title: Induction of nitric oxide synthase by lipopolysaccharide inhalation enhances substance P-induced microvascular leakage in guinea-pigs.
abstract: Inducible nitric oxide (NO) synthase (iNOS)-mediated hyperproduction of NO in airways has been reported in asthmatic patients. However, the role of NO in the pathogenesis of asthma has not yet been fully elucidated. The aim of this study was to examine whether the iNOS-derived NO affects airway microvascular leakage, one of the characteristic features of asthmatic airway inflammation. Guinea-pigs were exposed to lipopolysaccharide (LPS) (1 mg x mL(-1)) by inhalation in order to induce iNOS in the airways, and the histochemical staining of reduced nicotinamide-adenine dinucleotide phosphate (NADPH)-diaphorase activity was determined 5 h after the inhalation to confirm the iNOS induction. Airway microvascular leakage to subthreshold doses of substance P (0.3 microg x kg(-1), i.v.) was also examined in the absence and presence of an iNOS inhibitor (aminoguanidine) in LPS- or saline-exposed (control) animals using Evans blue dye and Monastral blue dye. In the LPS-exposed animals, increased NADPH-diaphorase activity was observed in the airway microvasculature compared with the control animals. Substance P caused significant airway microvascular leakage assessed by Evans blue dye in all airway levels in the LPS-exposed animals but not in the control group. This was also confirmed by Monastral blue dye extravasation. Aminoguanidine abolished this LPS-induced enhancement of plasma leakage to substance P without changing the systemic blood pressure. These results may suggest that inducible nitric oxide synthase-derived nitric oxide is capable of potentiating neurogenic plasma leakage in airways.
authors.affiliation: First Dept of Internal Medicine, Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Ohuchi
authors.forename: M
authors.initials: M
authors.lastname: Ichinose
authors.forename: M
authors.initials: M
authors.lastname: Miura
authors.forename: N
authors.initials: N
authors.lastname: Kageyama
authors.forename: M
authors.initials: M
authors.lastname: Tomaki
authors.forename: N
authors.initials: N
authors.lastname: Endoh
authors.forename: Y
authors.initials: Y
authors.lastname: Mashito
authors.forename: H
authors.initials: H
authors.lastname: Sugiura
authors.forename: K
authors.initials: K
authors.lastname: Shirato
mesh_terms: D000280:Administration, Inhalation; D000704:Analysis of Variance; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000201:enzymology / Q000473:pathology; D001985:Bronchial Provocation Tests; D019559:Capillary Leak Syndrome / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D002199:Capillary Permeability / Q000187:drug effects; D004195:Disease Models, Animal; D005070:Evans Blue / Q000494:pharmacology; D006168:Guinea Pigs; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008297:Male; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000378:metabolism*; D011336:Probability; D012016:Reference Values; D013373:Substance P / Q000493:pharmacokinetics
chemical_list: D008070:Lipopolysaccharides; D013373:Substance P; D005070:Evans Blue; D019001:Nitric Oxide Synthase