title: Role of activated neutrophils in chest trauma-induced septic acute lung injury.
abstract: More than 50% of severely injured patients have chest trauma. Second insults frequently result in acute lung injury (ALI), with sepsis being the main underlying condition. We aimed to develop a standardized, reproducible, and clinically relevant double-hit mouse model of ALI induced by chest trauma and polymicrobial sepsis and to investigate the pathophysiologic role of activated neutrophils. Lung contusion was applied to C57Bl/6 mice via a focused blast wave. Twenty-four hours later, sepsis was induced by cecal ligation and puncture. For polymorphonuclear leukocyte (PMN) depletion, animals received intravenous injections of PMN-depleting antibody. In response to blunt chest trauma followed by sepsis as well as after sepsis alone, a significant local and systemic inflammatory response with increased cytokine/chemokine levels in lung and plasma was observed. In contrast, lung apoptosis was markedly elevated only after a double hit. Intra-alveolar neutrophils and total bronchoalveolar lavage protein concentrations were markedly increased following isolated chest trauma or the combined insult, but not after sepsis alone. Lung myeloperoxidase activity was enhanced only in response to the double hit accompanied by histological disruption of the alveolar architecture, lung congestion, and marked cellular infiltrates. Neutrophil depletion significantly diminished lung interleukin 1β and interleukin 6 concentrations and reduced the degree of septic ALI. Here we have established a novel and highly reproducible mouse model of chest trauma-induced septic ALI characterizing a clinical relevant double-hit scenario. In particular, the depletion of neutrophils substantially mitigated the extent of lung injury, indicating a pathomechanistic role for neutrophils in chest trauma-induced septic ALI.
authors.affiliation: Department of Trauma, Hand, Plastic, and Reconstructive Surgery, University of Ulm, Ulm, Germany. mario.perl@uniklinik-ulm.de
authors.forename: Mario
authors.initials: M
authors.lastname: Perl
authors.forename: Christoph
authors.initials: C
authors.lastname: Hohmann
authors.forename: Stephanie
authors.initials: S
authors.lastname: Denk
authors.forename: Philipp
authors.initials: P
authors.lastname: Kellermann
authors.forename: Dapeng
authors.initials: D
authors.lastname: Lu
authors.forename: Sonja
authors.initials: S
authors.lastname: Braumüller
authors.forename: Max G
authors.initials: MG
authors.lastname: Bachem
authors.forename: Jörg
authors.initials: J
authors.lastname: Thomas
authors.forename: Markus W
authors.initials: MW
authors.lastname: Knöferl
authors.forename: Alfred
authors.initials: A
authors.lastname: Ayala
authors.forename: Florian
authors.initials: F
authors.lastname: Gebhard
authors.forename: Markus S
authors.initials: MS
authors.lastname: Huber-Lang
mesh_terms: D055371:Acute Lung Injury / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002245:Carbon Dioxide / Q000097:blood; D020169:Caspases / Q000378:metabolism; D018925:Chemokines / Q000097:blood; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D008168:Lung / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018375:Neutrophil Activation / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology*; D010100:Oxygen / Q000097:blood; D010313:Partial Pressure; D018805:Sepsis / Q000150:complications* / Q000276:immunology; D018746:Systemic Inflammatory Response Syndrome / Q000209:etiology / Q000276:immunology; D013898:Thoracic Injuries / Q000150:complications*; D014949:Wounds, Nonpenetrating / Q000150:complications; D019014:fas Receptor / Q000097:blood
chemical_list: D018925:Chemokines; D016207:Cytokines; D019014:fas Receptor; D002245:Carbon Dioxide; D020169:Caspases; D010100:Oxygen