An inhaled inducible nitric oxide synthase inhibitor reduces damage of Candida-induced acute lung injury

Shuji OHSUGI; Yoshinobu IWASAKI; Yoshizumi TAKEMURA; Kazuhiro NAGATA; Hidehiko HARADA; Ichiro YOKOMURA; Shigekuni HOSOGI; Tatsuya YUBA; Naomi NIISATO; Hiroaki MIYAZAKI; Hiroaki MATSUBARA; Shinji FUSHIKI; Yoshinori MARUNAKA

doi:10.2220/biomedres.28.91

Full Papers

An inhaled inducible nitric oxide synthase inhibitor reduces damage of Candida-induced acute lung injury

Shuji OHSUGI, Yoshinobu IWASAKI, Yoshizumi TAKEMURA, Kazuhiro NAGATA, Hidehiko HARADA, Ichiro YOKOMURA, Shigekuni HOSOGI, Tatsuya YUBA, Naomi NIISATO, Hiroaki MIYAZAKI, Hiroaki MATSUBARA, Shinji FUSHIKI, Yoshinori MARUNAKA

Author information

Shuji OHSUGI
Department of Respiratory Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine
Yoshinobu IWASAKI
Department of Respiratory Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine
Yoshizumi TAKEMURA
Department of Respiratory Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine
Research Center for Respiratory Cell Engeering, Doshisha University
Kazuhiro NAGATA
Department of Respiratory Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine
Hidehiko HARADA
Department of Respiratory Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine
Ichiro YOKOMURA
Department of Respiratory Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine
Shigekuni HOSOGI
Department of Respiratory Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine
Tatsuya YUBA
Department of Respiratory Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine
Naomi NIISATO
Department of Molecular Cell Physiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine
Hiroaki MIYAZAKI
Department of Molecular Cell Physiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine
Hiroaki MATSUBARA
Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine
Shinji FUSHIKI
Department of Pathology and Applied Neurobiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine
Yoshinori MARUNAKA
Department of Respiratory Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine
Department of Molecular Cell Physiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine

JOURNAL FREE ACCESS

2007 Volume 28 Issue 2 Pages 91-99

DOI https://doi.org/10.2220/biomedres.28.91

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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-α (TNF-α) and interleukin-1β (IL-1β) 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.

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