Z Gastroenterol 2011; 49 - P454
DOI: 10.1055/s-0031-1285725

Comparison of fibrogenesis in liver and heart: systemic and organ specific genetic determinants of experimental fibrosis

R Hall 1, P Müller 2, U Laufs 2, M Böhm 2, F Lammert 1, A Kazakov 2
  • 1Saarland University Hospital, Department of Medicine II, Homburg, Germany
  • 2Saarland University Hospital, Department of Medicine III, Homburg, Germany

Background: Various chronic human diseases result in organ fibrosis, i.e. excessive accumulation of extracellular matrix. Fibrosis is a multifactorial trait determined by both genetic and exogenous factors such as xenobiotics. Our aim is to compare fibrogenesis in liver and heart in an experimental model to dissect common and organ specific mechanisms of fibrosis. Further, we availed of a systems genetics approach to identify genetic modifiers of hepatic and cardiac fibrosis.

Methods: We induced fibrosis in the inbred mouse strains C57BL/6J (B) and DBA/2J (D, n=6 per group, males) by administration of the NO synthase inhibitor NG-nitro-L-arginine-methylester (L-NAME) in drinking water (5 weeks, ad libitum), or CCl4 i.p. (0.7mg/kg, 12 injections for 6 weeks). Collagen accumulation was assessed by Sirius red staining of liver and heart sections. The proliferation marker Ki-67 and fibroblast markers such as intracellular fibronectin were determined by immunohistochemistry. Thirty BXD recombinant inbred lines, generated from the parental strains B and D, served as genetically heterogeneous 'reference population’ for the identification of genetic risk factors.

Results: Whereas L-NAME treatment did induce cardiac but not hepatic fibrosis, CCl4 caused fibrosis both in liver and heart, a hitherto unknown phenomenon. We observed marked strain differences for both hepatic and cardiac fibrosis progression between C57BL/6 and DBA/2 inbred mice. Fibroblast proliferation and collagen accumulation was more pronounced in DBA/2 mice (collagen area liver B=2.5%, D=7.2%, P=0.0002; heart: B=0.6%, D=1.2%, P=0.006). Accordingly, CCl4 challenged BXD lines also differed markedly in fibrosis susceptibility. Of note, collagen levels in livers and hearts from BXD mice were significantly correlated (R=0.39, P<0.002), suggesting common genetic determinants of fibrogenesis.

Conclusions: CCl4 induces fibrosis in both liver and heart. In the experimental BXD population, hepatic and cardiac fibrosis susceptibility are correlated significantly. Hence, CCl4 induced fibrosis in BXD mouse lines provides a basic experimental framework to identify common and organ specific modifiers of fibrogenesis by genome-wide linkage studies.