Molecular mechanisms causing anemia in burn patients.
Catecholamine/s and the regulation of hematopoietic development in burn pathology.
Severely injured burn patients remain anemic for longer periods requiring multiple transfusions. Aside from the complications of injury itself, the patient is then exposed to transfusion-associated risks such as infections, immune and non-immune reactions, morbidity and mortality. Finding new alternate strategies to treat anemia in burn patients and reduce their transfusion requirements will improve the standard of care, outcome and economic cost. Our research focus is to understand the molecular mechanisms causing burn-induced anemia, and discover novel and effective therapeutic tools that will restore red cell production.
One of the defense mechanisms to burn injury is the instigation of a primitive sympathetic response in the host, resulting in a massive release of catecholamine/s commonly referred to as "fight or flight" phenomenon. The surge in catecholamine/s persists for up to two years in burn patients resulting in high turn over within the hematopoietic organs. Our laboratory has shown that hematopoietic stem cells that reside in the bone marrow express the receptors for catecholamine/s. Given that hematopoietic stem cells are the precursors to mature cell types of all lineages constituting the blood, burn induced catecholamine rich bone marrow environment is highly likely to influence hematopoietic development. Our studies indicate that administering specific catecholamine-blocking agents to mice following burn partially corrected the functionality of granulocytes and monocytes. Additionally, we have found in burn patients, that specific transcription factors in monocytes orchestrate their terminal differentiation by augmenting their macrophage production while dampening dendritic cell development.
Building on our observations, we are currently investigating how burn injury alters the commitment and developmental patterns of hematopoietic stem cells, and what transcription factors dictate their branching into red blood cells and white blood cells. We are also examining how adrenergic mechanisms orchestrate impaired hematopoiesis following burn injury. The National Institute of Health shares our interest in finding the mechanisms causing impaired erythropoiesis in post burn anemia of critical illness by awarding R01 grant. The five-year study will investigate four broad areas of research:
Hematopoietic stem cell commitment patterns temporal to burn injury.
Burn-induced adrenergic signals that orchestrate the imbalance in hematopoiesis.
The specific cross talk between growth factor signals and a- and ß- adrenergic signals that dampen erythroid lineage commitments and red cell production.
Translational implications of adrenergic blockade treatments in burn injured patients.
Hasan,S.; Johnson,N. B.; Mosier,M. J.; Shankar,R.; Conrad,P.; Szilagyi,A.; Gamelli,R. L.; Muthumalaiappan,K.Myelo-erythroid commitment after burn injury is under beta-adrenergic control via MafB regulation American journal of physiology.Cell physiology 2017 ;312(3):C286-C301
Hasan,S.; Mosier,M. J.; Conrad,P.; Szilagyi,A.; Gamelli,R. L.; Muthumalaiappan,K.Terminal Maturation of Orthochromatic Erythroblasts Is Impaired in Burn Patients Journal of burn care & research : official publication of the American Burn Association 2017 ; :
Hasan,S.; Mosier,M. J.; Szilagyi,A.; Gamelli,R. L.; Muthumalaiappan,K.Discrete beta-adrenergic mechanisms regulate early and late erythropoiesis in erythropoietin-resistant anemia Surgery 2017 ;162(4):901-916
Johnson,N. B.; Posluszny,J. A.; He,L. K.; Szilagyi,A.; Gamelli,R. L.; Shankar,R.; Muthumalaiappan,K.Perturbed MafB/GATA1 axis after burn trauma bares the potential mechanism for immune suppression and anemia of critical illness Journal of leukocyte biology 2016 ; :
Williams,K. N.; Szilagyi,A.; Conrad,P.; Halerz,M.; Kini,A. R.; Li,Y.; Gamelli,R. L.; Shankar,R.; Muthumalaiappan,K.Peripheral blood mononuclear cell-derived erythroid progenitors and erythroblasts are decreased in burn patients Journal of Burn Care & Research 2013 ;34(1):133-141
Williams,K. N.; Szilagyi,A.; He,L. K.; Conrad,P.; Halerz,M.; Gamelli,R. L.; Shankar,R.; Muthumalaiappan,K.Dendritic cell depletion in burn patients is regulated by MafB expression Journal of burn care & research : official publication of the American Burn Association 2012 ;33(6):747-758
Posluszny,J. A.,Jr; Muthumalaiappan,K.; Kini,A. R.; Szilagyi,A.; He,L. K.; Li,Y.; Gamelli,R. L.; Shankar,R.Burn injury dampens erythroid cell production through reprioritizing bone marrow hematopoietic response. Journal of Trauma-Injury Infection & Critical Care 2011 ;71(5):1288-1296