Erythropoietin Attenuates the Tissue Injury Associated With Hemorrhagic Shock and Myocardial Ischemia

Abstract

Here we investigate the effects of erythropoietin (EPO) on the tissue/organ injury caused by hemorrhagic shock (HS), endotoxic shock, and regional myocardial ischemia and reperfusion in anesthetized rats. Male Wistar rats were anesthetized with thiopental sodium (85 mg/kg i.p.) and subjected to hemorrhagic shock (HS; i.e., mean arterial blood pressure reduced to 45 mmHg for 90 min, followed by resuscitation with shed blood for 4 h), endotoxemia (for 6 h), or left anterior descending coronary artery occlusion (25 min) and reperfusion (2 h). HS and endotoxemia resulted in renal dysfunction and liver injury. Administration of EPO (300 IU/kg i.v., n = 10) before resuscitation abolished the renal dysfunction and liver injury in hemorrhagic, but not endotoxic, shock. HS also resulted in significant increases in the kidney of the activities of caspases 3, 8, and 9. This increase in caspase activity was not seen in HS rats treated with EPO. In cultured human proximal tubule cells, EPO concentration-dependently reduced the cell death and increase in caspase-3 activity caused by either ATP depletion (simulated ischemia) or hydrogen peroxide (oxidative stress). In the heart, administration of EPO (300 IU/kg i.v., n = 10) before reperfusion also caused a significant reduction in infarct size. In cultured rat cardiac myoblasts (H9C2 cells), EPO also reduced the increase in DNA fragmentation caused by either serum deprivation (simulated ischemia) or hydrogen peroxide (oxidative stress). We propose that the acute administration of EPO on reperfusion and/or resuscitation will reduce the tissue injury caused by ischemia-reperfusion of the heart (and other organs) and hemorrhagic shock.

Erythropoietin reduces the degree of arthritis caused by type II collagen in the mouse

“…Thus, our in vivo findings support the view that EPO directly protects cells by preventing activation of the apoptosis pathway. In support of this concept, Abdelrahman and colleagues have demonstrated that EPO also reduces the activation of caspase 3 caused by severe hemorrhage and resuscitation of the kidney, by inhibiting the activation of the caspase cascade via prevention of both the mitochondrial caspase 9 pathway and death receptor-mediated activation of caspase 8 (51).…”

Erythropoietin prevents lymphoid apoptosis but has no effect on survival in experimental sepsis

“…Antiapoptotic and tissue protective effects of EPO have been demonstrated most vigorously in models of ischemia-reperfusion injury affecting the brain, intestine, heart, and kidney, among other organs and tissues (14,(24)(25)(26). More recently, studies have indicated that EPO has cytoprotective effects in experimental models of inflammation and sepsis.…”

“…EPO, a hematopoietic growth factor with antiapoptotic properties, has been shown to have cytoprotective effects in various organs and tissues (14,15,17). We previously demonstrated that EPO attenuates splenic and thymic apoptosis in an endotoxic sepsis model (18).…”

“…Among the candidates for a therapeutic approach is erythropoietin (EPO), a hematopoietic growth factor shown to have antiapoptotic and cytoprotective effects in both animal and human models of hypoxia-ischemia (14)(15)(16)(17). We previously demonstrated that EPO decreases lipopolysaccharide (LPS)-induced thymic and splenic apoptosis (18).…”

Bridging Translation by Improving Preclinical Study Design in AKI

“…[64][65][66] Of these, one study reported a positive outcome with another treatment being compared with EPO, 65 and one study reported contrasting positive effects of EPO using a different model of AKI. 64 These data likely reflect the strong and persistent publication bias for reporting only positive outcomes of studies throughout the medical literature.…”