Multiple Doses of Erythropoietin Impair Liver Regeneration by Increasing TNF-α, the Bax to Bcl-xL Ratio and Apoptotic Cell Death

Abstract

BackgroundLiver 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.MethodologyRats undergoing 68% hepatectomy received daily either high dose (5000 IU/kg bw iv) or low dose (500 IU/kg bw iv) 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-α and IL-6 were evaluated. Further, hepatic Bcl-xL and Bax protein expression were analyzed by Western blot.Principal FindingsAdministration 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-α levels and shifted the Bcl-xL to Bax ratio towards the pro-apoptotic Bax resulting in significantly increased hepatocellular apoptosis.ConclusionsMultiple 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.

Impact of cold ischemia on cytokines after partial liver transplantation in rats

“…TNF-α expression correlates with the proliferative capacity of liver cells, and IL-10 may affect the capability of the liver to regenerate by downregulating TNF-α. Our results are consistent with those of recently published studies (Klemm et al, 2008;Sudo et al, 2008;Ito et al, 2009). …”

Alternative erythropoietin-mediated signaling prevents secondary microvascular thrombosis and inflammation within cutaneous burns

“…For example, EPO inhibited TNF-α-induced apoptosis of SH-SY5Y cells in vitro (28) as well as counteracted and reversed TNF-α-mediated effects in different in vivo models of neuronal injury (29,30). On the other hand, EPO has also been shown to induce TNF-α and apoptosis in a liver regeneration model (31). Because the effects of EPO are not uniquely mediated via the alternative CD131/EPO-R signaling pathway, this is clear evidence for a TNF-α suppressing effect of the alternate CD131/EPO-R signaling pathway in vivo, which is selectively activated by ARA290.…”

The Use of Erythropoietin in Liver Regeneration in Pigs after Partial Hepatectomy

“…The Klemm [38] study on the other hand, presented concurring results regarding the negative influence of low erythropoietin doses in liver regeneration. However, there are various discrepancies such animal models, administration mode, among others, in the current study as well as in Klemm's, making comparisons difficult.…”

“…Klemm [38] discovered that when EPO was administered in multiple doses of 500 and 5000 UI/kg intravenously, it interrupted liver regeneration.…”