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

Abstract

Following severe trauma, there is a profound elevation of catecholamine that is associated with a persistent anemic state. We have previously shown that β-blockade (βB) 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 βB protection of BM following trauma. Male Sprague-Dawley rats were subjected to either unilateral lung contusion (LC) ± βB, hemorrhagic shock (HS) ± βB, or both LC/HS ± βB. Propranolol (βB) was given immediately following resuscitation. Animals were sacrificed at 3and 24h 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-9was measured in plasma by ELISA. BM cellularity is decreased at 3h following LC, HS, and LC/HS. HS and LC/HS resulted in significant HPC mobilization in the peripheral blood. The addition of βB 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. βB significantly decreased G-CSF in both HS and LC/HS. Similarly, MMP-9is elevated following LC/HS, and βB prevents this elevation (390 ± 100pg/mL versus 275 ± 80pg/mL). βB 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 βB and suggests apossible mechanism how βB decreases HPC mobilization thus preserving BM cellularity. In contrast, βBprotection 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.