Abstract Injury-associated anemia develops in patients suffering major trauma and remains persistent when followed by critical illness. Currently, the only available treatment is blood transfusions. In the initial period of this award, we demonstrated that bone marrow erythropoietic dysfunction was linked to a hyperadrenergic state and that with critical illness and chronic stress this hyperadrenergic state is prolonged. We also described a novel critical illness rodent model that combined lung contusion, hemorrhagic shock and chronic stress that led to persistent anemia on day seven following initial injury. The prolonged adrenergic stimulation that occurred with chronic stress following injury and hemorrhagic shock worsened erythropoietic dysfunction, reduced the growth of erythroid progenitors, and exaggerated the mobilization of hematopoietic progenitors from the bone marrow. In addition, chronic stress led to the combined deficit of reduced iron availability due to hepcidin activation and reduced bone marrow erythropoietin receptor expression associated with an ineffective erythropoietin response that accompanied injury-associated anemia. These findings were confirmed in bone marrow obtained from severely injured trauma patients. In addition, we also demonstrated that we could improve erythropoietic function in our rodent model with either propranolol or clonidine, both agents act to reduce the effects of norepinephrine through two different mechanisms. The mechanistic studies proposed in this application are the natural extension of our recent findings and will test if chronic stress and prolonged adrenergic stimulation following injury and hemorrhagic shock are directly responsible for the persistence of injury-associated anemia with impaired differentiation and maturation of erythroid cells, and if reduction of chronic stress can improve anemia and alter recovery. To accomplish this, there are three specific aims: 1) To delineate if long term chronic stress results in a persistent inflammatory milieu that further impairs recovery of injury-associated anemia; 2) To determine if alterations in the erythropoietin receptor or hepcidin or stress-related genomic changes in erythroid differentiation is the primary event following injury and chronic stress contributing to persistent injury-associated anemia; 3) To determine the optimal therapeutic agent to reduce chronic stress and investigate if it leads to faster resolution of injury-associated anemia and improved recovery. The first aim will further characterize injury-associated anemia long-term and during recovery. The second aim will determine the how chronic stress mechanistically alters hepcidin function and stress-related genomic changes in erythropoiesis leading to impaired differentiation and maturation of erythroid cells. The third aim will determine the optimal therapeutic agent to reduce the hyperadrenergic state following trauma and possibly decrease the duration of persistent inju...