Targeting IL-1R1-Mediated Anemia in Complex Combat-Related Burns
Abstract
Deployed military Service Members are two times more likely to suffer a burn injury than civilians and up to 20% of combat-related casualties in recent conflicts involve burns. Nearly all of these burns have been caused by improvised explosive devices (IEDs), homemade bombs commonly used by terrorists and insurgent groups. Explosions lead to complex injuries and account for approximately 14% of the 352,612 traumatic brain injury (TBI) diagnosis in the U.S. military between 2000 and 2016. Thus, it is not surprising the surge in the use of IEDs in warfare as well as civilian mass casualty events has increased the incidence of concomitant burn injury and TBI. Concomitant burn injury and TBI is difficult for medical professionals to manage, in part, because there are differences in how burn patients and TBI patients are typically treated and because the pathophysiological mechanisms initiated by this type of injury are incompletely understood. It is imperative to learn more about the pathophysiological response to this type of injury, which can be associated with long-term disabilities and increased mortality compared to burn injuries that overlap with other forms of trauma. Anemia is a nearly universal pathophysiological consequence of burn injury and may contribute to the poor medical outcomes associated with concomitant burn injury and TBI. Anemia has been linked to poor neurologic outcomes in TBI patients and given long-term nervous system-related morbidity has been recognized in burn patients without TBI, the concomitant injury has potential to amplify these effects. At some point anemia must be corrected, especially in TBI patients, who are at risk for secondary brain injuries if anemia is severe enough to limit oxygen delivery to the brain. Conversely, transfusions have also been associated with poor outcomes in both burn patients and TBI patients. This clinical dilemma provides the rationale for conservative transfusion protocols that have been widely adopted, yet patients with 20%-60% total body surface area burns still receive an amount of blood that is roughly equivalent to that which is contained in the entire adult body. There are currently no therapeutic alternatives to reduce transfusion requirements in burn or trauma victims because erythropoietin (EPO) and iron supplements fail to effectively promote erythropoiesis in these patients. This resistance to EPO and iron supplements is characteristic of anemia of critical illness (ACI), an inflammation-driven anemia that limits iron availability, reduces red blood cell lifespan, and impairs erythropoiesis. ACI is a primary reason burn patients require transfusions and understanding the inflammation-based pathogenesis of ACI will greatly facilitate strategies for intervention with an expanding arsenal of therapeutics being developed by pharmaceutical companies to target very specific inflammatory mechanisms. This proposal addresses the FY21 MBRP Idea Development Award focus area by validating therapeutic interventions aimed at improving erythropoiesis in burn-injured military Service Members with concomitant blast-related TBI. Successful studies are anticipated to identify U.S. Food and Drug Administration-approved biologics and a new class of small molecule drugs entering clinical trials that could be used as therapeutics to reduce the incidence of anemia and transfusion in burn-injured military Service Members with concomitant blast-related TBI. Reducing the incidence of anemia and transfusion in victims of concomitant burn and TBI has potential to improve medical outcomes, including reducing the risk of secondary brain injury and long-term neurological morbidity. Further, this interdisciplinary proposal will produce a novel preclinical model of concomitant blast-related TBI that is currently missing in the field, a model that is essential to understanding the pathophysiology of this devastating injury.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210849
Entities
People
- Jason S. Gardner
Organizations
- United States Army
- University of Cincinnati