TUDCA attenuates intestinal injury and inhibits endoplasmic reticulum stress-mediated intestinal cell apoptosis in necrotizing enterocolitis

IF 4.7 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2019-09-01 DOI:10.1016/j.intimp.2019.05.050

Peng Li , Dong Fu , Qingfeng Sheng , Shenghua Yu , Xingqi Bao , Zhibao Lv

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引用次数: 27

Abstract

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-eIF2α 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.

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TUDCA可减轻坏死性小肠结肠炎的肠损伤，抑制内质网应激介导的肠细胞凋亡

新生儿坏死性小肠结肠炎(NEC)是一种严重炎症和肠细胞凋亡的危及生命的疾病。牛磺酸去氧胆酸(TUDCA)是公认的内质网应激(ERS)抑制剂，具有抑制细胞凋亡的作用。近年来，肠细胞凋亡已被证明在NEC的发病机制中至关重要。本研究的目的是探讨TUDCA在NEC治疗中的潜力以及体内和体外可能的机制。我们的研究结果表明，在NEC小鼠模型中，TUDCA降低了死亡率，延长了生存时间，显著减轻了肠道损伤，并抑制了肠道炎症。TUDCA对NEC小鼠模型的保护作用是通过抑制ERS标记物的表达水平和抑制肠细胞凋亡来实现的。此外，TUDCA增加了磷酸化akt (p-Akt)的表达。此外，我们在体外研究中证实了TUDCA通过调节PERK-eIF2α ERS通路和Akt通路抑制肠细胞凋亡。此外，在体外研究中，AKT特异性抑制剂MK2206可削弱TUDCA的作用。因此，这些结果表明，TUDCA可以减轻小鼠NEC模型的肠道损伤，并通过激活Akt通路抑制ers介导的肠道细胞凋亡。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.