Background Bone marrow (BM) dysfunction is common in severely injured trauma patients with release of hematopoietic progenitor cells (HPC) into the peripheral blood. Granulocyte colony stimulating factor (G-CSF) is a potent stimulator of HPC mobilization. We hypothesized that plasma G-CSF levels are elevated following trauma and correlate with post-injury anemia and infection Study Design Blood from 83 severely injured patients was collected at several time points for determination of G-CSF levels and HPC mobilization and compared to healthy volunteers. Data were categorized by age, gender, Injury Severity Score (ISS), and whether patient was in shock. Hemoglobin and transfusion requirements as well as hospital acquired infection data was recorded. Data are expressed as mean ± SEM. Results After trauma, there is a 50-fold increase in plasma levels of G-CSF in trauma patients compared to controls (1640.4±304.3 vs. 33.0±6.8, p<0.001). Patients who presented in shock had 5 time higher G-CSF levels than non-shock trauma patients and 75-fold increase compared to control (2528.7±536.4 vs. 728.0±191.0 vs. 33.0±6.8, p<0.001). Age, gender and ISS had no effect on G-CSF levels. HPC mobilization was sustained for up to 10 days following injury and involved multiple cells types. Higher G-CSF levels were is also associated with lower hemoglobin levels and greater transfusion requirements 3 weeks after injury and a higher incidence of hospital acquired pneumonia and bacteremia. Conclusions Plasma G-CSF is markedly elevated after injury and is greater in patients who present in shock. The rise in C-CSF was also associated with prolonged mobilization of HPC. Elevation of G-CSF in humans following severe trauma may play a significant role in the development of post traumatic BM dysfunction, anemia and infection.

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.

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.

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