Administration of rhHGF-activator via portal vein stimulates the regeneration of cirrhotic liver after partial hepatectomy in rats.
OBJECTIVE
Cirrhotic liver has less ability to regenerate than normal liver, but it can produce the precursor of hepatocyte growth factor (proHGF) similarly to normal liver after resection. Studies were performed to examine whether the exogenous administration of recombinant human (rh) HGF-activator converts proHGF to biologically active (mature) HGF, inducing an enhancement of liver regeneration in cirrhosis.


METHODS
Rats with liver cirrhosis were treated by 45% partial hepatectomy, and rhHGF-activator or vehicle was injected via the portal vein 24 h after resection. Liver injury and its regeneration, the conversion of proHGF to mature HGF, and the activation of its signal through HGF receptor (c-Met) were analyzed.


RESULTS
rhHGF-activator improved the recovery of liver function after resection in cirrhotic liver as compared with the control group. rhHGF-activator also enhanced the proliferating cell nuclear antigen labeling index and liver regeneration rate. rhHGF-activator converted the proHGF to mature HGF, showing the maximal effect at 10 min after injection, which was followed by tyrosine phosphorylation of insulin receptor substrate (IRS)-1, and the association of IRS-1 with c-Met and phosphatidylinositol 3-kinase.


CONCLUSIONS
Results demonstrate that the administration of rhHGF-activator stimulates the recovery of liver function and regeneration after resection in cirrhotic liver through the activation of proHGF and its intracellular signal. It may be potentially useful treatment for patients with liver cirrhosis.
Yanagida
Hidesuke
H
Department of Surgery, Kansai Medical University, Osaka, Japan.
Kaibori
Masaki
M
Hijikawa
Takeshi
T
Kwon
A-Hon
AH
Kamiyama
Yasuo
Y
Okumura
Tadayoshi
T
D000818:Animals; D003131:Combined Modality Therapy; D006498:Hepatectomy / Q000379:methods*; D017228:Hepatocyte Growth Factor / Q000378:metabolism / Q000494:pharmacology*; D007275:Injections, Intravenous / Q000379:methods; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000601:surgery*; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D011169:Portal Vein; D011498:Protein Precursors / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D020127:Recovery of Function / Q000187:drug effects
D011498:Protein Precursors; D011994:Recombinant Proteins; C086013:pro-hepatocyte growth factor; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met