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

Abstract

Introduction Propranolol has been shown previously to decrease the mobilization of hematopoietic progenitor cells (HPC) after acute injury in rodent models; however, this acute injury model does not reflect the prolonged period of critical illness after severe trauma. Using our novel lung contusion/hemorrhagic shock/chronic restraint stress model, we hypothesize that daily propranolol (Prop) administration will decrease prolonged mobilization of HPC without worsening lung healing. Methods Male Sprague-Dawley rats underwent six days of restraint stress after undergoing lung contusion or lung contusion/hemorrhagic shock. Restraint stress consisted of a daily two hour period of restraint interrupted every 30 minutes by alarms and repositioning. Each day after the period of restraint stress, the rats received intraperitoneal propranolol (10mg/kg). On day seven, peripheral blood was analyzed for granulocyte-colony stimulating factor (G-CSF) and stromal cell-derived factor 1 (SDF-1) via ELISA and for mobilization of HPC using c-kit and CD71 flow cytometry. The lungs were examined histologically to grade injury. Results Seven days after lung contusion and lung contusion/hemorrhagic shock, the addition of chronic restraint stress significantly increased the mobilization of HPC, which was associated with persistently increased levels of G-CSF and increased lung injury scores. The addition of propranolol to lung contusion/chronic restraint stress and lung contusion/hemorrhagic shock/chronic restraint stress models significantly decreased HPC mobilization and restored G-CSF levels to that of naïve animals without worsening lung injury scores. Conclusions Daily propranolol administration after both lung contusion and lung contusion/hemorrhagic shock subjected to chronic restraint stress decreased the prolonged mobilization of HPC from the bone marrow and decreased plasma G-CSF levels. Despite the decrease in mobilization of HPC, lung healing did not worsen. Alleviating chronic stress with propranolol may be a future therapeutic target to improve healing after severe injury.

Clonidine reduces norepinephrine and improves bone marrow function in a rodent model of lung contusion, hemorrhagic shock, and chronic stress

“…After severe trauma, NE and G-CSF have been demonstrated to be associated with prolonged HPC mobilization 1, 8, 12, 23–25 . Seven days after CS alone, HPC mobilization was significantly prolonged (Figure 2B).…”

“…In addition, increased NE levels attenuate growth of bone marrow erythroid progenitor cells, both in vitro and in vivo 1, 5, 8, 28 . By blocking beta-adrenergic receptors, daily propranolol use prevented prolonged HPC mobilization and improved the growth of bone marrow erythroid progenitors 12, 13, 22, 26, 26 . Our study examined the effects of clonidine on bone marrow function after trauma.…”

“…Severe trauma triggers a persistent hypercatecholamine state that is associated with increases in plasma levels of G-CSF and mobilization of bone marrow HPCs which disrupts function of the homeostatic bone marrow 1, 5, 8, 12, 23 . In three different injury models (CS, LCHS, and LCHS/CS), urine NE levels increased three to six fold.…”

Clonidine restores vascular endothelial growth factor expression and improves tissue repair following severe trauma

“…This model has previously been shown to produce a clinically significant and reproducible pulmonary contusion. 13–15 …”

“…Clonidine and propranolol doses were 75 μg/kg and 10 mg/kg, respectively, based on previous work demonstrating the safety and efficacy of these doses in reducing heart rate by 10–20% without causing significant hypotension. 13, 16 Propranolol and clonidine were administered once daily rather than more frequent dosing because the goal was to attenuate the neuroendocrine stress response following injury and daily restraint stress rather than to maintain a steady state of pharmacotherapy. Because norepinephrine has a short half-life, a single dose of propranolol or clonidine following resuscitation from hemorrhagic shock or cessation of restraint stress was given.…”