Lipoxin A4 Ameliorates Acute Pancreatitis-Associated Acute Lung Injury through the Antioxidative and Anti-Inflammatory Effects of the Nrf2 Pathway
Lipoxin A4 Ameliorates Acute Pancreatitis-Associated Acute Lung Injury through the Antioxidative and Anti-Inflammatory Effects of the Nrf2 Pathway
复制标题
脂氧素 A4 通过 Nrf2 通路的抗氧化和抗炎作用改善急性胰腺炎相关的急性肺损伤
DOI：
10.1155/2019/2197017
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发表时间：
2019-11-06
影响因子：
--
通讯作者：
Zhou，Mengtao
中科院分区：
文献类型：
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作者：
Ye，Wen;Zheng，Chenlei;Zhou，Mengtao
急性肺损伤（acute lung injury，ALI）是急性胰腺炎（acute pancreatitis，AP）的重要病理生理过程。许多方法已被广泛用于治疗AP-ALI，但很少有在早期炎症中有用。脂氧素A4（Lipoxin A4，LXA 4）是一种有效的抗炎和抗氧化介质，在急性肺损伤中已被广泛研究，但其保护机制尚不清楚。本研究旨在探讨LXA 4抗AP-ALI作用的可能靶点和机制。首先，我们证实LXA 4强烈抑制小鼠中的AP-ALI。接下来，使用ELISA、PCR和荧光检测来评估不同的参数，LXA 4显示出减少AP诱导的炎性细胞因子产生，并在体内和体外阻断活性氧（ROS）的产生。此外，TNF-α处理激活了人肺微血管内皮细胞（HPMECs）核因子E2相关因子2（Nrf 2）信号通路及其下游基因血红素加氧酶-1（HO-1），LXA 4进一步促进其表达。这项研究还提供了LXA 4磷酸化Ser 40并触发其核转位以激活Nrf 2的证据。此外，当使用Nrf 2敲除（Nrf 2-/-）小鼠和细胞进一步评估Nrf 2/HO-1通路的作用时，我们发现Nrf 2表达敲除部分消除了LXA 4对炎症因子水平降低的作用，同时消除了LXA 4对AP-ALI刺激的ROS产生的抑制作用。总体而言，LXA 4可能通过调节Nrf 2/HO-1通路来减弱AP诱导的炎症和ROS产生的消退以减轻ALI。这些发现为急性肺损伤的治疗奠定了基础。
Acute lung injury (ALI) is a critical event involved in the pathophysiological process of acute pancreatitis (AP). Many methods have been widely used for the treatment of AP-ALI, but few are useful during early inflammation. Lipoxin A4 (LXA4), a potent available anti-inflammatory and novel antioxidant mediator, has been extensively studied in AP-ALI, but its underlying mechanism as a protective mediator is not clear. This research was conducted to identify the possible targets and mechanisms involved in the anti-AP-ALI effect of LXA4. First, we confirmed that LXA4 strongly inhibited AP-ALI in mice. Next, using ELISA, PCR, and fluorescence detection to evaluate different parameters, LXA4 was shown to reduce the inflammatory cytokine production induced by AP and block reactive oxygen species (ROS) generation in vivo and in vitro. In addition, TNF-α treatment activated the nuclear factor E2-related factor 2 (Nrf2) signaling pathway and its downstream gene heme oxygenase-1 (HO-1) in human pulmonary microvascular endothelial cells (HPMECs), and LXA4 further promoted their expression. This study also provided evidence that LXA4 phosphorylates Ser40 and triggers its nuclear translocation to activate Nrf2. Moreover, when Nrf2-knockout (Nrf2−/−) mice and cells were used to further assess the effect of the Nrf2/HO-1 pathway, we found that Nrf2 expression knockdown partially eliminated the effect of LXA4 on the reductions in inflammatory factor levels while abrogating the inhibitory effect of LXA4 on the ROS generation stimulated by AP-ALI. Overall, LXA4 attenuated the resolution of AP-induced inflammation and ROS generation to mitigate ALI, perhaps by modulating the Nrf2/HO-1 pathway. These findings have laid a foundation for the treatment of AP-ALI.