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.