Dual effect of erythropoietin on liver protection and regeneration after subtotal hepatectomy in rats.
The only currently offered curative option for many patients with primary or secondary liver tumors is the resection of hepatic tumors. The aim of this study was to evaluate the role of recombinant human erythropoietin (rhEPO) in liver protection and regeneration after subtotal hepatectomy in rats. Rats undergoing 70% hepatectomy received an intraperitoneal injection of saline (control) or rhEPO (4 U/g) 30 minutes prior to resection. Liver function was assessed by the measurement of the international normalized ratio (INR) levels, and hepatic injury was assessed by serum alanine aminotransferase and aspartate aminotransferase levels. Hepatic apoptosis was assessed by intrahepatic caspase-3 activity and morphological criteria. The regeneration capacity of remnant livers was assessed over 7 days with the regenerated liver/body weight ratio, immunohistochemistry markers of cell proliferation (Ki-67) and angiogenesis (von Willebrand factor), and phosphorylated extracellular signal-regulated kinase signaling. Two and 4 days after subtotal hepatectomy, the regenerated liver/body weight ratio was significantly higher in animals treated with rhEPO versus the control group (P < 0.005). Serum liver enzymes and INR levels on days 2 and 4 post-hepatectomy were significantly lower in animals pretreated with rhEPO in comparison with the control group (P < 0.005). No statistically significant difference was noted in intrahepatic hepatic caspase-3 activity, immunohistochemistry for caspase-3, or a terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assay between the hepatectomized groups. In the rhEPO-pretreated group, the mitotic index, Ki-67 and von Willebrand factor expression, and extracellular signal-regulated kinase activity were significantly higher on day 2 post-hepatectomy (P < 0.05) in comparison with the control group. In conclusion, rhEPO treatment may offer a unique beneficial dual-function strategy for hepatic protection and regeneration immediately after subtotal hepatectomy in rats.
Greif
Franklin
F
Department of Surgery A, Rabin Medical Center, Beilinson Hospital, Petah Tiqwa, Israel.
Ben-Ari
Ziv
Z
Taya
Rasim
R
Pappo
Orit
O
Kurtzwald
Efrat
E
Cheporko
Yelena
Y
Ravid
Amiram
A
Hochhauser
Edith
E
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000378:metabolism; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D004921:Erythropoietin / Q000494:pharmacology*; D006498:Hepatectomy / Q000379:methods*; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D019934:International Normalized Ratio; D019394:Ki-67 Antigen / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D009929:Organ Size; D011183:Postoperative Complications / Q000188:drug therapy* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology; D014841:von Willebrand Factor / Q000378:metabolism
D019394:Ki-67 Antigen; D011994:Recombinant Proteins; D014841:von Willebrand Factor; D004921:Erythropoietin; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; C505410:Casp3 protein, rat; D053148:Caspase 3