23 Nadolol+Isosorbide-5-mononitrate (NAD+ISMN) vs NAD+ISMN + endoscopic band ligation in the prevention of rebleeding in patients with cirrhosis. Preliminary results of a multicenter RCT

Abstract

Background: BAC transgenesis of the gene for complement component 5 (C5) in C5 deficient FVB/N mice leads to increased susceptibility to liver fibrosis and confirms the identity of C5 as the fibrogenic locus mapped on proximal mouse chromosome 2 (Hillebrandt S. et al. Nat Genet 2005, 37:835 43). Recently, it has been postulated that the fibrosis phenotype in different organs is tightly regulated by the quality of the T-helper (Th)cell response (Wynn TA. Nat Rev Immunol 2004, 4:583 594). The aim of the present study was to characterise the intrahepatic immune regulation related to fibrogenesis in C5 BAC transgenic mice during chronic liver injury. Methods: Liver fibrosis in C5 BAC transgenic mice and in the FVB/N (C5 / ) background was induced by CC14 treatment for 6 weeks. Hepatic collagen concentrations and histological stages of fibrosis were determined for quantification of liver fibrosis. The hepatic mRNA expression of type 1 cytokines IL-12p35, IL-23p19, IL-27p28 and the expression levels of the regulatory cytoldnes IL-6 and TNF-c~ were measured in both strains by quantitative RT-PCR (Taqman). Results: After challenge with CC14, C5 BAC transgenic mice had significantly (P < 0.01) higher hepatic fibrosis stages (2.00 and collagen concentrations (352 12 mg/g) compared to non transgenic FVB/NJ mice (1.46 and 227 respectively). Expression of the regulatory cytoldnes IL-12p35, IL-23p19, IL-27p28 was significantly lower in C5 sufficient BAC transgenic mice compared to the C5 deficient FVB/NJ background (all P <0.05). This reduced expression of type 1 cytokines was correlated to severity of liver fibrosis. In contrast, the expression of IL-6 and TNF-c~ did not differ significantly between the mouse strains indicating that immune activation was not generally suppressed by C5 BAC transgenesis. Conclusions: The reduced expression of regulatory type 1 cytokines of the IL-12 family in fibrosis prone C5 sufficient mice is in line with the paradigm that polarized T cells regulate organ fibrosis and that a shift from Thl to Th2 cytokine subsets promotes fibrogenesis.