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

Abstract

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.

Early propranolol administration to severely injured patients can improve bone marrow dysfunction

“…This goal was chosen based on the success of propranolol use in burned children and in rodent studies. 20,22,25 In rodents, propranolol exhibited its protective effects in both a time- and dose-dependent fashion. 25 The protective effects of propranolol on BM have been guided by the ability of propranolol to decrease HR by 20% in rodents.…”

“…20,22,25 In rodents, propranolol exhibited its protective effects in both a time- and dose-dependent fashion. 25 The protective effects of propranolol on BM have been guided by the ability of propranolol to decrease HR by 20% in rodents. 25 In this trial, propranolol treatment did decrease HR, but only one third of patients maintained their HR goal for the entire duration of the study.…”

“…25 The protective effects of propranolol on BM have been guided by the ability of propranolol to decrease HR by 20% in rodents. 25 In this trial, propranolol treatment did decrease HR, but only one third of patients maintained their HR goal for the entire duration of the study. This is likely because an average of five doses per patient were missed.…”

β-Blockade use for Traumatic Injuries and Immunomodulation

“…(55–58) NE has dose dependent effects on bone marrow progenitor cell growth. (57) Adding NE at supraphysiologic concentrations to normal human bone marrow in vitro decreases bone marrow hematopoietic progenitor cell (HPC) growth by more than 95%.…”

Todralazine Protects Zebrafish from Lethal Effects of Ionizing Radiation: Role of Hematopoietic Cell Expansion

“…40 b 2 AR receptor antagonists block the trauma-induced mobilization of HSCs, thereby making the b 2 AR receptor modulation a potential strategy for HSC expansion. 40,41 The narrow deep cleft majorly hidden from the solvent makes the catecholamine (epinephrine)-binding site in b 2 AR a potential site for molecular docking. 42,43 Infact, this narrow deep cleft has been exploited for screening of compound libraries for identification of novel b 2 AR ligands.…”