Lipoxin A4 attenuates LPS-induced mouse acute lung injury via Nrf2-mediated E-cadherin expression in airway epithelial cells
Lipoxin A4 attenuates LPS-induced mouse acute lung injury via Nrf2-mediated E-cadherin expression in airway epithelial cells
复制标题
脂氧素 A4 通过 Nrf2 介导的气道上皮细胞中的 E-钙粘蛋白表达减轻 LPS 诱导的小鼠急性肺损伤。
DOI：
10.1016/j.freeradbiomed.2016.01.026
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发表时间：
2016-04-01
影响因子：
7.4
通讯作者：
Wu, Ping
中科院分区：
文献类型：
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作者：
Cheng, Xue;He, Songqing;Wu, Ping
急性肺损伤(ALI)的一个基本因素是炎症，它是身体对各种局部或全身刺激的免疫反应的一部分。脂氧素(LXs)是重要的内源性脂质，介导炎症的消退。在此之前，我们证明了LXA(4)能减轻脂多糖吸入所致的小鼠肺水肿、中性粒细胞的浸润和TNIF-oc的产生。在相同的模型中，目前的研究重点是呼吸道上皮的作用，呼吸道上皮是一线屏障，也是吸入毒物的主要目标。我们报道，LXA(4)强烈抑制脂多糖诱导的小鼠ALI，部分是通过保护气道上皮，保护E-钙粘蛋白的表达和气道通透性。通过冷冻成像和荧光检测，LXA(4)在体内和体外都被证明可以阻断脂多糖诱导的ROS的产生，并保持线粒体的氧化还原状态。为了进一步探讨核因子-E2相关因子2(Nrf2)是否以及如何参与LXA(4)的保护作用，我们在人上皮细胞系(16HBE)上进行了荧光共振能量转移(FRET)分析，以确定Nrf2与其负调控因子或胞浆抑制因子Kelch样ECH相关蛋白1(Keap1)之间的相对距离。这为我们提供了LXA(4)进一步促进脂多糖处理的16HBE细胞中Nrf2和Keap1解离的证据。结果还表明，LXA(4)通过将Nrf2在Ser40上磷酸化并触发其核转位来激活Nrf2。此外，将表达显性负突变的Nrf2作为野生型Nrf2的抑制剂，LXA(4)对E-钙粘蛋白表达的保护作用几乎完全被阻断。这些结果为LXA(4)通过Nrf2介导的E-钙粘蛋白表达抑制内毒素诱导的ALI提供了一种新的机制。(C)2016 Elsevier Inc.保留所有权利。
A fundamental element of acute lung injury (ALI) is the inflammation that is part of the body's immune response to a variety of local or systemic stimuli. Lipoxins (LXs) are important endogenous lipids that mediate resolution of inflammation. Previously, we demonstrated that LXA(4) reduced the LPS inhalation-induced pulmonary edema, neutrophil infiltration and TNIF-oc production in mice. With the same model, the current investigation focused on the role of the airway epithelium, a first-line barrier and a prime target of inhaled toxicants. We report that LXA(4) strongly inhibited LPS-induced ALI in mice, in part by protecting the airway epithelium and preserving the E-cadherin expression and airway permeability. Using a cryo-imaging assay and fluorescence detection, LXA(4) was shown to block LPS-induced ROS generation and preserve mitochondrial redox status both in vivo and in vitro. To further assess whether and how NF-E2-related factor 2 (Nrf2) was involved in the protective effect of LXA(4), fluorescence resonance energy transfer (FRET) analysis was employed in human epithelial cell line (16HBE), to determine the relative distance between Nrf2 and its negative regulator or cytosolic inhibitor, Kelch-like ECH-associated protein 1 (Keapl). It provided us the evidence that LXA(4) further promoted the dissociation of Nrf2 and Keapl in LPS-treated 16HBE cells. The results also showed that LXA(4) activates Nrf2 by phosphorylating it on Ser40 and triggering its nuclear translocation. Moreover, when the plasmid expression dominant negative mutation of Nrf2 was transfected as an inhibitor of wild-type Nrf2, the protective effect of LXA(4) on E-cadherin expression was almost completely blocked. These results provide a new mechanism by which LXA(4) inhibits LPS-induced ALI through Nrf2-mediated E-cadherin expression. (C) 2016 Elsevier Inc. All rights reserved.