Erythropoietin treatment improves liver regeneration and survival in rat models of extended liver resection and living donor liver transplantation

TY - JOUR

T1 - Erythropoietin treatment improves liver regeneration and survival in rat models of extended liver resection and living donor liver transplantation

AU - Bockhorn, Maximilian

AU - Fingas, Christian D

AU - Rauen, Ursula

AU - Canbay, Ali

AU - Sotiropoulos, Georgios C

AU - Frey, Ulrich

AU - Sheu, Shin-Yi

AU - Wohlschläger, Jeremias

AU - Broelsch, Christoph E

AU - Schlaak, Jörg F

PY - 2008/12/15

Y1 - 2008/12/15

N2 - 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.

AB - 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.

KW - Animals

KW - Cell Proliferation

KW - Erythropoietin

KW - Hepatectomy

KW - Hepatocytes

KW - Liver

KW - Liver Regeneration

KW - Liver Transplantation

KW - Male

KW - Models, Animal

KW - Oligonucleotide Array Sequence Analysis

KW - Rats

KW - Rats, Inbred Lew

KW - Recombinant Proteins

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - Treatment Outcome

U2 - 10.1097/TP.0b013e31818b22b4

DO - 10.1097/TP.0b013e31818b22b4

M3 - SCORING: Journal article

C2 - 19077893

VL - 86

SP - 1578

EP - 1585

JO - TRANSPLANTATION

JF - TRANSPLANTATION

SN - 0041-1337

IS - 11

ER -