Facilitation of survival in a rat fulminant hepatic failure model by combination therapy using recombinant G-CSF and tacrolimus.
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.
Aihaiti
Xuehelati
X
Department of Surgery, Division of Frontier Medical Science, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.
Hayamizu
Keisuke
K
Oishi
Koichi
K
Yoshimitsu
Masanori
M
Itamoto
Toshiyuki
T
Asahara
Toshimasa
T
D000818:Animals; D004261:DNA Replication / Q000187:drug effects; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D017114:Liver Failure, Acute / Q000188:drug therapy*; D008115:Liver Regeneration; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins; D016559:Tacrolimus / Q000627:therapeutic use*; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D011994:Recombinant Proteins; D016211:Transforming Growth Factor alpha; D042461:Vascular Endothelial Growth Factor A; D016179:Granulocyte Colony-Stimulating Factor; D007371:Interferon-gamma; D011972:Receptor, Insulin; D020780:Matrix Metalloproteinase 9; D016559:Tacrolimus