Adenosine 2B receptor antagonism alleviates liver fibrosis progression and induces mild fibrosis regression

YO Kim; M Stoll; B Hebich; S Robson; D Schuppan

doi:10.1055/s-0032-1323966

Zeitschrift für Gastroenterologie, Table of Contents

Adenosine 2B receptor antagonism alleviates liver fibrosis progression and induces mild fibrosis regression

YO Kim ¹, M Stoll ¹, B Hebich ¹, S Robson ², D Schuppan ¹^,²

¹Medicine I./Univ. Medical Center of the Johannes Gutenberg University Mainz, Molecular and Translational Medicine, Mainz, Germany
²Div. of Gastroenterology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, United States

Abstract

Introduction: The anti-inflammatory metabolite adenosine addresses 4 receptors, which are differenzially expressed on cells. Recent studies indicate a role for specific adenosine receptors in liver diseases, including NASH, hepatic inflammation and fibrosis. Since it is unclear how far the A2B receptor modulates fibrogenesis, we investigated the selective A2B receptor antagonist MRS1754 in liver fibrosis progression and regression models.

Methods: Mdr2(-/-) mice were injected intraperitoneally daily from week 6–10 of age either with vehicle (n=10), low dose (0,5mg/kg, n=10), or high dose MRS1754 (2mg/kg, n=10). A second cohort of mice was treated with weight adjusted oral CCl₄for 2 weeks to induce rapidly progressive fibrosis, with MRS1754 (0,5mg/kg or 2mg/kg) during the second week, or vehicle only (n=6 each). In the fibrosis regression cohort after 8 weeks of fibrosis induction with CCl₄, mice were injected daily with the two doses of MRS 1754 for 4 weeks (each n=10). Inflammation and fibrosis were quantified by histology, collagen determination, Sirius red morphometry, serum biochemistries and qPCR for fibrosis related transcripts.

Results: Mice treated with high dose MRS1754 deposited 32%- and 37% less relative (per g of liver) and total hepatic collagen when compared to vehicle treated controls. Transcript levels of TGFβ1, αSMA, TIMP-1, MMP-2 and MMP-9 remained unchanged, whereas MMP-13 gene expression was elevated in both treatment groups. In the CCl4 progression cohort low dose treatment had no effect on collagen deposition compared to the vehicle-treated group, while high dose treatment lowered hepatic collagen by 18%, with a significantly reduced fibrotic area after Sirius Red staining. Mice in the fibrosis regression cohort showed significantly less hepatic collagen in both MRS1754-treated groups compared to vehicle. Except for elevated MMP-13 in Mdr2(-/-) and MMP-2 in the CCl4 regression cohort transcript levels were not significantly altered.

Conclusions: In the models of fibrosis progression and regression, specific A2B receptor antagonism alleviated liver fibrosis. However, the exact mechanisms remain to be explored, since, except for some MMP-activation, major classical pathways of fibrogenesis or fibrolysis do not appear to be affected.