Yuba Tatsuya, Nagata Kazuhiro, Yamada Tadaaki, Osugi Shuji, Kuwahara Hiroomi, Iwasaki Yoshinobu, Handa Osamu, Naito Yuji, Fushiki Shinji, Yoshikawa Toshikazu, Marunaka Yoshinori
Department of Respiratory Molecular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
Respir Med. 2007 Apr;101(4):793-9. doi: 10.1016/j.rmed.2006.08.001. Epub 2006 Sep 18.
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.
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.
NOS play important roles in the pathogenesis of hyperoxic lung injury. Selective iNOS inhibitors may be useful for the treatment of hyperoxic lung injury.
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）产生过量一氧化氮被认为会促进高氧肺损伤。本研究旨在探讨诱导型一氧化氮合酶（iNOS）在小鼠高氧肺损伤中的作用。
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。高氧显著增加了支气管肺泡灌洗液中的总细胞计数、蛋白质浓度以及亚硝酸盐/硝酸盐水平，同时增加了肺组织中的促炎细胞因子水平。ONO显著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显著抑制了肺匀浆中iNOS蛋白表达和硝基酪氨酸的产生。暴露于高氧后，肺泡上皮细胞对8-羟基-2'-脱氧鸟苷呈阳性染色，这是活性氧对DNA氧化损伤的一个合适标志物。ONO减轻了这一发现。
NOS在高氧肺损伤的发病机制中起重要作用。选择性iNOS抑制剂可能对高氧肺损伤的治疗有用。
