Published online before print April 13, 2007

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(American Journal of Pathology. 2007;170:1954-1963.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.061056

Attenuation of Inflammation and Apoptosis by Pre- and Posttreatment of Darbepoetin- in Acute Liver Failure of Mice

Khoi Le Minh^*, Katja Klemm^*, Kerstin Abshagen^*, Christian Eipel^*, Michael D. Menger and Brigitte Vollmar^*

From the Institute for Experimental Surgery,^* University of Rostock, Rostock; and the Institute for Clinical and Experimental Surgery, University of Saarland, Homburg/Saar, Germany

In many liver disorders inflammation and apoptosis are important pathogenic components, finally leading to acute liver failure. Erythropoietin and its analogues are known to affect the interaction between apoptosis and inflammation in brain, kidney, and myocardium. The present study aimed to determine whether these pleiotropic actions also exert hepatoprotection in a model of acute liver injury. C57BL/6J mice were challenged with D-galactosamine (Gal) and Escherichia coli lipopolysaccharide (LPS) and studied 6 hours thereafter. Animals were either pretreated (24 hours before Gal-LPS exposure) or posttreated (30 minutes after Gal-LPS exposure) with darbepoetin- (DPO, 10 µg/kg i.v.). Control mice received physiological saline. Administration of Gal-LPS caused systemic cytokine release and provoked marked hepatic damage, characterized by leukocyte recruitment and microvascular perfusion failure, caspase-3 activation, and hepatocellular apoptosis as well as enzyme release and necrotic cell death. DPO-pretreated and -posttreated mice showed diminished systemic cytokine concentrations, intrahepatic leukocyte accumulation, and hepatic perfusion failure. Hepatocellular apoptosis was significantly reduced by 50 to 75% after DPO pretreatment as well as posttreatment. In addition, treatment with DPO also significantly abrogated necrotic cell death and liver enzyme release. In conclusion, these observations may stimulate the evaluation of DPO as hepatoprotective therapy in patients with acute liver injury.

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