Pre-treatment with erythropoietin (EPO) has been demonstrated to exert tissue protective effects against 'ischemia-reperfusion' type injuries. This protection may be mediated by mobilization of endothelial progenitor cells (EPCs) from the bone marrow, which are thought to secrete paracrine factors. These effects could be exploited to protect against tissue injury induced in cases where hemorrhage is foreseeable, for example, prior to major surgery. Here, we investigate the effects of EPO pre-treatment on the organ injury and dysfunction induced by hemorrhagic shock (HS). Recombinant human EPO (1000 iu/kg/day i.p.) was administered for 3 days and rats were subjected to HS on day 4 (pre-treatment protocol). Mean arterial pressure was reduced to 35 ± 5 mmHg for 90 minutes followed by resuscitation with 20 ml/kg Ringer's lactate for 10 minutes and 50% of the shed blood for 50 minutes. Rats were sacrificed 4 hours after the onset of resuscitation. EPC (CD34+/flk-1+ cell) mobilization was measured following 3 day pre-treatment with EPO in rats and was significantly increased when compared to rats pre-treated with PBS. EPO pre-treatment significantly attenuated organ injury and dysfunction (renal, hepatic, neuromuscular) caused by HS. In livers from rats subjected to HS, EPO enhanced the phosphorylation of Akt (activation), glycogen synthase kinase-3β (GSK-3β; inhibition), and endothelial nitric oxide synthase (eNOS; activation). In the liver, HS also caused an increase in nuclear translocation of p65 (activation of NF-κB), which was attenuated by EPO. This data suggests that repetitive dosing with EPO prior to injury may protect against the organ injury and dysfunction induced by HS, by a mechanism that may involve mobilization of CD34+/flk-1+ cells resulting in the activation of the Akt/eNOS survival pathway and inhibition of activation of GSK-3β and NF-κB.
- Received November 14, 2012.
- Accepted December 19, 2012.
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