Aihaiti X, Hayamizu K, Oishi K, Yoshimitsu M, Itamoto T, Asahara
T.Facilitation of survival in a rat fulminant hepatic
failure model by combination therapy using recombinant G-CSF and
Tacrolimus (FK506).
J Interferon Cytokine Res. 2006 Apr;26(4):226-34.
Department of Surgery, Division of Frontier Medical Science,
Graduate School of Biomedical Sciences, Hiroshima University,
Hiroshima, Japan.
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.
PMID: 16704299 |
