Discrete β-adrenergic mechanisms regulate early and late erythropoiesis in erythropoietin-resistant anemia.

Background. Anemia of critical illness is resistant to exogenous erythropoietin. Packed red blood cells transfusions is the only treatment option, and despite related cost and morbidity, there is a need for alternate strategies. Erythrocyte development can be divided into erythropoietin-dependent and erythropoietin-independent stages. We have shown previously that erythropoietin-dependent development is intact in burn patients and the erythropoietin-independent early commitment stage, which is regulated by beta 1/beta 2-adrenergic mechanisms, is compromised. Utilizing the scald burn injury model, we studied erythropoietin-independent late maturation stages and the effect of beta 1/beta 2, beta-2, or beta-3 blockade in burn mediated erythropoietin-resistant anemia. Methods. Burn mice were randomized to receive daily injections of propranolol (nonselective beta 1/beta 2 antagonist), nadolol (long-acting beta 1/beta 2 antagonist), butoxamine (selective beta 2 antagonist), or SR59230A (selective beta 3 antagonist) for 6 days after burn. Total bone marrow cells were characterized as nonerythroid cells, early and late erythroblasts, nucleated orthochromatic erythroblasts and enucleated reticulocyte subsets using CD71, Tel and Syto-16 by flow cytometry. Multipotential progenitors were probed for MafB expressing cells. Results. Although propranolol improved early and late erythroblasts, only butoxamine and selective beta 3-antagonist administrations were positively reflected in the peripheral blood hemoglobin and red blood cells count. While burn impeded early commitment and late maturation stages, beta 1/beta 2 antagonism increased the early erythroblasts through commitment stages via beta 2 specific MafB regulation. beta 3 antagonism was more effective in improving overall red blood cells through late maturation stages. Conclusion. The study unfolds novel beta 2 and beta 3 adrenergic mechanisms orchestrating erythropoietin resistant anemia after burn, which impedes both the early commitment stage and the late maturation stages, respectively.