Bench to bedside: A role for erythropoietin in sepsis

Abstract

Sepsis is the systemic inflammatory response to infection and can result in multiple organ dysfunction syndrome with associated high mortality, morbidity and health costs. Erythropoietin is a well-established treatment for the anaemia of renal failure due to its anti-apoptotic effects on red blood cells and their precursors. The extra-haemopoietic actions of erythropoietin include vasopressor, anti-apoptotic, cytoprotective and immunomodulating actions, all of which could prove beneficial in sepsis. Attenuation of organ dysfunction has been shown in several animal models and its vasopressor effects have been well characterised in laboratory and clinical settings. Clinical trials of erythropoietin in single organ disorders have suggested promising cytoprotective effects, and while no randomised trials have been performed in patients with sepsis, good quality data exist from studies on anaemia in critically ill patients, giving useful information of its pharmacokinetics and potential for harm. An observational cohort study examining the microvascular effects of erythropoietin is underway and the evidence would support further phase II and III clinical trials examining this molecule as an adjunctive treatment in sepsis.

Figure 1

Anti-apoptotic pathways regulated by erythropoietin. The binding of erythropoietin (EPO) to its dimerised cell surface receptor causes conformational change, leading to activation and autophosphorylation of Janus-tyrosine kinase-2 (Jak2). Jak2 phosphorylates nine tyrosine residues in the intracellular portion of the receptor, which allows interaction with signal transducers and activators of transcription protein (STATs) signalling molecules, and activates phosphoinostitol-3 kinase (PI3K) and hence protein kinase B (AKT). AKT regulates multiple pro-apoptotic and anti-apoptotic intermediates, including glycogen storage kinase-3β (GSK-3B), B-cell lymphoma protein 2 (Bcl-2)-related death promoter (Bad) and the pro-apoptotic forkhead box transcription factor O3a (FOXO3a), rendering it unable to activate transcription of apoptotic signalling genes. STATs cause transcription of the anti-apoptotic molecules Bcl-2 and proto-oncogene serine/threonine-protein kinase 3 (PIM-3). EPO also activates NF-κB, possibly in a cell-type-specific manner, which alters transcription of pro-apoptotic and anti-apoptotic proteins including inhibitor of apoptosis proteins. ASK-1, apoptosis signal-regulating kinase 1; Bcl-x_L, B-cell lymphoma extra large; cIAP, baculoviral inhibitor of apoptosis protein repeat-containing protein; eNOS, endogenous nitric oxide synthase; EpoR, erythropoietin receptor; HSP70, heat shock protein 70; XIAP, X-linked inhibitor of apoptosis protein.