Ferroptosis mediated DSS-induced ulcerative colitis associated with Nrf2/HO-1 signaling pathway
Ferroptosis mediated DSS-induced ulcerative colitis associated with Nrf2/HO-1 signaling pathway
复制标题
铁死亡介导的 DSS 诱导的溃疡性结肠炎与 Nrf2/HO-1 信号通路相关
DOI：
10.1016/j.imlet.2020.06.005
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发表时间：
2020-09-01
影响因子：
4.4
通讯作者：
Chen, Gang
中科院分区：
文献类型：
--
作者：
Chen, Yeru;Zhang, Piao;Chen, Gang
溃疡性结肠炎（UC）是一种以不受控制的炎症反应为特征的炎性疾病。以往研究表明免疫损伤引起炎症介质的改变，而铁凋亡与活性氧（ROS）的致死性积累有关。因此，本研究旨在研究铁凋亡在葡聚糖硫酸钠（DSS）诱导的UC中的作用。建立动物模型，采用westernblot法检测铁缺乏症的分子标志物。结果表明，与对照组相比，3%DSS组COX 2和ACSL 4表达显著增加，GPX 4和FTH 1水平显著降低（P < 0.05）。与3% DSS组相比，3% DSS + ferrostatin-1组、3% DSS + livestatin-1组和3% DSS + deferrone组体重和结肠长度显著增加，炎症指标和MDA水平显著降低（P < 0.05）。3%DSS组COX 2和ACSL 4的mRNA和蛋白表达明显上调，GPX 4和FTH 1的表达明显下调（P < 0.05），而给予Ferrostatin-1、Lip-1和DFP后，COX 2、ACSL 4、GPX 4和FTH 1的表达水平均得到恢复。免疫组化结果显示，与3%DSS组相比，3%DSS + Ferr-1组COX 2表达减弱，GPX 4表达增强（P < 0.05）。3% DSS + Ferr-1组核转录因子类胡萝卜素2相关蛋白2（Nrf 2）和HO-1的表达低于3% DSS组（P < 0.05）。这些数据表明，抑制铁凋亡可以有效地改善DSS诱导的UC参与阻断Nrf 2/HO-1信号通路。
Ulcerative colitis (UC) is an inflammatory disease characterized by an uncontrolled inflammatory response. Previous study showed that the immunological impairment elicted the alteration of inflammatory mediators, and ferroptosis was implicated with the lethal accumulation of reactive oxygen species (ROS). Therefore, this study aimed to investigate the role of ferroptosis in dextran sulfate sodium (DSS)-induced UC. The animal model was established and the molecular markers of ferroptosis were detected by using western blot. The results suggested that the expression of COX2 and ACSL4 was increased dramatically, while the level of GPX4 and FTH1 was deceased in 3% DSS group compared with Control group (P < 0.05). Meanwhile, the body weight and colon length were significantly increased, and the inflammation indexes and MDA levels were reduced in 3% DSS + ferrostatin-1 group, 3% DSS + liproxstatin-1 group and 3% DSS + deferprone group compared to 3% DSS group (P < 0.05). Additionally, the mRNA and protein level of COX2 and ACSL4 were obviously upregulated, but the GPX4 and FTH1 expression were downregulated in 3% DSS group (P < 0.05); however, the expression level of COX2, ACSL4, GPX4 and FTH1 was revered after ferrostatin-1, liproxstatin-1 (Lip-1) or deferprone (DFP) administration. The immunohistochemical assay showed that the staining intensity of COX2 was decreased and the staining intensity of GPX4 was increased in 3% DSS + Ferr-1 group compared with 3% DSS group (P < 0.05). Moreover, the nuclear factor erythoid 2-related 2 (Nrf2) and HO-1 expression were lower in 3% DSS + Ferr-1 group than 3% DSS group (P < 0.05). These data revealed that suppressing ferroptosis could effectively ameliorate DSS-induced UC involved in blocking Nrf2/HO-1 signaling pathway.