A novel potent inhibitor of inducible nitric oxide synthase, ONO-1714, reduces hyperoxic lung injury in mice.
A novel potent inhibitor of inducible nitric oxide synthase, ONO-1714, reduces hyperoxic lung injury in mice.
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DOI：
10.1016/j.rmed.2006.08.001
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发表时间：
2007-04
影响因子：
4.3
通讯作者：
T. Yuba;K. Nagata;Tadaaki Yamada;Shuji Osugi;Hiroomi Kuwahara;Y. Iwasaki;O. Handa;Y. Naito;S. Fushiki;T. Yoshikawa;Y. Marunaka
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文献类型：
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作者：
T. Yuba;K. Nagata;Tadaaki Yamada;Shuji Osugi;Hiroomi Kuwahara;Y. Iwasaki;O. Handa;Y. Naito;S. Fushiki;T. Yoshikawa;Y. Marunaka
研究目的高浓度氧疗用于治疗组织缺氧，但高氧会导致肺损伤。一氧化氮合酶（NOS）过度产生一氧化氮被认为会促进高氧性肺损伤。本研究旨在探讨诱导型一氧化氮合酶（iNOS）在小鼠高氧性肺损伤中的作用。测量和结果将小鼠暴露于>98%的氧气中72小时，并皮下注射ONO-1714（0.05mg/kg）（ONO）以阻断iNOS。高氧显着增加了支气管肺泡灌洗液中的总细胞计数、蛋白质浓度和亚硝酸盐/硝酸盐以及肺组织中的促炎细胞因子。 ONO 显着阻止了所有这些变量的增加。 ONO 抑制了肺损伤的组织学证据。 ONO 显着抑制肺匀浆中 iNOS 蛋白的表达和硝基酪氨酸的产生。暴露于高氧环境后，肺泡上皮细胞的 8-羟基-2'-脱氧鸟苷染色呈阳性，这是活性氧造成的 DNA 氧化损伤的正确标记。 ONO 削弱了这一发现。 结论 SNOS 在高氧性肺损伤的发病机制中发挥重要作用。选择性 iNOS 抑制剂可能有助于治疗高氧性肺损伤。
STUDY OBJECTIVESHigh-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 RESULTSMice 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.CONCLUSIONSNOS play important roles in the pathogenesis of hyperoxic lung injury. Selective iNOS inhibitors may be useful for the treatment of hyperoxic lung injury.