J Jason Hoth1, Jonathan D Wells, Sarah E Jones, Barbara K Yoza, Charles E McCall. 1. 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.
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. CONCLUSION: 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.
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-deficientmice showed a similar loss of primed response to LPS challenge. CONCLUSION: 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: Umme Amara; Michael A Flierl; Daniel Rittirsch; Andreas Klos; Hui Chen; Barbara Acker; Uwe B Brückner; Bo Nilsson; Florian Gebhard; John D Lambris; Markus Huber-Lang Journal: J Immunol Date: 2010-09-24 Impact factor: 5.422
Authors: Min Wang; Jennifer L Krauss; Hisanori Domon; Kavita B Hosur; Shuang Liang; Paola Magotti; Martha Triantafilou; Kathy Triantafilou; John D Lambris; George Hajishengallis Journal: Sci Signal Date: 2010-02-16 Impact factor: 8.192
Authors: J Jason Hoth; Jonathan D Wells; Noel A Brownlee; Elizabeth M Hiltbold; J Wayne Meredith; Charles E McCall; Barbara K Yoza Journal: Shock Date: 2009-04 Impact factor: 3.454
Authors: Lane M Smith; Jonathan D Wells; Vidula T Vachharajani; Barbara K Yoza; Charles E McCall; J Jason Hoth Journal: J Trauma Acute Care Surg Date: 2015-05 Impact factor: 3.313
Authors: Devin Cao; Michael G Strainic; Daniel Counihan; Shiva Sridar; Fengqi An; Wasim Hussain; Alvin H Schmaier; Marvin Nieman; M Edward Medof Journal: Am J Pathol Date: 2022-02 Impact factor: 4.307
Authors: Miriam Kalbitz; Michael Karbach; Sonja Braumueller; Philipp Kellermann; Florian Gebhard; Markus Huber-Lang; Mario Perl Journal: PLoS One Date: 2016-07-20 Impact factor: 3.240
Authors: Markus Huber-Lang; Kristina N Ekdahl; Rebecca Wiegner; Karin Fromell; Bo Nilsson Journal: Semin Immunopathol Date: 2017-09-12 Impact factor: 9.623
Authors: Jonathan H Foley; Bethany L Walton; Maria M Aleman; Alice M O'Byrne; Victor Lei; Micaela Harrasser; Kimberley A Foley; Alisa S Wolberg; Edward M Conway Journal: EBioMedicine Date: 2016-02-06 Impact factor: 8.143