Background Following severe trauma there is a profound elevation of catecholamines that is associated with a persistent anemic state. We have previously shown that beta blockade (BB) 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 BB protection of BM following trauma. Methods Male Sprague-Dawley rats were subjected to either unilateral lung contusion (LC)±BB, hemorrhagic shock (HS)±BB, or both LC/HS±BB. Propranolol (BB) was given immediately following resuscitation. Animals were sacrificed at 3 and 24 hours 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 3hrs following LC, HS and LC/HS. HS and LC/HS resulted in significant HPC mobilization in the peripheral blood. The addition of BB restored BM cellularity and reduced HPC mobilization. Three hours following HS and LC/HS, plasma G-CSF levels more than double, however LC alone showed no change in G-CSF. BB significantly decreased G-CSF in both HS and LC/HS. Similarly, MMP-9 is elevated following LC/HS and BB prevents this elevation (390±100pg/ml vs. 275±80pg/ml**). Conclusion BB 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 BB and suggests a possible mechanism how BB decreases HPC mobilization thus preserving BM cellularity. In contrast, BB 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.

Introduction Severe trauma induces a profound elevation of catecholamines that is associated with bone marrow (BM) hematopoietic progenitor cell (HPC) colony growth suppression, excessive BM HPC mobilization, and a persistent anemia. Previously, propranolol (BB) use after injury and shock has been shown to prevent this BM dysfunction and improve hemoglobin levels. This study seeks to further investigate the optimal therapeutic dose and timing of BB administration following injury and shock. Methods Male Sprague-Dawley rats were subjected to a combined lung contusion (LC), hemorrhagic shock (HS) model ± BB. In our dose response experiments, animals received BB at 1, 2.5, 5, or 10 mg/kg immediately following resuscitation. In our therapeutic window experiments, following LCHS rats were given BB immediately, 1 hour, or 3 hours following resuscitation. BM and peripheral blood (PB) were collected in all animals to measure cellularity, BM HPC growth, circulating HPCs, and plasma G-CSF levels. Results Propranolol at 5 and 10 mg/kg significantly reduced HPC mobilization, restored BM cellularity and BM HPC growth, and decreased plasma G-CSF levels. Propranolol at 5 and 10 mg/kg also significantly decreased heart rate. When BB was administered beyond 1 hour after LCHS, its protective effects on cellularity, BM HPC growth, HPC mobilization, and plasma G-CSF levels were greatly diminished. Conclusion Early Buse following injury and shock at a dose of at least 5mg/kg is required to maintain BM cellularity and HPC growth, prevent HPC mobilization, and reduce plasma G-CSF levels. This suggests that propranolol exerts its BM protective effect in a dose and time dependent fashion in a rodent model. Finally, heart rate may be a valuable clinical marker to assess effective dosing of propranolol.

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BACKGROUND β-blockade (BB) has been shown to prevent bone marrow (BM) dysfunction after trauma and hemorrhagic shock (HS). The impact of the sympathetic system and the role of BB on shock-induced distant organ injury is not known. This study will determine if BB has systemic effects and can diminish gut and lung injury after trauma and HS. METHODS Male Sprague-Dawley rats were subjected to lung contusion (LC) followed by 45 minute of HS. Animals (n = 6 per group) were then randomized to either receive propranolol (LCHS + BB) immediately after resuscitation or not (LCHS). Gut permeability was evaluated in by diffusion of Mr 4,000 of fluorescein dextran (FD4) from a segment of small bowel into peripheral blood. Villous injury and lung injury were graded histologically by a blinded reader. Plasma-mediated effects of BB were evaluated in vitro by an assessment of BM progenitor growth. RESULTS Animals undergoing LCHS had significantly higher plasma levels of FD4 compared with control animals (mean [SEM], 2.8 [0.4] µg/mL vs. 0.8 [0.2] µg/mL). However, animals receiving BB had a significant reduction in plasma FD4 compared with the LCHS group. With the use of BB after LCHS, both ileal and lung injury scores were similar to control. In addition, BM progenitor growth was inhibited by the addition of LCHS plasma, and LCHS + BB plasma showed no inhibition of BM progenitor growth. CONCLUSION Propranolol can protect against the detrimental effects of trauma and HS on gut permeability, villous, and lung injury. The effects of BB are likely systemic and appear to be mediated through plasma. BB likely blunts the exaggerated sympathetic response after shock and injury. Propranolol’s reduction of both BM dysfunction and distant organ injury further demonstrates the importance of the sympathetic nervous system and its role in potentiating end organ dysfunction after severe trauma.

Background-Following severe trauma there is a profound elevation of catecholamines that is associated with a persistent anemic state. We have previously shown that beta blockade (BB) 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 BB protection of BM following trauma.