Advanced oxidation protein products induce intestine epithelial cell death through a redox-dependent, c-jun N-terminal kinase and poly (ADP-ribose) polymerase-1-mediated pathway.
Advanced oxidation protein products induce intestine epithelial cell death through a redox-dependent, c-jun N-terminal kinase and poly (ADP-ribose) polymerase-1-mediated pathway.
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DOI：
10.1038/cddis.2013.542
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发表时间：
2014-01-16
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
晚期氧化蛋白产物(AOPPs)是一种新的氧化损伤的蛋白质标记物，已被证实在炎症性肠病(IBD)患者以及糖尿病和慢性肾脏疾病患者中积聚。然而，AOPPs在肠道上皮细胞中的作用尚不清楚。本研究旨在探讨AOPPs是否对肠上皮细胞(IEC)死亡和肠损伤有影响。用大鼠血清白蛋白(RSA)与次氯酸孵育制备的AOPP-白蛋白处理永生化大鼠肠上皮细胞(IEC-6)和正常SD大鼠。在体内和体外检测上皮细胞死亡、烟酰胺腺嘌呤二核苷酸磷酸(NADPH)氧化酶亚基活性、活性氧(ROS)生成、细胞凋亡相关蛋白表达和c-Jun氨基末端激酶(JNK)磷酸化。此外，我们还测量了23例克罗恩病(CD)患者的AOPPs沉积和IEC死亡。AOPP-RSA胞外积聚诱导IEC-6细胞凋亡。AOPPs的触发作用主要通过氧化还原依赖的途径介导，包括NADPH氧化酶衍生的ROS的产生、JNK的磷酸化和PARP-1的激活。正常大鼠慢性给予AOPP-RSA后，绒毛上皮细胞内AOPPs沉积，固有层炎性细胞增多。这些改变伴随着IEC死亡、炎性细胞浸润和肠道损伤。细胞死亡和肠道损伤均可通过罗布麻素的慢性治疗得到改善。此外，CD患者IECS和固有层炎性细胞中也可见AOPPs沉积。AOPPs免疫反应积分高，细胞凋亡率增加。我们的结果表明，AOPPs通过氧化还原介导的途径触发IEC死亡和肠组织损伤。这些数据表明，AOPPs可能是导致IBD进展的一个新的致病因素。靶向AOPP诱导的细胞机制可能成为IBD患者的一种有前途的治疗选择。
Advanced oxidation protein products (AOPPs), a novel protein marker of oxidative damage, have been confirmed to accumulate in patients with inflammatory bowel disease (IBD), as well as those with diabetes and chronic kidney disease. However, the role of AOPPs in the intestinal epithelium remains unclear. This study was designed to investigate whether AOPPs have an effect on intestinal epithelial cell (IEC) death and intestinal injury. Immortalized rat intestinal epithelial (IEC-6) cells and normal Sprague Dawley rats were treated with AOPP-albumin prepared by incubation of rat serum albumin (RSA) with hypochlorous acid. Epithelial cell death, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit activity, reactive oxygen species (ROS) generation, apoptosis-related protein expression, and c-jun N-terminal kinase (JNK) phosphorylation were detected both in vivo and in vitro. In addition, we measured AOPPs deposition and IEC death in 23 subjects with Crohn's disease (CD). Extracellular AOPP-RSA accumulation induced apoptosis in IEC-6 cultures. The triggering effect of AOPPs was mainly mediated by a redox-dependent pathway, including NADPH oxidase-derived ROS generation, JNK phosphorylation, and poly (ADP-ribose) polymerase-1 (PARP-1) activation. Chronic AOPP-RSA administration to normal rats resulted in AOPPs deposition in the villous epithelial cells and in inflammatory cells in the lamina propria. These changes were companied with IEC death, inflammatory cellular infiltration, and intestinal injury. Both cell death and intestinal injury were ameliorated by chronic treatment with apocynin. Furthermore, AOPPs deposition was also observed in IECs and inflammatory cells in the lamina propria of patients with CD. The high immunoreactive score of AOPPs showed increased apoptosis. Our results demonstrate that AOPPs trigger IEC death and intestinal tissue injury via a redox-mediated pathway. These data suggest that AOPPs may represent a novel pathogenic factor that contributes to IBD progression. Targeting AOPP-induced cellular mechanisms might emerge as a promising therapeutic option for patients with IBD.
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