A novel potent inhibitor of inducible nitric oxide synthase, ONO-1714, reduces hyperoxic lung injury in mice - 15/08/11

Doi : 10.1016/j.rmed.2006.08.001

Tatsuya Yuba ^a,^⁎ , Kazuhiro Nagata ^a, Tadaaki Yamada ^a, Shuji Osugi ^a, Hiroomi Kuwahara ^a, Yoshinobu Iwasaki ^a, Osamu Handa ^b, Yuji Naito ^c, Shinji Fushiki ^d, Toshikazu Yoshikawa ^e, Yoshinori Marunaka ^a
^a Department of Respiratory Molecular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
^b Department of Biomedical Safety Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
^c Department of Medical Proteomics, Kyoto Prefectural University of Medicine, Kyoto, Japan
^d Department of Pathology and Applied Neurobiology, Research Institute for Neurobiological Diseases and Geriatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan
^e Inflammation and Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan

Corresponding author. Tel.: +81752515511; fax: +81752515514.

Summary

Study objectives

High-concentration oxygen therapy is used to treat tissue hypoxia, but hyperoxia causes lung injury. Overproduction of nitric oxide by nitric oxide synthase (NOS) is thought to promote hyperoxic lung injury. The present study was conducted to examine the role of inducible nitric oxide synthase (iNOS) in hyperoxic lung injury in mice.

Measurements and results

Mice were exposed to >98% oxygen for 72h, and ONO-1714 (0.05mg/kg) (ONO) was subcutaneously administered to block iNOS. Hyperoxia significantly increased total cell count, protein concentration, and nitrites/nitrates in the bronchoalveolar lavage fluid and proinflammatory cytokines in the lung tissue. ONO significantly prevented the increases in all of these variables. ONO suppressed histologic evidence of lung injury. ONO markedly inhibited iNOS protein expression and nitrotyrosine production in lung homogenates. After exposure to hyperoxia, alveolar epithelial cells stained positively for 8-hydroxy-2′-deoxyguanosine, a proper marker of oxidative DNA damage by reactive oxygen species. ONO attenuated this finding.

Conclusions

NOS play important roles in the pathogenesis of hyperoxic lung injury. Selective iNOS inhibitors may be useful for the treatment of hyperoxic lung injury.

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Keywords : Hyperoxia, Oxidative stress, Acute lung injury, Nitrative stress, Inducible NO synthase inhibitor

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Vol 101 - N° 4

P. 793-799 - avril 2007 Retour au numéro

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A novel potent inhibitor of inducible nitric oxide synthase, ONO-1714, reduces hyperoxic lung injury in mice - 15/08/11

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Measurements and results

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