INDUCTION OF NITRIC-OXIDE SYNTHASE BY LIPOPOLYSACCHARIDE INHALATION ENHANCES SUBSTANCE-P-INDUCED MICROVASCULAR LEAKAGE IN GUINEA-PIGS

Inducible nitric oxide (NO) synthase (iNOS)-mediated hyperproduction o f NO in airways has been reported in asthmatic patients. However, the role of NO in the pathogenesis of asthma has not yet been fully elucid ated, The aim of this study was to examine whether the iNOS-derived NO affects airway microvascular leakage, one of the characteristic featu res of asthmatic airway inflammation. Guinea-pigs were exposed to lipo polysaccharide (LPS) (1 mg.mL(-1)) by inhalation in order to induce iN OS in the airways, and the histochemical staining of reduced nicotinam ide-adenine dinucleotide phosphate (NADPH)-diaphorase activity was det ermined 5 h after the inhalation to confirm the iNOS induction. Airway microvascular leakage to subthreshold doses of substance P (0.3 mu g. kg(-1), i.v.) was also examined in the absence and presence of an iNOS inhibitor (aminoguanidine) in LPS- or saline-exposed (control) animal s using Evans blue dye and Monastral blue dye. In the LPS-exposed anim als, increased NADPH-diaphorase activity was observed in the airway mi crovasculature compared with the control animals, Substance P caused s ignificant airway microvascular leakage assessed by Evans blue dye in all airway levels in the LPS exposed animals but not in the control gr oup. This was also confirmed by Monastral blue dye extravasation, Amin oguanidine abolished this LPS-induced enhancement of plasma leakage to substance P without changing-the systemic blood pressure. These resul ts may suggest that inducible nitric oxide synthase-derived nitric oxi de is capable of potentiating neurogenic plasma leakage in airways.