title: Mechanical ventilation interacts with endotoxemia to induce extrapulmonary organ dysfunction.
abstract: BACKGROUND
  Multiple organ dysfunction syndrome (MODS) is a common complication of sepsis in mechanically ventilated patients with acute respiratory distress syndrome, but the links between mechanical ventilation and MODS are unclear. Our goal was to determine whether a minimally injurious mechanical ventilation strategy synergizes with low-dose endotoxemia to induce the activation of pro-inflammatory pathways in the lungs and in the systemic circulation, resulting in distal organ dysfunction and/or injury.
  
  
  METHODS
  We administered intraperitoneal Escherichia coli lipopolysaccharide (LPS; 1 microg/g) to C57BL/6 mice, and 14 hours later subjected the mice to 6 hours of mechanical ventilation with tidal volumes of 10 ml/kg (LPS + MV). Comparison groups received ventilation but no LPS (MV), LPS but no ventilation (LPS), or neither LPS nor ventilation (phosphate-buffered saline; PBS).
  
  
  RESULTS
  Myeloperoxidase activity and the concentrations of the chemokines macrophage inflammatory protein-2 (MIP-2) and KC were significantly increased in the lungs of mice in the LPS + MV group, in comparison with mice in the PBS group. Interestingly, permeability changes across the alveolar epithelium and histological changes suggestive of lung injury were minimal in mice in the LPS + MV group. However, despite the minimal lung injury, the combination of mechanical ventilation and LPS resulted in chemical and histological evidence of liver and kidney injury, and this was associated with increases in the plasma concentrations of KC, MIP-2, IL-6, and TNF-alpha.
  
  
  CONCLUSIONS
  Non-injurious mechanical ventilation strategies interact with endotoxemia in mice to enhance pro-inflammatory mechanisms in the lungs and promote extra-pulmonary end-organ injury, even in the absence of demonstrable acute lung injury.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA. oshane@u.washington.edu
authors.forename: D Shane
authors.initials: DS
authors.lastname: O'Mahony
authors.forename: W Conrad
authors.initials: WC
authors.lastname: Liles
authors.forename: William A
authors.initials: WA
authors.lastname: Altemeier
authors.forename: Shireesha
authors.initials: S
authors.lastname: Dhanireddy
authors.forename: Charles W
authors.initials: CW
authors.lastname: Frevert
authors.forename: Denny
authors.initials: D
authors.lastname: Liggitt
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Martin
authors.forename: Gustavo
authors.initials: G
authors.lastname: Matute-Bello
mesh_terms: D000818:Animals; D019446:Endotoxemia / Q000150:complications / Q000503:physiopathology* / Q000628:therapy*; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009102:Multiple Organ Failure / Q000209:etiology* / Q000503:physiopathology*; D012121:Respiration, Artificial / Q000009:adverse effects*
chemical_list: D008070:Lipopolysaccharides