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: Yehuda Raveh, Fumito Ichinose, Pini Orbach, Kenneth D Bloch, Warren M Zapol
• Journal: Anesthesiology (Anesthesiology) Vol. 96 Issue 4 Pg. 926-33 (Apr 2002) ISSN: 0003-3022 [Print] United States
• PMID: 11964601 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Free Radical Scavengers
• Lipopolysaccharides
• Reactive Oxygen Species
• Nitric Oxide
• 3-nitrotyrosine
• Tyrosine
• Acetylcysteine

Topics

• Acetylcysteine (pharmacology)
• Administration, Inhalation
• Animals
• Female
• Free Radical Scavengers (pharmacology)
• Lipopolysaccharides (toxicity)
• Lung (drug effects, physiology)
• Male
• Mice
• Mice, Inbred C57BL
• Nitric Oxide (administration & dosage, pharmacology)
• Reactive Oxygen Species (metabolism)
• Tyrosine (analogs & derivatives, analysis)
• Vasodilation (drug effects)