RRC ID 42646
Author Aihaiti X, Hayamizu K, Oishi K, Yoshimitsu M, Itamoto T, Asahara T.
Title Facilitation of survival in a rat fulminant hepatic failure model by combination therapy using recombinant G-CSF and tacrolimus.
Journal J Interferon Cytokine Res
Abstract The mortality rate of fulminant hepatic failure (FHF) is high because of retarded liver regeneration. Recombinant human granulocyte colony-stimulating factor (rHuG-CSF) and tacrolimus are known to be immunosuppressive and supportive to liver regeneration. We investigated the effects of their combination therapy in a rat FHF model with a 68% partial hepatectomy and 24% liver necrosis. All rats without drug pretreatment died within 55 h. The median time was prolonged from 37 to 52 h by rHuG-CSF (250 microg/kg/day s.c. on days -5 to 0) and to 46 h by tacrolimus (0.5 mg/kg/day i.m. on days -2 to 0). Notably, the combination therapy facilitated DNA biosynthesis and survival prolongation, with a median of 77 h. The interferon-gamma (IFN-gamma) protein levels and natural killer cell (NK) activity in the liver were low at 12 h, and no further inhibition was detected by any treatment. Tacrolimus significantly upregulated the mRNA levels of insulin receptors and transforming growth factor-alpha (TGF-alpha), whereas rHuG-CSF did not. Regarding tissue remodeling-related factors, rHuG-CSF upregulated mRNA levels of vascular endothelial growth factor (VEGF) and matrix metalloproteinase- 9 (MMP-9), whereas tacrolimus did not. The combination treatment upregulated protein levels of both insulin receptors and VEGF. These results suggest that tacrolimus improves the hepatocyte replication and rHuG-CSF contributes to tissue reconstitution, and this combination therapy directly facilitates liver regeneration in the FHF model.
Volume 26(4)
Pages 226-34
Published 2006-4-1
DOI 10.1089/jir.2006.26.226
PMID 16704299
MeSH Animals DNA Replication / drug effects Disease Models, Animal Drug Therapy, Combination Granulocyte Colony-Stimulating Factor / therapeutic use* Hepatocytes / drug effects Hepatocytes / metabolism Immunosuppressive Agents / therapeutic use* Interferon-gamma / genetics Interferon-gamma / metabolism Killer Cells, Natural / immunology Liver / drug effects Liver / immunology Liver / metabolism Liver Failure, Acute / drug therapy* Liver Regeneration* Male Matrix Metalloproteinase 9 / genetics Matrix Metalloproteinase 9 / metabolism RNA, Messenger / analysis RNA, Messenger / metabolism Rats Rats, Sprague-Dawley Receptor, Insulin / genetics Receptor, Insulin / metabolism Recombinant Proteins Tacrolimus / therapeutic use* Transforming Growth Factor alpha / genetics Transforming Growth Factor alpha / metabolism Treatment Outcome Up-Regulation Vascular Endothelial Growth Factor A / genetics Vascular Endothelial Growth Factor A / metabolism
IF 2.032
Times Cited 1
Human and Animal Cells YAC-1(RCB1165)