Journal article

Publication year: 2012

Pages: 445-450

Journal: Biochemical and Biophysical Research Communications

Volume number: 418

Issue number: 3

ISSN: 0006-291X

eISSN: 1090-2104

Open access status: Green

DOI Link: https://doi.org/10.1016/j.bbrc.2012.01.036

Publisher: Elsevier

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 HE, 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-alpha 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. (C) 2012 Elsevier Inc. All rights reserved.

Harvard Citation style: Schmitt, J., Roderfeld, M., Sabrane, K., Zhang, P., Tian, Y., Mertens, J., et al. (2012) Complement factor C5 deficiency significantly delays the progression of biliary fibrosis in bile duct-ligated mice, Biochemical and Biophysical Research Communications, 418(3), pp. 445-450. https://doi.org/10.1016/j.bbrc.2012.01.036

APA Citation style: Schmitt, J., Roderfeld, M., Sabrane, K., Zhang, P., Tian, Y., Mertens, J., Frei, P., Stieger, B., Weber, A., Muellhaupt, B., Roeb, E., & Geier, A. (2012). Complement factor C5 deficiency significantly delays the progression of biliary fibrosis in bile duct-ligated mice. Biochemical and Biophysical Research Communications. 418(3), 445-450. https://doi.org/10.1016/j.bbrc.2012.01.036