Beta Blockade Protection of Bone Marrow Following Injury: A Critical Link between Heart Rate and Immunomodulation

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.