(1599) GM-CSF Attenuates TBI-Induced Immune Suppression and Lung Infection in a Post-Injury Pneumonia Model

Introduction: Traumatic brain injury (TBI) can be associated with infection, such as hospital acquired pneumonia. Post-TBI infection can lead to increased morbidity and mortality. To reverse these findings we have proposed the use of the cytokine granulocyte macrophage colony-stimulating factor (GM-CSF).

Methods: Prepubescent (28 day old) rats were injured with a moderately severe controlled cortical impact model and then had 25% blood volume removed by femoral vein cannulation. Following injury, animals were treated with either vehicle or 50 μg/kg GM-CSF daily for 2 days. Blood samples were obtained pre-injury and at post-injury days 1 and 2. Immune function (ex vivo cytokine response to immunostimulant) was assessed in blood samples. To simulate hospital acquired pneumonia, we performed intra-nasal inoculation of Streptococcus pneumoniae, and bacterial clearance was examined by plating lung tissue. Spatial memory was tested using a Barnes maze. To determine whether GM-CSF treatment induced neuroinflammation, we assessed brain tissue using immunohistochemistry (to identify microglia), histology (to assess neuronal count), and multiplex ELISA (to determine cytokine levels).

Results: Injury induced a 50% reduction in response to immunostimulation, which was reversed in animals treated with GM-CSF (p=0.005). While sham injured animals were able to largely clear bacterial infection of the lung, injured animals had a 6 fold increase in colony forming units, as compared with sham (p < 0.001), and this effect was reduced by 40% with GM-CSF treatment (p=0.003). Injured animals treated with vehicle showed 50% worse results on Barnes maze testing (p=0.003), and injured rats treated with GM-CSF demonstrated no difference from sham. As compared with injured animals treated with saline, brains from injured animals treated with GM-CSF showed no evidence of increased loss of neurons, increases in numbers of microglia, or increased cytokine response.

Conclusions: These data add to a growing body of literature suggesting that severe trauma can lead to clinically relevant immunosuppression. Our findings further suggest that GM-CSF may reverse these findings without increased neuro-inflammation.