A novel potent inhibitor of inducible nitric oxide synthase, ONO-1714, reduces hyperoxic lung injury in mice.

Abstract

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 72 h, and ONO-1714 (0.05 mg/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.

• Authors: Tatsuya Yuba, Kazuhiro Nagata, Tadaaki Yamada, Shuji Osugi, Hiroomi Kuwahara, Yoshinobu Iwasaki, Osamu Handa, Yuji Naito, Shinji Fushiki, Toshikazu Yoshikawa, Yoshinori Marunaka
• Journal: Respiratory medicine (Respir Med) Vol. 101 Issue 4 Pg. 793-9 (Apr 2007) ISSN: 0954-6111 [Print] England
• PMID: 16982182 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 7-chloro-3-imino-5-methyl-2-azabicyclo(4.1.0)heptane
• Amidines
• Cytokines
• Enzyme Inhibitors
• Heterocyclic Compounds, 2-Ring
• Nitrogen Oxides
• 3-nitrotyrosine
• Tyrosine
• Nitric Oxide Synthase Type II

Topics

• Amidines (administration & dosage)
• Animals
• Blotting, Western (methods)
• Bronchoalveolar Lavage Fluid (chemistry)
• Cell Differentiation (physiology)
• Cytokines (analysis)
• Drug Administration Schedule
• Enzyme Inhibitors (administration & dosage)
• Heterocyclic Compounds, 2-Ring (administration & dosage)
• Hyperoxia (metabolism, physiopathology, prevention & control)
• Immunohistochemistry (methods)
• Injections, Subcutaneous
• Lung (chemistry, drug effects, pathology)
• Lung Diseases (metabolism, physiopathology, prevention & control)
• Male
• Mice
• Mice, Inbred C57BL
• Nitric Oxide Synthase Type II (analysis, antagonists & inhibitors)
• Nitrogen Oxides (analysis)
• Tyrosine (analogs & derivatives, analysis)