Beta-Blockade Prevents Hematopoietic Progenitor Cell Suppression after Hemorrhagic Shock

Abstract

Background: Severe injury is accompanied by sympathetic stimulation that induces bone marrow (BM) dysfunction by both suppression of hematopoietic progenitor cell (HPC) growth and loss of cells via HPC mobilization to the peripheral circulation and sites of injury. Previous work demonstrated that beta-blockade (BB) given prior to tissue injury both reduces HPC mobilization and restores HPC colony growth within the BM. This study examined the effect and timing of BB on BM function in a hemorrhagic shock (HS) model. Methods: Male Sprague-Dawley rats underwent HS via blood withdrawal, maintaining the mean arterial blood pressure at 30-40 mm Hg for 45 min, after which the extracted blood was reinfused. Propranolol (10 mg/kg) was given either prior to or immediately after HS. Blood pressure, heart rate, BM cellularity, and death were recorded. Bone marrow HPC growth was assessed by counting colony-forming unit-granulocyte-, erythrocyte-, monocyte-, megakaryocyte (CFU-GEMM), burst-forming unit-erythroid (BFU-E), and colony-forming uniterythroid (CFU-E) cells. Results: Administration of BB prior to injury restored HPC growth to that of naïve animals (CFU-GEMM 59 ± 11 vs. 61 ± 4, BFU-E 68 ± 9 vs. 73 ± 3, and CFU-E 81 ± 35 vs. 78 ± 14 colonies/plate). Beta-blockade given after HS increased the growth of CFU-GEMM, BFU-E, and CFU-E significantly and improved BM cellularity compared with HS alone. The mortality rate was not increased in the groups receiving BB. Conclusion: Administration of propranolol either prior to injury or immediately after resuscitation significantly reduced post-shock BM suppression. After HS, BB may improve BM cellularity by decreasing HPC mobilization. Therefore, the early use of BB post-injury may play an important role in attenuating the BM dysfunction accompanying HS.

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

“…This phenomenon of stress induced HPC mobilization is best illustrated by Katayama et al (20) who showed a critical link between the sympathetic nervous system, particularly norepinephrine, and G-CSF induced mobilization. Previously we have shown that norepinephrine causes a dose-dependent reduction of BM HPC growth along with increased HPC mobilization from the BM (12)(13)(14). Therefore, severe trauma along with a prolonged hypercatecholamine state may be deleterious resulting in inhibition of BM HPC growth and continued loss of HPCs into peripheral blood that leads to persistent anemia and abnormal tissue healing.…”

“…Our findings are supported by Katayama et al (20) who demonstrated that the use of a beta-2 agonist augmented G-CSF induced mobilization and propranolol use diminished the mobilization of HPCs in normal mice. BB protects the BM from erythroid growth suppression and diminish HPC mobilization without delaying healing of injured tissue (13,14). High dose propranolol (25 mg/kg) was shown to block the deleterious effects of circulating catecholamines and improve cutaneous wound healing in burned chronically stressed mice (21).…”

“…Norepinephrine not only suppresses BM erythroid growth in a dose dependent fashion it also increases HPC egress into the peripheral blood (13). The loss of HPC cells into the periphery decreases BM cellularity and contributes to the persistent anemia following shock and injury (14). However, the mediators involved in BM HPC mobilization following trauma and shock have not been described.…”

Is the sympathetic system involved in shock-induced gut and lung injury?

“…1,2 This hypercatecholamine state after trauma and HS is associated with increased hematopoietic progenitor cell (HPC) mobilization from the bone marrow (BM) and suppression of BM HPC growth, thus contributing to the anemic state. 3,4 After injury and HS, nonselective β-blockade (BB) with propranolol has been shown to not only decrease the mobilization of the HPCs and restore BM HPC growth but also lessen the severity of anemia. 4 …”

“…15–17 In addition, we have previously shown that the use of BB can reduce BM dysfunction associated with injury and HS. 3,4 However, the impact of the sympathetic system and the role of BB on shock-induced distant organ injury is not known. Therefore, the aim of this study was to determine if BB use has systemic protective effects and can diminish gut and lung injury after trauma and HS.…”