Role of p38 mitogen-activated protein kinase in posttraumatic immunosuppression in mice

BACKGROUND: Patients with multiple injuries surviving the initial insult are highly susceptible to secondary pneumonia, frequently progressing into sepsis and multiorgan failure. However, the underlying mechanisms of posttraumatic immunosuppression are poorly understood. We hypothesized that dysregulated p38 mitogen-activated protein kinase (MAPK) signaling accounts for impaired lung protective immunity in a model of trauma/hemorrhage (T/H) and subsequent pneumococcal pneumonia in mice. METHODS: C57BL6/N mice were subjected to trauma by midline laparotomy, and T/H was induced by midline laparotomy followed by cannulation of femoral arteries and veins to induce hemorrhage. Subsequently, mice were infected with Streptococcus pneumoniae. In selected experiments, mice were treated with a p38 MAPK inhibitor or vehicle control immediately after induction of T/H. RESULTS: Mice subjected to T/H showed significantly increased p38 MAPK activation in their lungs, which was accompanied by a reduced Escherichia coli phagocytosis by macrophages from T/H mice in vitro and an impaired pneumococcal killing activity of T/H mice in vivo, overall resulting in increased mortality of T/H mice after infection with S. pneumoniae. Application of p38 MAPK inhibitor BIRB796 immediately after T/H induction improved the bacterial phagocytosis activity of macrophages from T/H mice in vitro and lung pneumococcal killing in vivo but did not improve the survival of T/H mice challenged with S. pneumoniae. CONCLUSION: T/H triggers sustained p38 MAPK activation in the lungs of mice, which attenuates lung macrophage antibacterial activities and renders mice more susceptible to pneumococcal pneumonia. However, no major role for dysregulated p38 MAPK to affect survival of T/H mice after pneumococcal challenge was detected, suggesting that dysregulated p38 MAPK activity may possibly play only a limited role in posttraumatic immunosuppression in mice. (J Trauma Acute Care Surg. 2012;73:861-868. Copyright (C) 2012 by Lippincott Williams & Wilkins)