Patients suffering major trauma and critical illness develop an injury-associated persistent anemia which is not related to acute blood loss. Understanding the pathophysiology of this persistent anemia would avoid the use of blood transfusions which is currently the only available treatment. Our overall goal is to develop treatment strategies for this persistent anemia. Injury and hemorrhagic shock worsen bone marrow (BM) dysfunction and inhibit the differentiation of hematopoietic progenitor cells (HPC) and lead to increased mobilization of HPC from the BM to the peripheral blood and sites of injury. Our recent studies suggest that this BM dysfunction is linked to a hyperadrenergic state and that with critical illness this hyperadrenergic state is prolonged. This proposal will test the central hypothesis that chronic adrenergic stimulation following injury and hemorrhagic shock worsens BM dysfunction further inhibiting the differentiation of HPCs and exaggerating the mobilization of HPCs from BM contributing to injury-associated persistent anemia.
Our specific aims are to:
Aim 1. Determine the effects of a persistent inflammatory milieu on BM erythroid differentiation and anemia.
Aim 2. Determine if excessive and ongoing HPC mobilization contributes to persistent anemia.
These aims will be examined in our established model of lung contusion and hemorrhagic shock followed by daily restraint to simulated chronic stress. To compliment both these aims we will also examine the use of beta adrenergic blockade and 6-hydroxydopamine to decrease the hyperadrenergic state and prevent BM dysfunction and thus alleviate persistent anemia.
This research will study the deleterious effects of chronic stress following acute injury which is hypothesized to exacerbate injury-associated persistent anemia. In addition, this research will examine the potential therapeutic benefit of beta blockade in reducing stress hormones thereby decreasing the incidence of injury-associated persistent anemia and the need for blood transfusion. There are currently no alternative treatments for anemia except blood transfusions and a reduction in the number of blood transfusions can decrease costs, the number of infections, and death.