Genetic deficiency of NADPH oxidase does not diminish, but rather enhances, LPS-induced acute inflammatory responses in vivo.
Genetic deficiency of NADPH oxidase does not diminish, but rather enhances, LPS-induced acute inflammatory responses in vivo.
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DOI：
10.1016/j.freeradbiomed.2008.12.003
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发表时间：
2009-03-15
影响因子：
7.4
通讯作者：
Frei, Balz
中科院分区：
文献类型：
--
作者：
Zhang, Wei-Jian;Wei, Hao;Frei, Balz
关键词：
活性氧(ROS)和氧化应激被认为在脓毒症的细胞功能障碍和组织损伤的病因学中起着核心作用。然而，来自体内研究的有限和有争议的证据表明，ROS介导的细胞信号过程在脓毒症期间引发急性炎症反应。由于NADPH氧化酶是ROS的主要细胞来源之一，我们利用NADPH氧化酶gp91Phox或p47Phox亚基缺陷的小鼠，在体内研究了该酶在脂多糖(LPS)诱导的急性炎症中的作用。将年龄和体重匹配的C57BL/6J野生型(WT)和gp91Phox−/−和p47Phox−/−小鼠分别腹腔注射。给予50µg脂多糖或生理盐水，在不同时间点处死动物，最长达24小时。我们发现，与WT小鼠相比，gp91Phox−/−和p47Phox−/−小鼠的血清和组织中的内毒素诱导的急性炎症反应并没有明显减少。相反，NADPH氧化酶的遗传缺陷与炎症介质的基因表达增强以及中性粒细胞向肺和心脏募集的增加有关。此外，在两个基因敲除株中都没有观察到对内毒素诱导的败血症死亡的保护作用。我们的研究结果表明，NADPH氧化酶介导的ROS产生和细胞氧化还原信号并不促进而是限制了体内内毒素诱导的急性炎症反应。
Reactive oxygen species (ROS) and oxidative stress are thought to play a central role in the etiology of cell dysfunction and tissue damage in sepsis. However, there is limited and controversial evidence from in vivo studies that ROS mediate cell signaling processes that elicit acute inflammatory responses during sepsis. Since NADPH oxidase is one of the main cellular sources of ROS, we investigated the role of this enzyme in lipopolysaccharide (LPS)-induced acute inflammation in vivo, utilizing mice deficient in the gp91phox or p47phox subunits of NADPH oxidase. Age and body-weight matched C57BL/6J wild-type (WT) and gp91phox−/− and p47phox−/− mice were injected i.p. with 50 µg LPS or saline vehicle, and sacrificed at different time points up to 24 hours. We found that LPS-induced acute inflammatory responses in serum and tissues were not significantly diminished in gp91phox−/− and p47phox−/− mice compared to WT mice. Rather, genetic deficiency of NADPH oxidase was associated with enhanced gene expression of inflammatory mediators and increased neutrophil recruitment to lung and heart. Furthermore, no protection from LPS-induced septic death was observed in either knockout strain. Our findings suggest that NADPH oxidase-mediated ROS production and cellular redox signaling do not promote but instead limit LPS-induced acute inflammatory responses in vivo.
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