title: Epithelium-dependent and -independent inhibitory effects of sivelestat, a neutrophil elastase inhibitor, on substance P-induced contraction of airway smooth muscle in lipopolysaccharide-treated guinea-pigs.
abstract: The underlying mechanism involved in the interaction between neutrophil elastase inhibitors and tachykinins has not been elucidated. In this study we have examined the effects of sivelestat, a neutrophil elastase inhibitor, on the in vitro responses of airways from lipopolysaccharide (LPS)-untreated or -treated guinea-pigs to substance P. Substance P (0.01-30 micromol/l) produced concentration-dependent contractions of both tracheal and bronchial ring preparations of LPS-untreated or -treated guinea-pigs. Responsiveness to substance P in these isolated airway preparations was augmented by either epithelium removal or LPS treatment. In epithelium-intact tracheal ring preparations isolated from LPS-untreated guinea-pigs, sivelestat (100 micromol/l) significantly inhibited substance P-induced contractions. The inhibitory action was markedly attenuated by pretreatment with L-NAME (100 micromol/l) or indomethacin (2 micromol/l), and was almost undetected following removal of the epithelium. On the other hand, in bronchial ring preparations isolated from LPS-untreated guinea-pigs, sivelestat had only a very slight effect on substance P-induced contraction of the epithelium-intact preparation, whereas sivelestat greatly inhibited contraction in epithelium-removed bronchial ring preparations. In LPS-treated guinea-pigs, whether the epithelium was intact or not, sivelestat significantly inhibited the substance P-induced contraction of bronchial ring preparations. Pretreatment with L-NAME (100 micromol/l) or indomethacin (2 micromol/l) did not affect the inhibitory effect of sivelestat in bronchial ring preparations. In conclusion, epithelium removal or LPS treatment induced hyperreactivity to substance P in the guinea-pig airway. Sivelestat caused epithelium-, nitric oxide- and prostaglandin-dependent inhibition of the substance P-induced contraction of isolated guinea-pig tracheal ring preparations. In contrast, the inhibitory effect of sivelestat on substance P-induced contraction of guinea-pig bronchial ring preparations is mediated by epithelium-, nitric oxide- and prostaglandin-independent mechanisms. Sivelestat may be effective in reducing the airway hyperresponsiveness to tachykinins induced by epithelial injury as occurs in LPS-mediated inflammatory lung diseases.
authors.affiliation: Department of Intensive and Critical Care Medicine, Dokkyo University School of Medicine, Tochigi, Japan.
authors.forename: Naomi
authors.initials: N
authors.lastname: Takayama
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Uchida
mesh_terms: D000818:Animals; D001980:Bronchi / Q000187:drug effects / Q000503:physiopathology; D005998:Glycine / Q000031:analogs & derivatives* / Q000502:physiology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology; D011189:Potassium Chloride / Q000494:pharmacology; D011453:Prostaglandins / Q000502:physiology; D020545:Respiratory Mucosa / Q000187:drug effects / Q000502:physiology*; D012137:Respiratory System / Q000187:drug effects*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D013373:Substance P / Q000494:pharmacology*; D013449:Sulfonamides; D015320:Tachykinins / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects / Q000503:physiopathology
chemical_list: D008070:Lipopolysaccharides; D011453:Prostaglandins; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; D015320:Tachykinins; D009569:Nitric Oxide; D013373:Substance P; D011189:Potassium Chloride; C069195:sivelestat; D019272:Leukocyte Elastase; D005998:Glycine; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin