Darbepoetin-α verringert die Nekroinflammation und mildert die cholestatische Fibrose in Mäusen

Abstract

Biliary obstruction and cholestasis result in hepatocellular necro-inflammation and lead to the development of liver fibrosis. Herein, we evaluated the therapeutic efficacy of Darbepoetin-α (DPO), a recombinant longer acting analogue of erythropoietin in a model of extrahepatic cholestasis. C57BL/6J mice underwent common bile duct ligation (BDL) and were treated either with DPO (10 μg/kg i. p.) or physiologic saline every third day, beginning 24 h after BDL. Mice were sacrificed at 2, 5 and 14 days after BDL. BDL provoked cholestatic hepatitis characterized by biliary infarcts with accumulation of macrophages followed by marked collagen deposition and increased gene expression of profibrotic transcripts. DPO treatment significantly diminished the area of focal necrosis, reduced the infiltration of macrophages, lowered collagen deposition, decreased levels of profibrotic transcripts, and inverted the pattern of Smad mRNA expression. Moreover, DPO prevented systemic anemia caused by BDL. Finally, DPO treatment significantly prolonged the survival time after BDL. These findings suggest that DPO, a clinically well established substance, could represent an efficient therapeutic option for patients with cholestatic liver disease.