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NOX1/NADPH oxidase in bone marrow-derived cells modulates intestinal barrier function.
Free Radical Biology and Medicine ( IF 7.1 ) Pub Date : 2019-12-12 , DOI: 10.1016/j.freeradbiomed.2019.12.009
Junjie Liu 1 , Kazumi Iwata 1 , Kai Zhu 2 , Misaki Matsumoto 1 , Kenjiro Matsumoto 3 , Nozomi Asaoka 1 , Xueqing Zhang 1 , Masakazu Ibi 1 , Masato Katsuyama 4 , Masato Tsutsui 5 , Shinichi Kato 3 , Chihiro Yabe-Nishimura 1
Affiliation  

The involvement of reactive oxygen species (ROS) has been suggested in the development of inflammatory bowel disease (IBD). An impaired intestinal barrier function is common in IBD patients. Here, we report the central role of NOX1/NADPH oxidase, a major source of ROS in nonphagocytic cells, in intestinal barrier dysfunction. By in vivo imaging using L-012 as a probe, a time-dependent increase in ROS was demonstrated in the abdomen of wild-type mice (WT) administered lipopolysaccharide (LPS: 6 mg/kg i.p.), but it was almost completely abolished in mice deficient in Nox1 (Nox1-KO) or the inducible nitric oxide synthase gene (iNOS-KO). By ex vivo imaging, increased ROS production was mainly shown in the ileum, where enhanced immunostaining of NOX1 was observed on the apical side of the epithelium. On the other hand, a punctate staining pattern of 3-nitrotyrosine, a marker of peroxynitrite production, was demonstrated in the lamina propria. When LPS-induced intestinal hyperpermeability was assessed by the oral administration of fluorescein isothiocyanate-conjugated dextran (FD-4), it was significantly suppressed in Nox1-KO as well as iNOS-KO. When Nox1-KO adoptively transferred with WT bone marrow were treated with LPS, the serum level of FD-4 was significantly elevated, whereas it remained unchanged in WT receiving bone marrow derived from Nox1-KO. Concomitantly, the activation of matrix metalloproteinase-9 induced by LPS was alleviated not only in intestinal tissue but also in peritoneal macrophages of Nox1-KO. Up-regulation of iNOS by LPS was significantly inhibited in macrophages deficient in Nox1, illustrating a functional hierarchy in NOX1/iNOS signaling. Together, these findings suggest that NOX1 in bone marrow-derived cells, but not epithelial cells, perturbs intestinal barrier integrity during endotoxemia.

中文翻译:

骨髓来源细胞中的 NOX1/NADPH 氧化酶调节肠道屏障功能。

已经提出活性氧(ROS)参与炎症性肠病(IBD)的发展。肠屏障功能受损在 IBD 患者中很常见。在这里,我们报告了 NOX1/NADPH 氧化酶(非吞噬细胞中 ROS 的主要来源)在肠屏障功能障碍中的核心作用。通过使用 L-012 作为探针的体内成像,在给予脂多糖 (LPS: 6 mg/kg ip) 的野生型小鼠 (WT) 的腹部中证实了 ROS 的时间依赖性增加,但它几乎完全被废除在 Nox1 (Nox1-KO) 或诱导型一氧化氮合酶基因 (iNOS-KO) 缺陷的小鼠中。通过离体成像,增加的 ROS 产生主要显示在回肠中,其中在上皮的顶端观察到 NOX1 的免疫染色增强。另一方面,在固有层中证实了 3-硝基酪氨酸的点状染色模式,这是过氧亚硝酸盐产生的标志物。当通过口服异硫氰酸荧光素共轭葡聚糖 (FD-4) 评估 LPS 诱导的肠道通透性过高时,它在 Nox1-KO 和 iNOS-KO 中受到显着抑制。当用 WT 过继转移的 Nox1-KO 用 LPS 处理骨髓时,FD-4 的血清水平显着升高,而在接受来自 Nox1-KO 的骨髓的 WT 中它保持不变。同时,LPS 诱导的基质金属蛋白酶 9 的活化不仅在肠道组织中得到缓解,而且在 Nox1-KO 的腹膜巨噬细胞中也得到缓解。在缺乏 Nox1 的巨噬细胞中,LPS 对 iNOS 的上调受到显着抑制,说明 NOX1/iNOS 信号中的功能层次结构。总之,这些发现表明,骨髓衍生细胞中的 NOX1 在内毒素血症期间扰乱了肠道屏障的完整性,而不是上皮细胞。
更新日期:2019-12-13
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