Attenuation of inflammation and apoptosis by pre- and posttreatment of darbepoetin-alpha in acute liver failure of mice.
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-alpha (DPO, 10 mug/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.
Le Minh
Khoi
K
Institute for Experimental Surgery, University of Rostock, D-18055 Rostock, Germany.
Klemm
Katja
K
Abshagen
Kerstin
K
Eipel
Christian
C
Menger
Michael D
MD
Vollmar
Brigitte
B
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D000068256:Darbepoetin alfa; D004921:Erythropoietin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D005688:Galactosamine / Q000494:pharmacology; D006397:Hematinics / Q000494:pharmacology / Q000627:therapeutic use; D007249:Inflammation / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
C494812:Bcl2l1 protein, mouse; D016207:Cytokines; D006397:Hematinics; D008070:Lipopolysaccharides; D018809:Proliferating Cell Nuclear Antigen; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D004921:Erythropoietin; D000068256:Darbepoetin alfa; D005688:Galactosamine; D053148:Caspase 3