β-Blockade Protection of Bone Marrow Following Trauma: The Role of G-CSF

Background. Following severe trauma, there is a profound elevation of catecholamine that is associated with a persistent anemic state. We have previously shown that beta-blockade (beta B) prevents erythroid growth suppression and decreases hematopoietic progenitor cell (HPC) mobilization following injury. Under normal conditions, granulocyte colony stimulating factor (G-CSF) triggers the activation of matrix metalloprotease-9 (MMP-9), leading to the egress of progenitor cells from the bone marrow (BM). When sustained, this depletion of BM cellularity may contribute to BM failure. This study seeks to determine if G-CSF plays a role in the beta B protection of BM following trauma. Methods. Male Sprague-Dawley rats were subjected to either unilateral lung contusion (LC) +/- beta B, hemorrhagic shock (HS) +/- beta B, or both LC/HS +/- beta B. Propranolol (beta B) was given immediately following resuscitation. Animals were sacrificed at 3 and 24 h and HPC mobilization was assessed by evaluating BM cellularity and flow cytometric analysis of peripheral blood for HPCs. The concentration of G-CSF and MMP-9 was measured in plasma by ELISA. Results. BM cellularity is decreased at 3 h following LC, HS, and LC/HS. HS and LC/HS resulted in significant HPC mobilization in the peripheral blood. The addition of beta B restored BM cellularity and reduced HPC mobilization. Three h following HS and LC/HS, plasma G-CSF levels more than double, however LC alone showed no change in G-CSF. beta B significantly decreased G-CSF in both HS and LC/HS. Similarly, MMP-9 is elevated following LC/HS, and beta B prevents this elevation (390 +/- 100 pg/mL versus 275 +/- 80 pg/mL). Conclusion. beta B protection of the BM following shock and injury may be due to reduced HPC mobilization and maintenance of BM cellularity. Following shock, there is an increase in plasma G-CSF and MMP-9, which is abrogated by beta B and suggests a possible mechanism how beta B decreases HPC mobilization thus preserving BM cellularity. In contrast, beta B protection of BM following LC is not mediated by G-CSF. Therefore, the mechanism of progenitor cell mobilization from the BM is dependent on the type of injury. Published by Elsevier Inc.