NOX1/NADPH Oxidase Expressed in Colonic Macrophages Contributes to the Pathogenesis of Colonic Inflammation in Trinitrobenzene Sulfonic Acid-Induced Murine Colitis
NOX1/NADPH Oxidase Expressed in Colonic Macrophages Contributes to the Pathogenesis of Colonic Inflammation in Trinitrobenzene Sulfonic Acid-Induced Murine Colitis
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DOI：
10.1124/jpet.116.235580
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发表时间：
2017-01-01
影响因子：
3.5
通讯作者：
Kato, Shinichi
中科院分区：
文献类型：
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作者：
Yokota, Haruka;Tsuzuki, Ayaka;Kato, Shinichi
NOX1/NADPH氧化酶是一种非吞噬活性氧产生酶亚型，在结肠中高度表达，但该亚型的生理和病理生理作用尚不完全清楚。本研究在三硝基苯磺酸(TNBS)诱导的小鼠结肠炎模型中研究了NOX1在结肠炎发生发展中的作用。在野生型(WT)小鼠中，直肠内注射TNBS引起严重结肠炎，伴随体重减轻、腹泻和髓过氧化物酶(MPO)活性增加。相比之下，NOX1基因缺陷(NOX1KO)小鼠的结肠炎严重程度显著减轻(宏观损伤评分、体重减轻、腹泻评分和MPO活性的抑制率分别为73.1%、36.8%、83.3%和98.4%)。TnBS诱导的炎症细胞因子(肿瘤坏死因子-α和白介素1-β)、趋化因子(CXCL1和CXL2)和诱导型一氧化氮合酶(INOS)的表达也明显低于NOX1KO组(抑制率分别为100.8%、89.0%、63.5%、96.7%和97.1%)。NOX1mRNA不仅在固有层表达，而且在分离的小鼠腹膜巨噬细胞中也有表达。NOX1K0小鼠巨噬细胞经脂多糖刺激后，其肿瘤坏死因子α、白介素1β和诱导型一氧化氮合酶的表达水平显著降低(抑制率分别为68.1%、67.0%和79.3%)。这些结果提示，NOX1/NADPH氧化酶通过上调炎性细胞因子、趋化因子和iNOS在TNBS诱导的结肠炎发病机制中起重要作用。结肠巨噬细胞中的NOX1可能成为炎症性肠病药物干预的潜在靶点。
NOX1/NADPH oxidase, a non phagocytic isoform of reactive oxygen species-producing enzymes, is highly expressed in the colon, but the physiologic and pathophysiologic roles of this isoform are not fully understood. The present study investigated the role of NOX1 in the development of colonic inflammation in a trinitrobenzene sulfonic acid (TNBS)-induced murine colitis model. Intrarectal injection of TNBS caused severe colitis accompanied by body weight loss, diarrhea, and increased myeloperoxidase (MPO) activity in wild-type (WT) mice. In contrast, the severity of colitis was significantly attenuated in NOX1-deficient (NOX1KO) mice (the inhibitions of macroscopic damage score, body weight loss, diarrhea score, and MPO activity were 73.1%, 36.8%, 83.3%, and 98.4%, respectively). TNBS-induced upregulation of inflammatory cytokines (tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 beta), chemokines (CXCL1 and CXLC2), and inducible nitric oxide synthase (iNOS) was also significantly less in NOX1KO than in \NT mice (the inhibitions were 100.8%, 89.0%, 63.5%, 96.7%, and 97.1%, respectively). Expression of NOX1 mRNA was detected not only in the lamina propria but also in peritoneal macrophages isolated from \NT mice. Increased expression of TNF alpha, IL-1 beta, and iNOS in peritoneal macrophages exposed to lipopolysaccharide was significantly attenuated in macrophages isolated from NOX1K0 mice (68.1%, 67.0%, and 79.3% inhibition, respectively). These findings suggest that NOX1/NADPH oxidase plays an important role in the pathogenesis of TNBS-induced colonic inflammation via upregulation of inflammatory cytokines, chemokines, and iNOS. NOX1 in colonic macrophages may become a potential target in pharmacologic intervention for inflammatory bowel disease.