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 injury-associated anemia. Combining rodent and human studies gives us the opportunity to mechanistically study injury-associated persistent anemia and its recovery, as well as identify potential therapeutic interventions to reduce morbidity and mortality associated with anemia and transfusion.

Public Health Relevance

Anemia is a common complication following severe traumatic injury and remains prevalent while in the intensive care unit. Utilizing our rodent model of injury-associated anemia, we will investigate how chronic stress contributes to the persistence of anemia, impaired iron and erythropoietic function, and delayed recovery. These studies will provide a strong foundation for future clinical interventions to help alleviate anemia following severe trauma.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Zhao, Xiaoli
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University of Florida
Schools of Medicine
United States
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Loftus, Tyler J; Rosenthal, Martin D; Croft, Chasen A et al. (2018) The effects of beta blockade and clonidine on persistent injury-associated anemia. J Surg Res 230:175-180
Horiguchi, Hiroyuki; Loftus, Tyler J; Hawkins, Russell B et al. (2018) Innate Immunity in the Persistent Inflammation, Immunosuppression, and Catabolism Syndrome and Its Implications for Therapy. Front Immunol 9:595
Loftus, Tyler J; Brakenridge, Scott C; Croft, Chasen A et al. (2018) Successful nonoperative management of uncomplicated appendicitis: predictors and outcomes. J Surg Res 222:212-218.e2
Mira, Juan C; Nacionales, Dina C; Loftus, Tyler J et al. (2018) Mouse Injury Model of Polytrauma and Shock. Methods Mol Biol 1717:1-15
Loftus, Tyler J; Brakenridge, Scott C; Murphy, Travis W et al. (2018) Anemia and blood transfusion in elderly trauma patients. J Surg Res 229:288-293
Loftus, Tyler J; Mira, Juan C; Stortz, Julie A et al. (2018) Persistent Inflammation and Anemia among Critically Ill Septic Patients. J Trauma Acute Care Surg :
Efron, Philip A; Mohr, Alicia M; Bihorac, Azra et al. (2018) Persistent inflammation, immunosuppression, and catabolism and the development of chronic critical illness after surgery. Surgery 164:178-184
Loftus, Tyler J; Mohr, Alicia M; Moldawer, Lyle L (2018) Dysregulated myelopoiesis and hematopoietic function following acute physiologic insult. Curr Opin Hematol 25:37-43
Loftus, Tyler J; Kannan, Kolenkode B; Carter, Christy S et al. (2018) Persistent injury-associated anemia in aged rats. Exp Gerontol 103:63-68
Loftus, Tyler J; Morrow, Megan L; Lottenberg, Lawrence et al. (2018) The Impact of Prior Laparotomy and Intra-abdominal Adhesions on Bowel and Mesenteric Injury Following Blunt Abdominal Trauma. World J Surg :

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