The long-term goal of this proposal is to elucidate the mechanism(s) of the persistent anemia observed following severe trauma. Blood loss is commonplace after trauma and repeated and multiple transfusions given over several weeks are often necessary to correct a persistent anemia in critically injured patients. Blood transfusions are immunosuppressive, carry the risk of transmitting blood-borne infectious agents and are costly. Thus, the ability to correct this anemia would be of great clinical importance. These investigators and others have shown that endogenous erythropoietin levels are elevated after injury, so the etiology and mechanism of this post-injury anemia are likely to reside within the bone marrow (BM). Successful erythropoiesis requires interaction between hematopoietic progenitor cells and the BM stroma (the supporting matrix of the BM) within the BM microenvironment. To elucidate the mechanisms of post-injury anemia, this proposal will investigate:
(aim 1) the effect of trauma on the growth and differentiation of BM progenitor cells. In these studies bone marrow and peripheral blood from trauma patients and age matched healthy volunteers will be obtained and the number and phenotype of the progenitor cells determined. These cells will be cultured and assessed for their ability to proliferate and differentiate into red blood cells. Adhesion receptors which anchor these cells in the BM will also be evaluated. The results of these experiments will be correlated to the patient demographics and outcome;
(aim 2) the effect of trauma on the ability of the BM stroma to grow and support hematopoiesis. In this aim, BM from trauma patients and age matched controls will be cultured to determine whether the BM stroma can grow to confluence in a monolayer. Failure of the stroma to grow in culture been demonstrated to correlate with BM failure in hematologic diseases. Stromal monolayers will be cultured with BM progenitors to assess whether they can support erythropoiesis and whether they produce extracellular matrix proteins which help anchor the progenitor cells to the BM;
(aim 3) The effect of plasma on BM hematopoietic cellular progenitors, BM stroma, or both. In these studies plasma obtained from trauma patients will be added to cultures of hematopoietic progenitors or BM stroma and the growth will be compared to cultures grown with normal plasma. A strength of the proposal is that a BM aspirate for an individual patient can be utilized for both BM progenitor cell and stromal cultures. In addition the effect of plasma from this patient will also be studied; thus reults can be correlated with patient demographics and known outcomes. This proposal is novel; there app[ear to have been no detailed studies of BM erythropoietic function in trauma patients. Understanding the mechanisms behind post-trauma anemia will allow therapeutic interventions improving endogenous erythropoiesis to be targeted.
| Cook, Kristin M; Sifri, Ziad C; Baranski, Gregg M et al. (2013) The role of plasma granulocyte colony stimulating factor and bone marrow dysfunction after severe trauma. J Am Coll Surg 216:57-64 |
| Fonseca, Rodrigo B; Mohr, Alicia M; Wang, Lai et al. (2005) The impact of a hypercatecholamine state on erythropoiesis following severe injury and the role of IL-6. J Trauma 59:884-9; discussion 889-90 |
| Fonseca, Rodrigo B; Mohr, Alicia M; Wang, Lai et al. (2004) Adrenergic modulation of erythropoiesis following severe injury is mediated through bone marrow stroma. Surg Infect (Larchmt) 5:385-93 |
| Song, Xiaosong; Mohr, Alicia M; Rameshwar, Pranela et al. (2002) Delayed differentiation of HL-60 cells following exposure to hypoxia. J Surg Res 108:243-9 |
| Wu, J C; Livingston, D H; Hauser, C J et al. (2001) Trauma inhibits erythroid burst-forming unit and granulocyte-monocyte colony-forming unit growth through the production of TGF-beta1 by bone marrow stroma. Ann Surg 234:224-32 |
