The Role of Substance P in Pulmonary Clearance of Bacteria in Comparative Injury Models

Abstract

Neural input to the immune system can alter its ability to clear pathogens effectively. Patients suffering mild traumatic brain injury (mTBI) have shown reduced rates of pneumonia and a murine model replicated these findings, with better overall survival of TBI mice compared with sham-injured mice. To further investigate the mechanism of improved host response in TBI mice, this study developed and characterized a mild tail trauma model of similar severity to mild TBI. Both mild tail trauma and TBI induced similar systemic changes that normalized within 48 hours, including release of substance P. Examination of tissues showed that injuries are limited to the target tissue (ie, tail in tail trauma, brain in mTBI). Pneumonia challenge showed that mild TBI mice showed improved immune responses, characterized by the following: i) increased survival, ii) increased pulmonary neutrophil recruitment, iii) increased bacterial clearance, and iv) increased phagocytic cell killing of bacteria compared with tail trauma. Administration of a neurokinin-1ereceptor antagonist to block substance P signaling eliminated the improved survival of mTBI mice. Neurokinin-1ereceptor antagonism did not alter pneumonia mortality in tail trauma mice. These data show that immune benefits of trauma are specific to mTBI and that tail trauma is an appropriate control for future studies aimed at elucidating the mechanisms of improved innate immune responses in mTBI mice. Neural input exerts significant control on the ability of the immune system to clear pathogens effectively. Early studies have shown that stress has a profound detrimental effect on the immune response. 1 Psychologic or physiologic stress can result in dysregulation of these pathways, such as chronic activation, which ultimately leads to immunosuppression. 2 Activation of the vagus nerve also has been shown to induce powerful anti-inflammatory effects through the a7 nicotinic acetylcholine receptor. In severe traumatic brain injury (TBI) patients, it has been proposed that hyperactivity of the vagus depresses immune responses through strong dampening of proinflammatory mediator production. 3 In contrast to these studies showing that the neuroimmune axis decreases immune responses, our previous work documented that head trauma patients showed significantly reduced rates of pneumonia compared with blunt trauma patients. 4 A murine model of mild traumatic brain injury (mTBI) was able to reproduce these findings with enhanced resistance to bacterial pneumonia compared with sham injury mice. 4 mTBI mice showed improved survival, augmented pulmonary neutrophil recruitment, and reduced bacterial burdens compared with sham-injured mice. These findings show that neuroimmune modulation can show beneficial effects by improving immune function. Further investigation into the mechanisms by which mTBI augments the innate immune response could offer valuable insight into fighting infections in today's increasingly

Mild Traumatic Brain Injury in Mice Beneficially Alters Lung NK1R and Structural Protein Expression to Enhance Survival after Pseudomonas aeruginosa Infection

“…mTBI was performed as previously described. 8,9 Under isoflurane anesthesia, mice were placed prone on an acrylic bed with their head resting on a foam pad under a 170-g steel rod encased in a guide tube. The rod is dropped from 5.2 cm above the skull to impact a point in the midline of the skull, producing a 5 kg/cm 2 impact force halfway between the interauricular and interorbital lines.…”

“…The control trauma model, tail trauma (TT), was performed as previously described. 8 TT was induced by placing isofluraneanesthetized mice in a prone position under the weightdrop mTBI apparatus. The 170-g rod was dropped from a height of 8.5 cm on the tail 2 cm from the base.…”

“…7 Although counterintuitive, these prior two-hit injury studies support the authors' laboratory's previous work that mTBI in both patients and a murine model of mTBI reduced mortality rates compared with trauma controls when infected with Psd. 8,9 The mechanisms of the downstream mTBI beneficial effects are still under investigation, although some pathways have been described.…”

“…One beneficial response of mTBI investigated in previous studies 8,9 suggests that substance P (SP) plays an important role in augmenting the immune response after mTBI. SP is an 11eamino acid neuropeptide that acts through the tachykinin neurokinin-1 receptor (NK1R; official name TACR1).…”

“…Shortly after trauma, it appears that the amount of SP released between groups is not the sole factor influencing the augmented immune response of mTBI mice. Although previous work in the authors' laboratory explored the role of SP in this augmented immune response, 8,9 this study aims to identify any beneficial alterations the mTBI may have on the site of infection versus TT at the point immediately prior to the pathogenic insult.…”