Erythropoietin promotes hepatic regeneration after extended liver resection in rats.
OBJECTIVE
It has been proven in various animal studies that recombinant human erythropoietin (rHuEPO) protects renal, cardiac and neuronal, as well as hepatic, tissue from ischemia, and promotes regeneration of adult central nervous system neurons. To date, no data are available as to whether rHuEPO has the ability to stimulate liver regeneration after liver resection.


METHODS
Rats undergoing 70% or 90% hepatectomy received an intraportalvenous administration (i.p.) of rHuEPO prior to resection or a subcutaneous injection (s.c.) for 3 days postoperatively, control animals were treated with surgery and saline injection only. Regeneration capacity of remnant livers was studied over 7 days by histology and immunohistochemistry (Ki-67, proliferating cell nuclear antigen [PCNA]). Polymerase chain reaction was carried out to measure transforming growth factor beta (TGF-beta), hypoxia induced factor (HIF), signal transducing activator 3 and vascular endothelial growth factor.


RESULTS
Ten-day survival in rats undergoing 90% hepatectomy significantly increased in i.p.-pretreated animals. After 70% hepatectomy the mitotic index was significantly increased in both rHuEPO-treated groups. These data were confirmed by PCNA and Ki-67 expression, which was significantly increased in the treated groups 24 h and 2 days after liver resection. TGF-beta and HIF mRNA both were upregulated in control animals 3 h after surgery.


CONCLUSIONS
rHuEPO effectively increased liver regeneration in rats after 70% liver resection and enhanced survival after 90% hepatectomy. Thus, rHuEPO may increase the regenerative capacity after major hepatectomy.
Schmeding
Maximilian
M
Department of General, Visceral and Transplantation Surgery at Charité, Campus Virchow Klinikum, Universitaetsmedizin Berlin, Germany. maximilian.schmeding@charite.de
Boas-Knoop
Sabine
S
Lippert
Steffen
S
Ruehl
Martin
M
Somasundaram
Radjan
R
Dagdelen
Tarkan
T
Neuhaus
Peter
P
Neumann
Ulf P
UP
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004921:Erythropoietin / Q000008:administration & dosage / Q000494:pharmacology*; D006498:Hepatectomy; D006801:Humans; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D019394:Ki-67 Antigen / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D008940:Mitotic Index; D023421:Models, Animal; D011169:Portal Vein; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D019394:Ki-67 Antigen; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D004921:Erythropoietin