Prophylaktische wie auch therapeutische Gabe von Darbepoetin alpha wirkt anti-inflammatorisch und anti-apoptotisch im Modell des akuten septischen Leberschadens der Maus

Abstract

A variety of liver disorders, which can lead to acute liver failure, are often associated with excessive hepatocellular apoptosis. Reducing programmed cell death of hepatocytes might alleviate acute liver failure and, consequently, mortality. In this study, we investigated the anti-apoptotic effect of darbepoietin (DPO) in a murine model of acute liver failure. For this purpose C57BL/6J mice were challenged with D-galactosamine (GalN) and E. coli lipopolysaccharide (LPS) 24 hours after or 30 minutes before administration of DPO. Hepatic microcirculation and inflammatory response were analyzed 6 hours after GalN/LPS treatment using intravital fluorescence microscopy. In addition, hepatocellular apoptosis, hepatocellular necrosis, plasma levels of AST, ALT, LDH, and GLDH, and PCNA protein expression were determined. Injection of GalN/LPS lead to hepatic damage, including increased intrahepatic leukocyte accumulation and remarkably decreased microvascular perfusion as well as increased hepatocellular apoptosis and enzyme release. Treatment with DPO ameliorated hepatic microcirculation, attenuated leukocyte recruitment, reduced hepatocellular apoptosis and liver enzyme release in GalN-sensitized mice subjected to LPS (⊡ Table 1). In conclusion, DPO could alleviate GalN/LPS-treated mice from acute liver failure possibly through blockade of hepatocellular apoptosis.