Multiple doses of erythropoietin impair liver regeneration by increasing TNF-alpha, the Bax to Bcl-xL ratio and apoptotic cell death.
BACKGROUND
Liver resection and the use of small-for-size grafts are restricted by the necessity to provide a sufficient amount of functional liver mass. Only few promising strategies to maximize liver regeneration are available. Apart from its erythropoiesis-stimulating effect, erythropoietin (EPO) has meanwhile been recognized as mitogenic, tissue-protective, and anti-apoptotic pleiotropic cytokine. Thus, EPO may support regeneration of hepatic tissue.


METHODS
Rats undergoing 68% hepatectomy received daily either high dose (5000 IU/kg bw i.v.) or low dose (500 IU/kg bw i.v.) recombinant human EPO or equal amounts of physiologic saline. Parameters of liver regeneration and hepatocellular apoptosis were assessed at 24 h, 48 h and 5 d after resection. In addition, red blood cell count, hematocrit and serum EPO levels as well as plasma concentrations of TNF-alpha and IL-6 were evaluated. Further, hepatic Bcl-x(L) and Bax protein expression were analyzed by Western blot.


RESULTS
Administration of EPO significantly reduced the expression of PCNA at 24 h followed by a significant decrease in restitution of liver mass at day 5 after partial hepatectomy. EPO increased TNF-alpha levels and shifted the Bcl-x(L) to Bax ratio towards the pro-apoptotic Bax resulting in significantly increased hepatocellular apoptosis.


CONCLUSIONS
Multiple doses of EPO after partial hepatectomy increase hepatocellular apoptosis and impair liver regeneration in rats. Thus, careful consideration should be made in pre- and post-operative recombinant human EPO administration in the setting of liver resection and transplantation.
Klemm
Katja
K
Institute for Experimental Surgery, University of Rostock, Rostock, Germany.
Eipel
Christian
C
Cantré
Daniel
D
Abshagen
Kerstin
K
Menger
Michael D
MD
Vollmar
Brigitte
B
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001772:Blood Cell Count; D001973:Bromodeoxyuridine; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004921:Erythropoietin / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D006400:Hematocrit; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D008099:Liver / Q000033:anatomy & histology / Q000166:cytology / Q000201:enzymology; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins; D000637:Transaminases / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*; D051020:bcl-X Protein / Q000378:metabolism*
D016207:Cytokines; D018809:Proliferating Cell Nuclear Antigen; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D004921:Erythropoietin; D000637:Transaminases; D001973:Bromodeoxyuridine