Erythropoietin treatment improves liver regeneration and survival in rat models of extended liver resection and living donor liver transplantation.
BACKGROUND
Inadequate liver regeneration is still an unsolved problem in major liver resection and living donor liver transplantation (LDLT). Therefore, we have investigated the use of erythropoietin (EPO) as an exogenous stimulator of liver regeneration in rat models of liver resection and LDLT.


METHODS
Rats were treated with EPO or heat-inactivated EPO-vehicles. Animals underwent 70% or 90% partial hepatectomy (PH) or 30% partial liver transplantation (pLTx). Serum and liver samples were taken to investigate liver function, liver-to-body weight ratio (LBWR), hepatocyte-proliferation (Ki-67), apoptosis (terminal deoxynucleotide transferase-mediated dUTP nick-end labeling-assay), proregenerative cytokines (interleukin [IL]-6/tumor necrosis factor-alpha), and angiogenesis. Gene expression was assessed by in-house cDNA array and quantitative real-time polymerase chain reaction. As clinical parameters, LBWR and overall survival were determined.


RESULTS
Erythropoietin led to improved liver regeneration as shown by an increased LBWR/Ki-67 after PH and pLTx. Liver damage, indicated by the serum activity of aspartate aminotransferase, alanine aminotransferase, and glutamate dehydrogenase was reduced after PH. After surgery EPO treatment induced modulation of c-jun, IL-6, p53, and the antiapoptotic gene Bcl-XL, which was accompanied by a decreased apoptosis rate (0.56% vs. 1.03%; P<0.04). IL-6 production was increased at 12 hr, although no effects could be found concerning tumor necrosis factor-alpha production and angiogenesis. In addition, EPO-treated rats showed a significantly improved 28-day survival after 90% PH (92% vs. 67%) and pLTx (88% vs. 38%).


CONCLUSIONS
Erythropoietin treatment significantly improved liver regeneration and survival after PH and pLTx and may therefore represent a promising strategy to optimize the clinical outcome after extended liver resection and LDLT in the future.
Bockhorn
Maximilian
M
Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Germany. maxbockhorn@hotmail.com
Fingas
Christian D
CD
Rauen
Ursula
U
Canbay
Ali
A
Sotiropoulos
Georgios C
GC
Frey
Ulrich
U
Sheu
Shin-Yi
SY
Wohlschläger
Jeremias
J
Broelsch
Christoph E
CE
Schlaak
Jörg F
JF
D000818:Animals; D049109:Cell Proliferation; D004921:Erythropoietin / Q000627:therapeutic use*; D006498:Hepatectomy / Q000379:methods; D022781:Hepatocytes / Q000166:cytology; D008099:Liver / Q000473:pathology*; D008115:Liver Regeneration; D016031:Liver Transplantation; D008297:Male; D023421:Models, Animal; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D011917:Rats, Inbred Lew; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016896:Treatment Outcome
D011994:Recombinant Proteins; D004921:Erythropoietin