Superoxide dismutase-overexpressing mice are resistant to ozone-induced tissue injury and increases in nitric oxide and tumor necrosis factor-α
Superoxide dismutase-overexpressing mice are resistant to ozone-induced tissue injury and increases in nitric oxide and tumor necrosis factor-α
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DOI：
10.1165/rcmb.2003-0044oc
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发表时间：
2004-03-01
影响因子：
6.4
通讯作者：
Laskin, DL
中科院分区：
文献类型：
--
作者：
Fakhrzadeh, L;Laskin, JD;Laskin, DL
活性氧中间体参与了吸入性刺激物引起的肺损伤。本研究使用过表达铜/锌超氧化物歧化酶(SOD+/+)的小鼠来分析它们在臭氧诱导的肺部炎症和细胞毒性中的作用。臭氧(0.8ppm，3h)处理野生型小鼠后，小鼠肺泡灌洗液蛋白含量明显增加，24~48h达最大值，肺巨噬细胞和4-羟基烯烃含量显著增加。相比之下，臭氧处理的SOD+/+小鼠的支气管肺泡灌洗液蛋白和巨噬细胞含量以及4-羟基烯烃含量处于对照水平。也没有证据表明过氧亚硝酸盐介导的肺损伤，表明SOD+/+小鼠对臭氧毒性具有抵抗力。而来自野生型小鼠的肺泡巨噬细胞在吸入臭氧后产生更多的一氧化氮，并表达更多的诱导型一氧化氮合酶、磷脂酶A(2)和肿瘤坏死因子-α，而这在来自SOD+/+小鼠的细胞中并不明显。也没有观察到臭氧诱导的白细胞介素10的降低。在野生型小鼠中，臭氧吸入导致核因子-kappaB的激活，它调节促炎基因的活性。这种反应在SOD+/+小鼠中显著降低。这些数据表明，抗氧化酶在臭氧诱导的组织损伤和炎症介质的产生中起着关键作用。
Reactive oxygen intermediates have been implicated in lung injury induced by inhaled irritants. The present studies used mice overexpressing Cu/Zn-superoxide dismutase (SOD+/+) to analyze their role in ozone-induced lung inflammation and cytotoxicity. Treatment of wild-type mice with ozone (0.8 ppm, 3 h) resulted in increased bronchoalveolar lavage fluid protein, which was maximal after 24-48 h. Significant increases in lung macrophages and 4-hydroxyalkenals were also observed. In contrast, bronchoalveolar lavage fluid protein and macrophage content and 4-hydroxyalkenals were at control levels in ozone-treated SOD+/+ mice. There was also no evidence of peroxynitrite-mediated lung damage, demonstrating that SOD+/+ mice are resistant to ozone toxicity. Whereas alveolar macrophages from wild-type mice produced increased amounts of nitric oxide and expressed more inducible nitric oxide synthase, phospholipase A(2), and tumor necrosis factor-alpha after ozone inhalation, this was not evident in cells from SOD+/+ mice. Ozone-induced decreases in interleukin-10 were also not observed. In wild-type mice, ozone inhalation resulted in activation of nuclearfactor-kappaB, which regulates proinflammatory gene activity. This response was significantly reduced in SOD+/+ mice. These data demonstrate that antioxidant enzymes play a critical role in ozone-induced tissue injury and in inflammatory mediator production.