Darbepoetin-α inhibits the perpetuation of necro-inflammation and delays the progression of cholestatic fibrosis in mice

Abstract

Biliary obstruction and cholestasis result in hepatocellular necro-inflammation and lead to the development of liver fibrosis. The objective of this study was to analyze whether the multiple tissue-protective properties of erythropoietin are salutary in an experimental model of liver fibrosis. For this purpose, C57BL/6J mice underwent common bile duct ligation (BDL) and were treated with either darbepoetin-α (10 μg/kg i.p.) or physiological saline every third day, beginning 24 h after BDL. Mice were killed at 2, 5, 14, and 28 days after BDL. Beside hematological parameters, markers of inflammation and fibrosis were assessed histomorphometrically and immunohistochemically as well as by quantitative real-time PCR. In addition, a 7-week survival study was performed. BDL provoked cholestatic hepatitis characterized by biliary infarcts with accumulation of macrophages followed by marked collagen deposition and increased expression of profibrotic gene transcripts. Darbepoetin-α treatment significantly diminished the area of focal necrosis, reduced the infiltration of macrophages, decreased levels of profibrotic genes, and lowered collagen deposition. Moreover, darbepoetin-α significantly reduced systemic anemia caused by BDL. Finally, darbepoetin-α treatment significantly prolonged the survival time after BDL. This study suggests that darbepoetin-α, which is a clinically well-established substance, might be used as an efficient therapeutic option for patients with chronic cholestatic liver disease.