title: Apoptotic and inflammatory signaling via Fas and tumor necrosis factor receptor I contribute to the development of chest trauma-induced septic acute lung injury.
abstract: BACKGROUND
  Direct acute lung injury (ALI) is still associated with a high mortality, whereas the underlying pathomechanisms are not yet fully understood. In this regard, epithelial cell death in the lungs has been attributed an important role in the pathogenesis of this clinical entity. Based on this background here, we hypothesized that signaling through Fas and tumor necrosis factor receptor 1 (TNFR-1) is involved in mediating apoptosis and inflammation in chest trauma induced septic ALI.
  
  
  METHODS
  Male C57BL/6 mice (wild-type [WT]), male mutant mice expressing nonfunctional Fas receptor (B6.MRL-Faslpr/J [lpr]) (lpr) and male TNFR-1-deficient mice (TNFR-1(-/-)) were subjected to a model of direct ALI consisting of blunt chest trauma followed by cecal ligation and puncture.Cytokine/chemokine concentrations of plasma, bronchoalveolar lavage (BAL) fluids, and lung tissue were investigated as well as BAL protein and lung myeloperoxidase. Lung histology was assessed; lung caspase 3, TUNEL-positive cells, and apoptotic polymorphonuclear neutrophil were measured, followed by a survival study.
  
  
  RESULTS
  Cytokine/chemokine levels in plasma, BAL, and lung tissue were markedly increased in WT animals following ALI, whereas lpr and TNFR-1((-/-) showed significantly decreased levels. BAL protein levels were substantially elevated following ALI, but lpr animals presented markedly diminished protein levels compared with WT and TNFR-1(-/-) animals. Lung myeloperoxidase level was only increased 12 hours after ALI in WT animals, whereas lung myeloperoxidase levels in lpr and TNFR-1(-/-) animals were not increased compared with sham. Lung histology revealed beneficial effects in lpr and TNFR-1(-/-). Lung active caspase 3 after ALI was substantially decreased in lpr and TNFR-1(-/-) mice compared with WT. Interestingly, an early but not persisting survival benefit was observed in lpr and TNFR-1 animals(-/-).
  
  
  CONCLUSIONS
  Pathomechanistically, Fas and TNFR-1 signaling contributed to the apoptotic and inflammatory response in a clinically relevant double-hit model of trauma-induced septic ALI. Moreover, this was associated with a temporary survival benefit.
authors: Department of Trauma, University of Ulm, Ulm, Germany.
authors: Sebastian
authors: S
authors: Weckbach
authors: Christoph
authors: C
authors: Hohmann
authors: Stephanie
authors: S
authors: Denk
authors: Philipp
authors: P
authors: Kellermann
authors: Markus S
authors: MS
authors: Huber-Lang
authors: Bernd
authors: B
authors: Baumann
authors: Thomas
authors: T
authors: Wirth
authors: Florian
authors: F
authors: Gebhard
authors: Max
authors: M
authors: Bachem
authors: Mario
authors: M
authors: Perl
mesh_terms: D055371:Acute Lung Injury / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*; D018805:Sepsis / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D013898:Thoracic Injuries / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D019014:fas Receptor / Q000378:metabolism*
chemical_list: C491899:Fas protein, mouse; D047888:Receptors, Tumor Necrosis Factor, Type I; D019014:fas Receptor