Do all β-blockers attenuate the excess hematopoietic progenitor cell mobilization from the bone marrow following trauma/hemorrhagic shock?

Abstract

BACKGROUND Severe injury results in increased mobilization of hematopoietic progenitor cells (HPC) from the bone marrow (BM) to sites of injury, which may contribute to persistent BM dysfunction after trauma. Norepinephrine is a known inducer of HPC mobilization, and nonselective β-blockade with propranolol has been shown to decrease mobilization after trauma and hemorrhagic shock (HS). This study will determine the role of selective β-adrenergic receptor blockade in HPC mobilization in a combined model of lung contusion (LC) and HS. METHODS Male Sprague-Dawley rats were subjected to LC, followed by 45 minutes of HS. Animals were then randomized to receive atenolol (LCHS + β1B), butoxamine (LCHS + β2B), or SR59230A (LCHS + β3B) immediately after resuscitation and daily for 6 days. Control groups were composed of naive animals. BM cellularity, %HPCs in peripheral blood, and plasma granulocyte-colony stimulating factor levels were assessed at 3 hours and 7 days. Systemic plasma-mediated effects were evaluated in vitro by assessment of BM HPC growth. Injured lung tissue was graded histologically by a blinded reader. RESULTS The use of β2B or β3B following LCHS restored BM cellularity and significantly decreased HPC mobilization. In contrast, β1B had no effect on HPC mobilization. Only β3B significantly reduced plasma G-CSF levels. When evaluating the plasma systemic effects, both β2B and β3B significantly improved BM HPC growth as compared with LCHS alone. The use of β2 and β3 blockade did not affect lung injury scores. CONCLUSION Both β2 and β3 blockade can prevent excess HPC mobilization and BM dysfunction when given after trauma and HS, and the effects seem to be mediated systemically, without adverse effects on subsequent healing. Only treatment with β3 blockade reduced plasma G-CSF levels, suggesting different mechanisms for adrenergic-induced G-CSF release and mobilization of HPCs. This study adds to the evidence that therapeutic strategies that reduce the exaggerated sympathetic stimulation after severe injury are beneficial and reduce BM dysfunction.

Daily propranolol prevents prolonged mobilization of hematopoietic progenitor cells in a rat model of lung contusion, hemorrhagic shock, and chronic stress

“…Those animals undergoing LCHS alone had a lung injury score of 3.7±0.8 on day seven. These findings are consistent with previously published data (11, 25). Exposure to CRS worsened the lung injury score at seven days compared to those animals undergoing LC and the LCHS alone (Table 2).…”

“…Propranolol has also been studied in other models of acute injury and decreases the release of HPC (24). Despite the involvement of HPC with healing of injured tissue, the decrease in circulating HPC after propranolol administration did not negatively impact healing (11, 25). It has been hypothesized that the propranolol mitigates the release of HPC by decreasing norepinephrine binding to beta adrenergic receptors in bone marrow but this has been only examined in the short term after acute injury (1, 11).…”

“…Despite the involvement of HPC with healing of injured tissue, the decrease in circulating HPC after propranolol administration did not negatively impact healing (11, 25). It has been hypothesized that the propranolol mitigates the release of HPC by decreasing norepinephrine binding to beta adrenergic receptors in bone marrow but this has been only examined in the short term after acute injury (1, 11). Our study evaluated the effect of daily administration of propranolol (Prop) to rats subjected to a novel model of lung contusion, hemorrhagic shock, and chronic restraint stress on the mobilization of HPC, plasma levels of G-CSF and SDF-1, and healing of the injured lung tissue.…”

“…In a rodent model of acute injury such as lung contusion, the number of HPC in peripheral blood will return to normal a few days after injury (11, 12). This acute injury model in a rodent depicts the migration of HPC and the normal healing of injured tissue.…”

Discrete β-adrenergic mechanisms regulate early and late erythropoiesis in erythropoietin-resistant anemia

“…Recent investigations in trauma model have shown the effects of non-selective (propranolol) and selective beta-blocker (SR59230A, a beta3 AR blocker) in preventing hematopoietic progenitor cell mobilization into the peripheral blood (21). However, only selective beta3 AR blocker reduced plasma G-CSF levels (48). G-CSF administration has been reported to negatively influence erythropoiesis (49–51) supporting our results that late stage erythropoiesis may be rescued with SR59230A by sequestering the cytokine, which is elevated in burn patients (52).…”