Sitagliptin activates the p62-Keap1-Nrf2 signalling pathway to alleviate oxidative stress and excessive autophagy in severe acute pancreatitis-related acute lung injury.
Sitagliptin activates the p62-Keap1-Nrf2 signalling pathway to alleviate oxidative stress and excessive autophagy in severe acute pancreatitis-related acute lung injury.
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DOI：
10.1038/s41419-021-04227-0
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发表时间：
2021-10-11
影响因子：
9
通讯作者：
Wang W
中科院分区：
文献类型：
--
作者：
Kong L;Deng J;Zhou X;Cai B;Zhang B;Chen X;Chen Z;Wang W
急性肺损伤（ALI）是重症急性胰腺炎（SAP）的一种并发症。西格列汀（SIT）是一种二肽基肽酶4（DPP4）抑制剂，具有抗炎和抗氧化作用；然而，其在SAP - ALI中的作用机制仍不清楚。在本研究中，我们探讨了SIT对SAP - ALI的影响以及SAP诱导的肺部炎症所涉及的特定通路，包括氧化应激、自噬以及p62 - 类Kelch ECH相关蛋白1（Keap1） - 核因子E2相关因子2（Nrf2）信号通路。Nrf2基因敲除（Nrf2−/−）小鼠和野生型（WT）小鼠预先接受SIT（100 mg/kg）处理，随后给予雨蛙肽和脂多糖（LPS）以诱导胰腺和肺损伤。用小干扰RNA - Nrf2转染BEAS - 2B细胞并给予LPS处理，测量炎症、活性氧（ROS）水平和自噬的变化。SIT减轻了肺组织的病理损伤、水肿和髓过氧化物酶活性，降低了促炎细胞因子的表达，并通过激活p62 - Keap1 - Nrf2信号通路以及促进Nrf2的核转位，抑制了过度自噬和ROS产生。在Nrf2基因敲除小鼠中，SIT的抗炎作用减弱，导致ROS积累和过度自噬。在BEAS - 2B细胞中，LPS诱导ROS产生并激活自噬，Nrf2敲低进一步增强了这种作用。本研究表明，SIT通过p62 - Keap1 - Nrf2信号通路以及Nrf2的核转位减轻SAP - ALI相关的氧化应激和过度自噬，提示其在SAP - ALI中的治疗潜力。
Acute lung injury (ALI) is a complication of severe acute pancreatitis (SAP). Sitagliptin (SIT) is a DPP4 inhibitor that exerts anti-inflammatory and antioxidant effects; however, its mechanism of action in SAP-ALI remains unclear. In this study, we investigated the effects of SIT on SAP-ALI and the specific pathways involved in SAP-induced lung inflammation, including oxidative stress, autophagy, and p62–Kelch-like ECH-associated protein 1 (Keap1)–NF-E2-related factor 2 (Nrf2) signalling pathways. Nrf2 knockout (Nrf2−/−) and wild-type (WT) mice were pre-treated with SIT (100 mg/kg), followed by caerulein and lipopolysaccharide (LPS) administration to induce pancreatic and lung injury. BEAS-2B cells were transfected with siRNA-Nrf2 and treated with LPS, and the changes in inflammation, reactive oxygen species (ROS) levels, and autophagy were measured. SIT reduced histological damage, oedema, and myeloperoxidase activity in the lung, decreased the expression of pro-inflammatory cytokines, and inhibited excessive autophagy and ROS production via the activation of the p62–Keap1–Nrf2 signalling pathway and promotion of the nuclear translocation of Nrf2. In Nrf2-knockout mice, the anti-inflammatory effect of SIT was reduced, resulting in ROS accumulation and excessive autophagy. In BEAS-2B cells, LPS induced ROS production and activated autophagy, further enhanced by Nrf2 knockdown. This study demonstrates that SIT reduces SAP-ALI-associated oxidative stress and excessive autophagy through the p62–Keap1–Nrf2 signalling pathway and nuclear translocation of Nrf2, suggesting its therapeutic potential in SAP-ALI.
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影响因子：
29.4
作者：
Gukovskaya AS;Gukovsky I;Algül H;Habtezion A
通讯作者：
Habtezion A
影响因子：
3.1
作者：
Cao, Chao;Yin, Chengfen;Chai, Yanfen
通讯作者：
Chai, Yanfen
影响因子：
4
作者：
Jang, Jae-Hwi;Baerts, Lesley;Jungraithmayr, Wolfgang
通讯作者：
Jungraithmayr, Wolfgang
影响因子：
4.7
作者：
Jang, Jae-Hwi;Janker, Florian;Jungraithmayr, Wolfgang
通讯作者：
Jungraithmayr, Wolfgang
DOI：
10.3390/antiox9090816
发表时间：
2020-09-02
期刊：
Antioxidants (Basel, Switzerland)
影响因子：
--
作者：
Jang BK;Lee JW;Choi H;Yim SV
通讯作者：
Yim SV