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

Abstract

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.

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

“…However, severe traumatic Injury and shock are associated with significant increases in norepinephrine levels and subsequently increased mobilization of HPC (15, 17). Previously, propranolol administration in acute injury rodent models has been shown to mitigate the release of HPC from the bone marrow (11, 24). This is the first study to demonstrate that chronic restraint stress significantly prolongs the mobilization of HPC and that this effect of CRS following LC and LCHS can be abrogated with daily propranolol use.…”

“…Lung contusion was created as described previously by Baranski et al (24). In brief, after IP administration of 50 mg/kg pentobarbital, the animals were secured with their right forelimb retracted cephalad .…”

“…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).…”

Mesenchymal stem cells reverse bone marrow dysfunction following injury and stress

“…This is characterized by both depression of BM and cellularity and HPC growth within the BM itself as well as mobilization of HPCs to the periphery with an associated elevation in plasma G-CSF 2,3 . With exposure to CS, this response is further potentiated, resulting in persistent BM dysfunction lasting more than seven days after injury 7 .…”

“…In our rodent lung contusion (LC) model, BM dysfunction is observed soon following injury and is characterized by depression of BM cellularity, decreased growth of hematopoietic progenitor cell (HPC) colonies, and mobilization of HPCs to the peripheral blood 2,3 . Despite this early dysfunction, rats demonstrate recovery to normal usually by seven days following injury.…”