Oridonin protects LPS-induced acute lung injury by modulating Nrf2-mediated oxidative stress and Nrf2-independent NLRP3 and NF-B pathways
Oridonin protects LPS-induced acute lung injury by modulating Nrf2-mediated oxidative stress and Nrf2-independent NLRP3 and NF-B pathways
复制标题
冬凌草甲素通过调节 Nrf2 介导的氧化应激和不依赖 Nrf2 的 NLRP3 和 NF-B 通路来保护 LPS 诱导的急性肺损伤
DOI：
10.1186/s12964-019-0366-y
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发表时间：
2019-06-11
影响因子：
8.4
通讯作者：
Peng, Liping
中科院分区：
文献类型：
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作者：
Yang, Huahong;Lv, Hongming;Peng, Liping
氧化应激及其引起的炎症反应是急性肺损伤(ALI)的重要病理过程。核因子红系相关因子2(Nrf2)是一种重要的转录因子，具有抗氧化潜能，已成为治疗多种疾病的主要靶点。冬凌草甲素(Oridonin，ORI)是从冬凌草属植物冬凌草中分离得到的一种具有抗氧化和抗炎作用的天然物质。方法采用四甲基偶氮唑盐比色法、Western blotting法、小鼠模型和苏木精-伊红(H&E)染色等方法，探讨ORI对内毒素诱导的RAW264.7细胞和小鼠肺损伤的保护作用机制。此外，ORI还可抑制内毒素诱导的促炎通路NLRP3、炎症体和核因子-B通路的激活。通过使用Nrf2抑制剂，这两条通路也被证明是不依赖Nrf2的。与此相一致的是，ORI可减轻脂多糖诱导的小鼠肺组织病理改变，减少肺组织髓过氧化物酶和丙二醛的生成，减少GSH和超氧化物歧化酶的表达。此外，脂多糖诱导的NLRP3炎症体和核因子-B途径在Nrf2缺陷小鼠中的表达更为明显，但仍可被ORI逆转。结论ORI通过Nrf2非依赖的抗炎和Nrf2依赖的抗氧化作用对内毒素诱导的ALI起到保护作用。
BackgroundOxidative stress and the resulting inflammation are essential pathological processes in acute lung injury (ALI). Nuclear factor erythroid 2-related factor 2 (Nrf2), a vital transcriptional factor, possesses antioxidative potential and has become a primary target to treat many diseases. Oridonin (Ori), isolated from the plant Rabdosia Rrubescens, is a natural substance that possesses antioxidative and anti-inflammatory effects. Our aim was to study whether the anti-inflammatory and antioxidant effects of Ori on LPS-induced ALI were mediated by Nrf2.MethodsMTT assays, Western blotting analysis, a mouse model, and hematoxylin-eosin (H & E) staining were employed to explore the mechanisms by which Ori exerts a protective effect on LPS-induced lung injury in RAW264.7 cells and in a mouse model.ResultsOur results indicated that Ori increased the expression of Nrf2 and its downstream genes (HO-1, GCLM), which was mediated by the activation of Akt and MAPK. Additionally, Ori inhibited LPS-induced activation of the pro-inflammatory pathways NLRP3 inflammasome and NF-B pathways. These two pathways were also proven to be Nrf2-independent by the use of a Nrf2 inhibitor. In keeping with these findings, Ori alleviated LPS-induced histopathological changes, the enhanced production of myeloperoxidase and malondialdehyde, and the depleted expression of GSH and superoxide dismutase in the lung tissue of mice. Furthermore, the expression of LPS-induced NLRP3 inflammasome and NF-B pathways was more evident in Nrf2-deficient mice but could still be reversed by Ori.ConclusionsOur results demonstrated that Ori exerted protective effects on LPS-induced ALI via Nrf2-independent anti-inflammatory and Nrf2-dependent antioxidative activities.