title: Induction of cellular antioxidant defense by amifostine improves ventilator-induced lung injury.
abstract: OBJECTIVE
  To test the hypothesis that preconditioning animals with amifostine improves ventilator-induced lung injury via induction of antioxidant defense enzymes. Mechanical ventilation at high tidal volume induces reactive oxygen species production and oxidative stress in the lung, which plays a major role in the pathogenesis of ventilator-induced lung injury. Amifostine attenuates oxidative stress and improves lipopolysaccharide-induced lung injury by acting as a direct scavenger of reactive oxygen and nitrogen species. This study tested effects of chronic amifostine administration on parameters of oxidative stress, lung barrier function, and inflammation associated with ventilator-induced lung injury.
  
  
  METHODS
  Randomized and controlled laboratory investigation in mice and cell culture.
  
  
  METHODS
  University laboratory.
  
  
  METHODS
  C57BL/6J mice.
  
  
  METHODS
  Mice received once-daily dosing with amifostine (10-100 mg/kg, intraperitoneal injection) 3 days consecutively before high tidal volume ventilation (30 mL/kg, 4 hrs) at day 4. Pulmonary endothelial cell cultures were exposed to pathologic cyclic stretching (18% equibiaxial stretch) and thrombin in a previously verified two-hit model of in vitro ventilator-induced lung injury.
  
  
  RESULTS
  Three-day amifostine preconditioning before high tidal volume attenuated high tidal volume-induced protein and cell accumulation in the alveolar space judged by bronchoalveolar lavage fluid analysis, decreased Evans Blue dye extravasation into the lung parenchyma, decreased biochemical parameters of high tidal volume-induced tissue oxidative stress, and inhibited high tidal volume-induced activation of redox-sensitive stress kinases and nuclear factor-kappa B inflammatory cascade. These protective effects of amifostine were associated with increased superoxide dismutase 2 expression and increased superoxide dismutase and catalase enzymatic activities in the animal and endothelial cell culture models of ventilator-induced lung injury.
  
  
  CONCLUSIONS
  Amifostine preconditioning activates lung tissue antioxidant cell defense mechanisms and may be a promising strategy for alleviation of ventilator-induced lung injury in critically ill patients subjected to extended mechanical ventilation.
authors.affiliation: Section of Pulmonary and Critical Care, Lung Injury Center, Department of Medicine, University of Chicago, IL, USA.
authors.forename: Panfeng
authors.initials: P
authors.lastname: Fu
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Murley
authors.forename: David J
authors.initials: DJ
authors.lastname: Grdina
authors.forename: Anna A
authors.initials: AA
authors.lastname: Birukova
authors.forename: Konstantin G
authors.initials: KG
authors.lastname: Birukov
mesh_terms: D004999:Amifostine / Q000627:therapeutic use*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002478:Cells, Cultured; D004727:Endothelium / Q000187:drug effects / Q000378:metabolism; D016166:Free Radical Scavengers / Q000627:therapeutic use*; D007249:Inflammation / Q000188:drug therapy; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D055397:Ventilator-Induced Lung Injury / Q000188:drug therapy*
chemical_list: D000975:Antioxidants; D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D004999:Amifostine