Substance P Mediates Reduced Pneumonia Rates After Traumatic Brain Injury

Abstract

Objectives Traumatic brain injury results in significant morbidity and mortality and is associated with infectious complications, particularly pneumonia. However, whether traumatic brain injury directly impacts the host response to pneumonia is unknown. The objective of this study was to determine the nature of the relationship between traumatic brain injury and the prevalence of pneumonia in trauma patients and investigate the mechanism of this relationship using a murine model of traumatic brain injury with pneumonia. Design Data from the National Trauma Data Bank and a murine model of traumatic brain injury with postinjury pneumonia. Setting Academic medical centers in Cincinnati, OH, and Boston, MA. Patients/Subjects Trauma patients in the National Trauma Data Bank with a hospital length of stay greater than 2 days, age of at least 18 years at admission, and a blunt mechanism of injury. Subjects were female ICR mice 8–10 weeks old. Interventions Administration of a substance P receptor antagonist in mice. Measurements and Main Results Pneumonia rates were measured in trauma patients before and after risk adjustment using propensity scoring. In addition, survival and pulmonary inflammation were measured in mice undergoing traumatic brain injury with or without pneumonia. After risk adjustment, we found that traumatic brain injury patients had significantly lower rates of pneumonia compared to blunt trauma patients without traumatic brain injury. A murine model of traumatic brain injury reproduced these clinical findings with mice subjected to traumatic brain injury demonstrating increased bacterial clearance and survival after induction of pneumonia. To determine the mechanisms responsible for this improvement, the substance P receptor was blocked in mice after traumatic brain injury. This treatment abrogated the traumatic brain injury–associated increases in bacterial clearance and survival. Conclusions The data demonstrate that patients with traumatic brain injury have lower rates of pneumonia compared to non–head-injured trauma patients and suggest that the mechanism of this effect occurs through traumatic brain injury–induced release of substance P, which improves innate immunity to decrease pneumonia.

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

“…The current study also showed that specific blockade of substance P (SP) signaling decreased survival to a pulmonary pathogen only in mTBI mice, confirming the mechanism of the improved survival. 4 The significance of this work is highlighted further by a 2015 report showing that TBI patients had increased levels of SP. 8 The mechanism of improved survival occurs through enhanced phagocytic cell clearance of bacteria.…”

“…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.…”

“…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.…”

“…4 To address this issue, a model of peripheral injury was needed for comparison. In our previous clinical study, blunt nonehead trauma patients were used as controls, but our murine studies used shaminjured mice.…”

“…In our previous clinical study, blunt nonehead trauma patients were used as controls, but our murine studies used shaminjured mice. 4 Traumatic injury models have been shown to have drastic effects on immunity. For example, a pulmonary contusion model showed enhanced neutrophil recruitment and expression of inflammatory mediators in response to an intratracheal lipopolysaccharide challenge.…”