Abstract
Erythropoietin (EPO) is the major hormone stimulating the production and differentiation of red blood cells. EPO is used widely for treating anemia of critical illness or anemia induced by chemotherapy. EPO at pharmacological doses is used in this setting to raise hemoglobin levels (by preventing the apoptosis of erythroid progenitor cells) and is designed to reduce patient exposure to allogenic blood through transfusions. Stroke, heart failure, and acute kidney injury are a frequently encountered clinical problem. Unfortunately, in the intensive care unit advances in supportive interventions have done little to reduce the high mortality associated with these conditions. Tissue protection with EPO at high, nonpharmacological doses after injury has been found in the brain, heart, and kidney of several animal models. It is now well known that EPO has anti-apoptotic effects in cells other than erythroid progenitor cells, which is considered to be independent of EPOs erythropoietic activities. This review article summarizes what is known in preclinical models of critical illness and discusses why this does not correlate with randomized, controlled clinical trials.
Highlights
Inflammation, renal failure, or blood loss due to frequent phlebotomies, gastric stress bleeding, coagulation disorders, or surgical procedures [1] often results in anemia in patients attending the intensive care unit (ICU)
We have demonstrated that preconditioning mice with EPO (1,000 U/kg/day for 3 days) in a protocol that has been shown to mobilize endothelial progenitor cells (EPCs) [6] was associated with a greater degree of renal protection in a model of renal ischemia/reperfusion injury (IRI) (30 minutes ischemia and 24 hours reperfusion) compared with the administration of a single dose of EPO (1,000 U/kg) at the time of reperfusion [6]
During the past decade, several key lines of evidence have strongly supported the view that endogenous EPO may play a crucial role in dampening the excessive tissue injury associated with by IRI and inflammation, but as yet there is no evidence that EPO may accelerate recovery after injury
Summary
Inflammation, renal failure, or blood loss due to frequent phlebotomies, gastric stress bleeding, coagulation disorders, or surgical procedures [1] often results in anemia in patients attending the intensive care unit (ICU). A recent study has shown that EPO administration within 2 hours of a lipopolysaccharide (LPS) insult prevented apoptosis, excessive nitric oxide production, peroxynitrite formation, and tissue hypoxia, but without any significant alterations in tissue neutrophilia, NF-B activation, or the increased serum levels of proinflammatory chemokines and HMGB-1 [4] Much of this data is consistent with previous findings, which have shown that EPO (10 IU/ml) prevents the expression of iNOS protein induced by interferon-g and LPS in rat oligodendrocytes [50]. It is likely that the anti-inflammatory effects of EPO in this model of chronic inflammation are–at least in part–secondary to prevention of tissue injury (both apoptosis and necrosis), which would result in the reduced formation of proinflammatory cytokines in the circulation [52] Both inflammatory and vascular endothelial cells have been shown to express EPOR [53,54]. Timing of administration may be very important; animal studies have taught us that there is a definitive window of treatment after injury
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