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


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.
Yuba
Tatsuya
T
Department of Respiratory Molecular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan. bulltyb@koto.kpu-m.ac.jp
Nagata
Kazuhiro
K
Yamada
Tadaaki
T
Osugi
Shuji
S
Kuwahara
Hiroomi
H
Iwasaki
Yoshinobu
Y
Handa
Osamu
O
Naito
Yuji
Y
Fushiki
Shinji
S
Yoshikawa
Toshikazu
T
Marunaka
Yoshinori
Y
D000578:Amidines / Q000008:administration & dosage*; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002454:Cell Differentiation / Q000502:physiology; D016207:Cytokines / Q000032:analysis; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D006574:Heterocyclic Compounds, 2-Ring / Q000008:administration & dosage; D018496:Hyperoxia / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D007150:Immunohistochemistry / Q000379:methods; D007279:Injections, Subcutaneous; D008168:Lung / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D008171:Lung Diseases / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D052247:Nitric Oxide Synthase Type II / Q000032:analysis / Q000037:antagonists & inhibitors*; D009589:Nitrogen Oxides / Q000032:analysis; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis
C407360:7-chloro-3-imino-5-methyl-2-azabicyclo(4.1.0)heptane; D000578:Amidines; D016207:Cytokines; D004791:Enzyme Inhibitors; D006574:Heterocyclic Compounds, 2-Ring; D009589:Nitrogen Oxides; C002744:3-nitrotyrosine; D014443:Tyrosine; D052247:Nitric Oxide Synthase Type II