The role of C5a in the innate immune response after experimental blunt chest trauma

The inflammatory response after severe blunt chest trauma often leads to acute lung injury and acute respiratory distress syndrome which are associated with high mortality rates. Whereas the role of innate immunity in acute lung injury has been broadly investigated, the immune response after blunt chest trauma is still poorly understood. Therefore, the role of complement and neutrophils was determined in bilateral lung injury induced by a single blast wave. The following time-points were investigated posttrauma: sham, 1, 6, 12, and 24 h. There was a time-dependent systemic activation of complement as determined by CH-50 and presence of C5a-dependent chemotactic plasma activity. Moreover, factor H, a complement regulatory protein, was increased systemically and locally after injury. Anti-C5a treatment immediately after trauma ameliorated these peaks. After an initial systemic leukopenic phase, a marked leukocytosis occurred. The latter was normalized by C5a blockade. In parallel, white blood cell count in bronchioalveolar lavage fluids was increased as a function of time and was significantly decreased by anti-C5a treatment. Trauma-induced lung injury was also associated with dramatic changes in neutrophil function, namely early enhanced chemotaxis and phagocytosis, followed by prolonged functional defects-all of which were ameliorated by anti-C5a treatment. Furthermore, blockade of C5a ameliorated the buildup of the proinflammatory cytokine TNF-alpha, diminished the increase of cytokine-induced neutrophil chemoattractant 1, and altered the levels of the anti-inflammatory cytokine IL-10. These data suggest that blunt chest trauma leads to systemic activation of complement and robust C5a generation, which causes perturbations in defensive functions of neutrophils. Thus, C5a might represent a potential target for therapeutic immunomodulation to prevent immune dysfunctions post-trauma and thereby, perhaps, the progression to acute respiratory distress syndrome.