Multiple Doses of Erythropoietin Impair Liver Regeneration by Increasing TNF-α, 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. METHODOLOGY: 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. PRINCIPAL FINDINGS: 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

Regulation of hepatic blood flow: The hepatic arterial buffer response revisited

The interest in the liver dates back to ancient times when it was considered to be the seat of life processes. The liver is indeed essential to life, not only due to its complex functions in biosynthesis, metabolism and clearance, but also its dramatic role as the blood volume reservoir. Among parenchymal organs, blood flow to the liver is unique due to the dual supply from the portal vein and the hepatic artery. Knowledge of the mutual communication of both the hepatic artery and the portal vein is essential to understand hepatic physiology and pathophysiology. To distinguish the individual importance of each of these inflows in normal and abnormal states is still a challenging task and the subject of ongoing research. A central mechanism that controls and allows constancy of hepatic blood flow is the hepatic arterial buffer response. The current paper reviews the relevance of this intimate hepatic blood flow regulatory system in health and disease. We exclusively focus on the endogenous interrelationship between the hepatic arterial and portal venous inflow circuits in liver resection and transplantation, as well as inflammatory and chronic liver diseases. We do not consider the hepatic microvascular anatomy, as this has been the subject of another recent review

Serum EPO concentration, hematocrit and red blood cell count

<p>Serum EPO concentration, hematocrit and red blood cell (RBC) count in animals at 24 h, 48 h and 5 d after pHx and daily administration of EPO at a dose of either 5000 IU/kg bw or 500 IU/kg bw. Control animals received equivalent volumes of physiologic saline (Con). For determination of physiological baseline values blood samples were obtained from non-resected, untreated rats (baseline). Data are given as means±SEM; Mann-Whitney rank sum test, ^* P<0.05 vs Con at the respective time point and EPO dose.</p

Anti-apoptotic Bcl-x_L and pro-apoptotic Bax as well as the Bcl-x_L/Bax ratio.

<p>Protein expression of anti-apoptotic Bcl-x_L (A) and pro-apoptotic Bax (B) as well as the Bcl-x_L/Bax ratio (C) in animals at 24 h, 48 h and 5 d after pHx and daily administration of high dose EPO (5000 IU/kg bw iv; closed bars) or physiologic saline solution (open bars). Data are normalized to ß-actin as loading control. Means±SEM; unpaired Student's t-test. * P<0.05 vs the saline-treated group at the respective time point.</p