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Substance P Mediates Reduced Pneumonia Rates After Traumatic Brain Injury

Yang, Sung MD; Stepien, David PhD; Hanseman, Dennis PhD; Robinson, Bryce MD; Goodman, Michael D. MD; Pritts, Timothy A. MD, PhD; Caldwell, Charles C. PhD; Remick, Daniel G. MD; Lentsch, Alex B. PhD

doi: 10.1097/CCM.0000000000000486
Neurologic Critical Care

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.

Supplemental Digital Content is available in the text.

1Institute for Military Medicine, Division of Trauma and Critical Care, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH.

2Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA.

Drs. Yang and Stepien contributed equally to this work.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (

Dr. Stepien received grant and support for article research from the National Institutes of Health (NIH) (NHLBI T32 HL07501). Dr. Pritts provided expert testimony for the Attorney General and State of Ohio (for legal work with Ohio State Attorney General). His institution received grant support from the NIH and the United States Air Force (Research Grants). Dr. Remick received support for article research from the NIH (HL007501, GM82962, and GM97320). His institution received grant support from the NIH. Dr. Lentsch received support for article research from the NIH (GM08478). He received grant support from United States Air Force (FA8650-10-2-6B01). His institution received grant support from the NIH (T32 Training Grant). The remaining authors have disclosed that they do not have any potential conflicts of interest.

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