We previously published an unexpected finding that mild traumatic brain injury (mTBI) in experimental animals enhances pulmonary defenses against bacterial pneumonia. This finding was validated in patients with mild brain injury who had a lower incidence of pneumonia compared to blunt trauma patients. We show that mTBI enhances innate immune responses and blunts deleterious coagulation responses in a mouse pneumonia model. These findings, coupled with substantial new preliminary data, provide the rationale for our hypothesis that the neuroimmune response to mild traumatic brain injury primes the host so that it will survive a subsequent pathogen challenge. New data demonstrate that the neurotransmitter substance P (SP) is released into the murine lung and plasma within minutes of mTBI. Neurokinin 1 (NK1R) is the preferred receptor of SP and NK1R agonists and an FDA approved NK1R antagonist are available. These reagents will allow us to precisely determine the mechanisms of how mTBI signaling through NK1R augments host responses to improve survival. This experimental design increases scientific reproducibility by both augmenting and blocking the same receptor to prove a cause and effect relationship.
Specific aim 1 will determine how SP enhances pulmonary neutrophil recruitment to a pathogen challenge. We will use three distinctly different pathogens, Pseudomonas aeruginosa, Streptococcus pneumoniae, and Candida albicans to identify shared innate immune pathways that foster neutrophil recruitment. Tail trauma will replicate blunt trauma patients and SP function will be manipulated by augmenting or blocking its receptor. The second specific aim will determine the mechanisms of how SP augments phagocytic cell eradication of pathogens from the lung. A novel, recently published flow cytometry assay examines three different phagocytic cell functions simultaneously to provide clear data concerning which function(s) are altered. Inflammation and coagulation are intimately linked, and new data show that mTBI blunts disseminated intravascular coagulation (DIC) during pneumonia by enhancing fibrinolysis.
Aim 3 will determine the protective mechanisms provided by SP. These three aims are inter-related which allows efficient use of resources. For example, after trauma and pathogen challenge we can determine in a single mouse how NK1R activation alters neutrophil recruitment, neutrophil function and coagulation responses. These studies are innovative since they challenge existing dogma that TBI only increases susceptibility to pathogens and increases DIC. The studies also have clinical relevance since NK1R antagonists are FDA approved to treat nausea in chemotherapy patients, which may increase their risk of infection. Further, NK1R agonists may augment the hosts? ability combat pathogens and would serve as a welcome addition to combat the emergence of antimicrobial resistant pathogens.
We made the surprising finding that people or mice with a mild head injury are protected against pneumonia. The proposed studies will attempt to find the reasons why this protection against bacteria occurs. If we can determine how the host protects itself, we may find a new way to treat people with bacterial infections.
