title: The volatile anesthetic isoflurane prevents ventilator-induced lung injury via phosphoinositide 3-kinase/Akt signaling in mice.
abstract: BACKGROUND
  Mechanical ventilation leads to ventilator-induced lung injury in animals, and can contribute to acute lung injury/acute respiratory distress syndrome in humans. Acute lung injury/acute respiratory distress syndrome currently causes an unacceptably high rate of morbidity and mortality among critically ill patients. Volatile anesthetics have been shown to exert anti-inflammatory and organ-protective effects in vivo. We investigated the effects of the volatile anesthetic isoflurane on lung injury during mechanical ventilation.
  
  
  METHODS
  C57BL/6N mice were ventilated with a tidal volume of 12 mL/kg body weight for 6 hours in the absence or presence of isoflurane, and, in a second series, with or without the specific phosphoinositide 3-kinase/Akt inhibitor LY294002. Lung injury was determined by comparative histology, and by the isolation of bronchoalveolar lavage for differential cell counting and analysis of cytokine levels using enzyme-linked immunosorbent assays. Lung homogenates were analyzed for protein expression by Western blotting.
  
  
  RESULTS
  Mechanical ventilation caused increases in alveolar wall thickening, cellular infiltration, and an elevated ventilator-induced lung injury score. Neutrophil influx and cytokine (i.e., interleukin-1β, and macrophage inflammatory protein-2) release were enhanced in the bronchoalveolar lavage of ventilated mice. The expression levels of the stress proteins hemeoxygenase-1 and heat shock protein-70 were elevated in lung tissue homogenates. Isoflurane ventilation significantly reduced lung damage, inflammation, and stress protein expression. In contrast, phosphorylation of Akt protein was substantially increased during mechanical ventilation with isoflurane. Inhibition of phosphoinositide 3-kinase/Akt signaling before mechanical ventilation completely reversed the lung-protective effects of isoflurane treatment in vivo.
  
  
  CONCLUSIONS
  Inhalation of isoflurane during mechanical ventilation protects against lung injury by preventing proinflammatory responses. This protection is mediated via phosphoinositide 3-kinase/Akt signaling.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, University Medical Center Freiburg, Hugstetter Str. 55, D-79106 Freiburg, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Faller
authors.forename: Karl M
authors.initials: KM
authors.lastname: Strosing
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Ryter
authors.forename: Hartmut
authors.initials: H
authors.lastname: Buerkle
authors.forename: Torsten
authors.initials: T
authors.lastname: Loop
authors.forename: Rene
authors.initials: R
authors.lastname: Schmidt
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoetzel
mesh_terms: D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D018840:HSP70 Heat-Shock Proteins / Q000032:analysis; D051547:Heme Oxygenase-1 / Q000032:analysis; D007530:Isoflurane / Q000494:pharmacology*; D054086:KATP Channels / Q000502:physiology; D007649:Ketamine / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D012121:Respiration, Artificial; D015398:Signal Transduction / Q000502:physiology*; D055397:Ventilator-Induced Lung Injury / Q000517:prevention & control*
chemical_list: D018685:Anesthetics, Inhalation; D018840:HSP70 Heat-Shock Proteins; D054086:KATP Channels; D007649:Ketamine; D007530:Isoflurane; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt