5 deficiency significantly delays the progression of biliary fibrosis in bile duct-ligated mice.
abstract: Fibrogenesis represents the universal response of the liver to chronic liver injury. Complement factor C5 has been linked to fibrosis in murine toxic liver injury and human chronic hepatitis C. C5 may also play a central role in chronic cholestatic disorders, since the BA receptor FXR has been characterized as an activator of the C3 gene. We aimed to investigate, whether C5 deficiency is able to prevent biliary fibrosis in the mouse bile-duct-ligation model. BDL for 1-4 weeks was performed in either Hc(0)/Hc(0) mice (deficient for C5) or WT controls. BA levels were measured by RIA. Histological examination included H&E, sirius-red and immunohistochemistry. mRNA expression was quantified by RT-PCR. Protein expression levels were determined by Western blotting or ELISA. Enzymatic MMP-activity was analysed by zymography. One week BDL leads to fibrosis in WT (F2.0 ± 0), while it is almost absent in Hc(0)/Hc(0) mice (F0.5 ± 0.5). No differences in fibrosis can be detected at week-4. Together with delayed fibrogenesis at week-1, fibrotic markers are decreased in Hc(0)/Hc(0) mice. Expression of the inflammatory cytokine TNF-α is decreased in Hc(0)/Hc(0) mice. In parallel C5 deficiency leads to an attenuated peribiliary infiltration of CD45(+) cells in fibrotic areas together with decreased MMP-9 expression and gelatinase activity. The present study proves a functional role of C5 during biliary fibrogenesis. C5 deficiency leads to attenuated inflammation and normalized MMP-9 activity concomitantly with a significant reduction of fibrosis. C5 appears to be an attractive target for future therapeutic intervention in chronic cholestatic liver disease.
authors.affiliation: Division for Gastroenterology and Hepatology, University Hospital Zurich, Switzerland.
authors.forename: Johannes
authors.initials: J
authors.lastname: Schmitt
authors.forename: Martin
authors.initials: M
authors.lastname: Roderfeld
authors.forename: Karim
authors.initials: K
authors.lastname: Sabrane
authors.forename: Pan
authors.initials: P
authors.lastname: Zhang
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Tian
authors.forename: Joachim C
authors.initials: JC
authors.lastname: Mertens
authors.forename: Pascal
authors.initials: P
authors.lastname: Frei
authors.forename: Bruno
authors.initials: B
authors.lastname: Stieger
authors.forename: Achim
authors.initials: A
authors.lastname: Weber
authors.forename: Beat
authors.initials: B
authors.lastname: Müllhaupt
authors.forename: Elke
authors.initials: E
authors.lastname: Roeb
authors.forename: Andreas
authors.initials: A
authors.lastname: Geier
mesh_terms: D000818:Animals; D001652:Bile Ducts / Q000473:pathology*; D015415:Biomarkers; D003176:Complement C3 / Q000096:biosynthesis; D003182:Complement C5 / Q000172:deficiency*; D018450:Disease Progression; D007962:Leukocytes / Q000276:immunology; D008026:Ligation; D008105:Liver Cirrhosis, Biliary / Q000276:immunology* / Q000473:pathology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains
chemical_list: D015415:Biomarkers; D003176:Complement C3; D003182:Complement C5; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse