title: Complement mediates a primed inflammatory response after traumatic lung injury.
abstract: BACKGROUND
  Pulmonary contusion (PC) is a common, potentially lethal injury that results in the priming for exaggerated responses to subsequent immune challenge such as an infection (second hit). We hypothesize a PC-induced complement (C) activation participates in the priming effect for a second hit.
  
  
  METHODS
  Male, 8 weeks to 9 weeks, C57BL/6 mice (wild-type, C5) underwent blunt chest trauma resulting in PC. At 3 hours/24 hours after injury, the inflammatory response was measured in tissue, serum, and bronchoalveolar lavage (BAL). The thrombin inhibitor, hirudin, was used to determine if injury-induced thrombin participated in the activation of C. Injury-primed responses were tested by challenging injured mice with bacterial endotoxin (lipopolysaccharide, LPS) as a second hit. Inflammatory responses were assessed at 4 hours after LPS challenge. Data were analyzed using one-way analysis of variance with Bonferroni multiple comparison posttest (significance, p ≤ 0.05). Protocols were approved by the Institutional Animal Care and Use Committee.
  
  
  RESULTS
  We found significantly increased levels of C5a in the BAL of injured animals as early as 24 hours, persisting for up to 72 hours after injury. Hirudin-treated injured mice had significantly decreased levels of thrombin in the BAL that correlated with reduced C5a levels. Injured mice challenged with intratracheal (IT) LPS had increased C5a and inflammatory response. Conversely, inhibition of C5a or its receptor, C5aR, before LPS challenge correlated with decreased inflammatory responses; C5a-deficient mice showed a similar loss of primed response to LPS challenge.
  
  
  CONCLUSIONS
  Complement C5a levels in the BAL are increased over several days after PC. Premorbid inhibition of thrombin markedly decreases C5a levels after PC, suggesting that thrombin-induced C activation is the major pathway of activation after PC. Similarly, inhibition of C5a after PC will decrease injury-primed responses to LPS stimulation. Our findings suggest cross-talk between the coagulation and complement systems that induce immune priming after PC.
authors.affiliation: From the Department of General Surgery (J.J.H., J.D.W., B.K.Y.), and Section on Molecular Medicine (C.E.M.), Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
authors.forename: J Jason
authors.initials: JJ
authors.lastname: Hoth
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Wells
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Jones
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Yoza
authors.forename: Charles E
authors.initials: CE
authors.lastname: McCall
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D003167:Complement Activation / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D015936:Complement C5a / Q000032:analysis; D003288:Contusions / Q000150:complications* / Q000276:immunology; D006629:Hirudins / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000209:etiology* / Q000276:immunology / Q000503:physiopathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D055370:Lung Injury / Q000150:complications* / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D044087:Receptor, Anaphylatoxin C5a / Q000032:analysis; D013917:Thrombin / Q000032:analysis; D014949:Wounds, Nonpenetrating / Q000150:complications / Q000276:immunology
chemical_list: D006629:Hirudins; D008070:Lipopolysaccharides; D044087:Receptor, Anaphylatoxin C5a; D015936:Complement C5a; D013917:Thrombin