title: Radical scavengers protect murine lungs from endotoxin-induced hyporesponsiveness to inhaled nitric oxide.
abstract: BACKGROUND
  Sepsis is associated with an impaired pulmonary vasodilator response to inhaled nitric oxide (NO). A combination of NO and other inflammatory mediators appears to be responsible for endotoxin-induced pulmonary vascular hyporesponsiveness to inhaled NO. The authors investigated whether scavengers of reactive oxygen species could preserve inhaled NO responsiveness in endotoxin-challenged mice.
  
  
  METHODS
  The vasorelaxation to inhaled NO was studied in isolated, perfused, and ventilated lungs obtained from mice 16 h after an intraperitoneal challenge with saline or 50 mg/kg Escherichia coli lipopolysaccharide. In some mice, challenge with saline or lipopolysaccharide was followed by intraperitoneal administration of N-acetylcysteine, dimethylthiourea, EUK-8, or polyethylene glycol-conjugated catalase.
  
  
  RESULTS
  The pulmonary vasodilator response of U46619-preconstricted isolated lungs to ventilation with 0.4, 4, and 40 ppm inhaled NO in lipopolysaccharide-challenged mice was reduced to 32, 43, and 60%, respectively, of that observed in saline-challenged mice (P < 0.0001). Responsiveness to inhaled NO was partially preserved in lipopolysaccharide-challenged mice treated with a single dose of N-acetylcysteine (150 or 500 mg/kg) or 20 U/g polyethylene glycol-conjugated catalase (all P < 0.05 vs. lipopolysaccharide alone). Responsiveness to inhaled NO was fully preserved by treatment with either dimethylthiourea, EUK-8, two doses of N-acetylcysteine (150 mg/kg administered 3.5 h apart), or 100 U/g polyethylene glycol-conjugated catalase (all P < 0.01 vs. lipopolysaccharide alone).
  
  
  CONCLUSIONS
  When administered to mice concurrently with lipopolysaccharide challenge, reactive oxygen species scavengers prevent impairment of pulmonary vasodilation to inhaled NO. Therapy with scavengers of reactive oxygen species may provide a means to preserve pulmonary vasodilation to inhaled NO in sepsis-associated acute lung injury.
authors.affiliation: Department of Anesthesia, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Yehuda
authors.initials: Y
authors.lastname: Raveh
authors.forename: Fumito
authors.initials: F
authors.lastname: Ichinose
authors.forename: Pini
authors.initials: P
authors.lastname: Orbach
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Bloch
authors.forename: Warren M
authors.initials: WM
authors.lastname: Zapol
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000280:Administration, Inhalation; D000818:Animals; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008168:Lung / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000008:administration & dosage / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000032:analysis; D014664:Vasodilation / Q000187:drug effects
chemical_list: D016166:Free Radical Scavengers; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D000111:Acetylcysteine