The immune response to bacterial pneumonia following traumatic brain injury

Abstract

Traumatic brain injury (TBI) is an important clinical problem affecting 1.7 million Americans annually. TBI affects peripheral organs beyond the nervous system with particularly profound effects on the lung, predisposing TBI patients to develop respiratory dysfunction due to bacterial pneumonia. Previous clinical and basic science studies have suggested TBI induces an immune depressed state rendering TBI patients more susceptible to pneumonia. As no mechanism has been proven as a cause for TBI-induced immune modulation we created an animal model of TBI and bacterial pneumonia to investigate the effects of TBI on pulmonary immune function. Our model revealed that instead of increasing susceptibility to bacterial pneumonia, TBI results in a more robust neutrophil recruitment in the lung that allows for faster bacterial clearance and increased survival after bacterial challenge. This response is paradoxically accomplished with significant decreases in pro-inflammatory cytokine production. An important neural mediator of pulmonary inflammation is substance P which acts through the neurokinin-1 receptor (NK-1R) to recruit neutrophils to the lung and increase pulmonary vascular permeability. Treatment with an NK-1R antagonist abolished the increased bacterial killing and recruitment in TBI mice but treatment of sham injury animals with an NK-1R agonist increased their lung neutrophil recruitment and bacterial killing. These findings point to an important role of substance P after TBI and in the immune response to pneumonia. We complemented the findings in our animal model with patient data from the National Trauma Database comparing the incidence of pneumonia among TBI and non-neurotrauma patients. After matching patients by demographics, vital signs, hospital, and importantly injury severity score, we found TBI patients had a decreased incidence of pneumonia. This finding is contrary to the findings of previously published studies that did not account for the confounding factor of injury severity. Our studies offer a new perspective on immune function after TBI and possibly a new therapeutic approach to pneumonia in TBI and non-TBI patients alike.