TUDCA attenuates intestinal injury and inhibits endoplasmic reticulum stress-mediated intestinal cell apoptosis in necrotizing enterocolitis
TUDCA attenuates intestinal injury and inhibits endoplasmic reticulum stress-mediated intestinal cell apoptosis in necrotizing enterocolitis
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TUDCA 减轻坏死性小肠结肠炎肠道损伤并抑制内质网应激介导的肠细胞凋亡
DOI：
10.1016/j.intimp.2019.05.050
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发表时间：
2019-09-01
影响因子：
5.6
通讯作者：
Lv, Zhibao
中科院分区：
文献类型：
--
作者：
Li, Peng;Fu, Dong;Lv, Zhibao
新生儿坏死性小肠结肠炎(NEC)是一种严重的炎症反应和肠道细胞凋亡，严重威胁生命的疾病。牛磺酸脱氧胆酸(TUDCA)是公认的内质网应激(ERS)抑制剂，可抑制细胞凋亡。近年来，肠上皮细胞凋亡在NEC的发病机制中发挥了重要作用。本研究旨在探讨TUDCA治疗NEC的潜力及其在体内和体外的可能机制。结果表明，TUDCA可降低NEC模型小鼠的死亡率，延长存活时间，显著减轻肠道损伤，并抑制肠道炎症。TUDCA对NEC模型小鼠的保护作用是通过抑制ERS标志物的表达和抑制肠细胞的凋亡来实现的。此外，TUDCA还增加磷酸化Akt(p-Akt)的表达。此外，我们在体外实验中证实了TUDCA通过调节PERK-eIF2αERS通路和Akt通路来抑制肠道细胞的凋亡。体外实验中，AKT特异性抑制剂MK2206可减弱TUDCA的作用。因此，上述结果表明，TUDCA可减轻NEC模型小鼠的肠道损伤，并通过激活Akt通路抑制ERS介导的肠道细胞凋亡。
Neonatal necrotizing enterocolitis (NEC) is a life-threatening disease with severe inflammation and intestinal cell apoptosis. Tauroursodeoxycholic acid (TUDCA) is a recognized endoplasmic reticulum stress (ERS) inhibitor which can inhibit cell apoptosis. Recently, intestinal cell apoptosis has been demonstrated to be vital for the pathogenesis of NEC. The purpose of the present study was to investigate the potential of TUDCA in the treatment of NEC and the possible mechanisms in vivo and in vitro. Our results showed that TUDCA reduced mortality rates, prolonged survival times, significantly diminished intestinal damage, and inhibited intestinal inflammation in the mouse model of NEC. The protective effect of TUDCA on the NEC mouse model was realized through inhibiting the expression levels of ERS markers and inhibiting the apoptosis of intestinal cells. In addition, TUDCA increased the expression of phospho-Akt (p-Akt). Furthermore, we confirmed that TUDCA inhibited the apoptosis of intestinal cells by modulating the PERK-eIF2 alpha ERS pathway and the Akt pathway in vitro studies. Besides, TUDCA effects were impaired by AKT specific inhibitor MK2206 in vitro studies. Therefore, these results indicated that TUDCA alleviated intestinal injury in a mouse model of NEC and inhibited ERS-mediated intestinal cell apoptosis by activating the Akt pathway.