Liu Qinmei, Lv Hongming, Wen Zhongmei, Ci Xinxin, Peng Liping
Department of Respiration, The First Hospital of Jilin University, Changchun, China.
Front Immunol. 2017 Nov 9;8:1518. doi: 10.3389/fimmu.2017.01518. eCollection 2017.
Among the cellular response mechanisms, the nuclear factor erythroid-2 related factor 2 (Nrf2) pathway is considered a survival pathway that alleviates oxidative injury, while both the NOD-like receptor protein 3 (NLRP3) and NF-κB pathways are pro-inflammatory pathways that cause damage to cells. These pathways are implicated in the development and resolution of acute lung injury (ALI). Isoliquiritigenin (ISL), a flavonoid from the liquorice compound, is suggested to be a regulator of the above pathways, but the mechanisms of how the NLRP3/NF-κB pathway interacts with Nrf2 and its protective effects in ALI remain unknown. In the present study, ISL inhibited reactive oxygen species (ROS) generation and cytotoxicity induced by t-BHP and pro-inflammatory enzymes production induced by LPS in RAW 264.7 cells. Such cytoprotective effects coincided with the induction of AMP-activated protein kinase (AMPK)/Nrf2/antioxidant response element (ARE) signaling and the suppression of the NLRP3 and NF-κB pathways. Consistent with these findings, ISL treatment significantly alleviated lung injury in LPS-induced ALI mice, which was reflected by reductions in histopathological changes, pulmonary edema, and protein leakage. At the same time, the increased levels of inflammatory cell exudation and pro-inflammatory mediators, the enhanced production of ROS, myeloperoxidase, and malondialdehyde, and the depleted expression of GSH and superoxide dismutase induced by LPS were ameliorated by ISL. Furthermore, ISL notably activated AMPK/Nrf2/ARE signaling and inhibited LPS-induced NLRP3 and NF-κB activation in the lung. Moreover, although inhibition of the LPS-induced histopathological changes and ROS production were attenuated in Nrf2-deficient mice, the repression of the NLRP3 and NF-κB pathways by ISL was Nrf2-dependent and Nrf2-independent, respectively. In conclusion, our results are the first to highlight the beneficial role and relevant mechanisms of ISL in LPS-induced ALI and provide novel insight into its application.
在细胞反应机制中，核因子红细胞2相关因子2（Nrf2）途径被认为是一条减轻氧化损伤的生存途径，而NOD样受体蛋白3（NLRP3）和核因子κB（NF-κB）途径都是导致细胞损伤的促炎途径。这些途径与急性肺损伤（ALI）的发生和消退有关。异甘草素（ISL）是一种来自甘草化合物的黄酮类化合物，被认为是上述途径的调节剂，但NLRP3/NF-κB途径如何与Nrf2相互作用及其在ALI中的保护作用仍不清楚。在本研究中，ISL抑制了叔丁基过氧化氢（t-BHP）诱导的活性氧（ROS）生成和细胞毒性，以及脂多糖（LPS）诱导的RAW 264.7细胞中促炎酶的产生。这种细胞保护作用与AMP激活蛋白激酶（AMPK）/Nrf2/抗氧化反应元件（ARE）信号的诱导以及NLRP3和NF-κB途径的抑制相一致。与这些发现一致，ISL治疗显著减轻了LPS诱导的ALI小鼠的肺损伤，这表现为组织病理学变化、肺水肿和蛋白质渗漏的减少。同时，ISL改善了LPS诱导的炎症细胞渗出和促炎介质水平的升高、ROS、髓过氧化物酶和丙二醛产生的增加，以及LPS诱导的谷胱甘肽（GSH）和超氧化物歧化酶表达的减少。此外，ISL显著激活了肺中的AMPK/Nrf2/ARE信号，并抑制了LPS诱导的NLRP3和NF-κB激活。此外，虽然在Nrf2缺陷小鼠中，LPS诱导的组织病理学变化和ROS产生的抑制作用减弱，但ISL对NLRP3和NF-κB途径的抑制分别是Nrf2依赖性和非Nrf2依赖性的。总之，我们的结果首次突出了ISL在LPS诱导的ALI中的有益作用和相关机制，并为其应用提供了新的见解。
