title: An inhaled inducible nitric oxide synthase inhibitor reduces damage of Candida-induced acute lung injury.
abstract: Excessive nitric oxide (NO) generated by inducible nitric oxide synthase (iNOS) aggravates acute lung injury (ALI) by producing peroxynitrite. We previously showed by immunostaining that the expression of iNOS was suppressed by inhalation of N(G)-nitro-L-arginine methyl ester in mice with Candida-induced ALI. This study tested the hypothesis that a novel iNOS inhibitor suppresses not only iNOS expression, but also iNOS messenger RNA (mRNA) production by interrupting a positive feedback loop at the time of NO production in Candida-induced ALI. Mice were pretreated by inhalation of saline or ONO-1714, a selective iNOS inhibitor, and were given an intravenous injection of Candida albicans to induce ALI. After inhalation of 1 mM aerosolized ONO-1714, the nitrite-nitrate concentration in bronchoalveolar lavage fluid (BALF) at 24 h was significantly lower than that after inhalation of saline. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) levels and neutrophils in BALF were decreased by inhalation of ONO-1714. Inhalation of ONO-1714 markedly suppressed nitrotyrosine production and inhibited the expression of iNOS mRNA as well as proteins in the lung. Survival was prolonged by inhalation of ONO-1714. We conclude that pretreatment with inhaled ONO-1714 suppresses the production of peroxinitrite and decreases oxidative stress associated with peroxinitrite in Candida-induced ALI.
authors.affiliation: Department of Respiratory Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Ohsugi
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Iwasaki
authors.forename: Yoshizumi
authors.initials: Y
authors.lastname: Takemura
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nagata
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Harada
authors.forename: Ichiro
authors.initials: I
authors.lastname: Yokomura
authors.forename: Shigekuni
authors.initials: S
authors.lastname: Hosogi
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Yuba
authors.forename: Naomi
authors.initials: N
authors.lastname: Niisato
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Miyazaki
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Matsubara
authors.forename: Shinji
authors.initials: S
authors.lastname: Fushiki
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Marunaka
mesh_terms: D000280:Administration, Inhalation; D000578:Amidines / Q000494:pharmacology; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D002177:Candidiasis / Q000188:drug therapy*; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology*; D006574:Heterocyclic Compounds, 2-Ring / Q000494:pharmacology; D006801:Humans; D008171:Lung Diseases / Q000382:microbiology*; D055370:Lung Injury; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000737:chemistry; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D018384:Oxidative Stress; D030421:Peroxynitrous Acid / Q000737:chemistry
chemical_list: C407360:7-chloro-3-imino-5-methyl-2-azabicyclo(4.1.0)heptane; D000578:Amidines; D004791:Enzyme Inhibitors; D006574:Heterocyclic Compounds, 2-Ring; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase