The Second Affiliated Hospital and School of Pharmacy, Dalian Medical University, Dalian, Liaoning, China.
The First Affiliated Hospital and School of Pharmacy, Anhui Medical University, Hefei, Anhui, China.
J Cell Physiol. 2019 Jun;234(6):8862-8872. doi: 10.1002/jcp.27548. Epub 2018 Oct 28.
Epithelial-mesenchymal transition (EMT) is considered to be the key event in the formation of pulmonary fibrosis (PF). High-mobility group box 1 (HMGB1) is a novel mediator of EMT. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a critical transcription factor for protecting against PF. However, it is unknown the relationship between Nrf2 and HMGB1 in EMT-mediated PF. Bleomycin (BLM)-induced PF in Nrf2-knockout (Nrf2 ) and wild-type (WT) mice and transforming growth factor β1 (TGF-β1)-induced EMT in rat type II alveolar epithelial cell line (RLE-6TN) and human alveolar epithelial cell line (A549) were established to observe the relationship among Nrf2, HMGB1, and EMT by western blot and immunohistochemistry. BLM-induced EMT was more severe and the expression of HMGB1 was more increased in Nrf2 mice compared with WT mice. In vitro, Nrf2 activation attenuated TGF-β1-induced EMT and ROS production accompanied by the downregulation of HMGB1. In contrast, silencing Nrf2 enhanced TGF-β1-induced EMT and ROS production along with increased the protein expression and the release of HMGB1. Moreover, HMGB1 activation aggravated TGF-β1-induced EMT and HMGB1 deficiency alleviated TGF-β1-induced EMT. Furthermore, HMGB1 silence attenuated the protective effect of Nrf2 on EMT. These findings suggest downregulation of HMGB1, which is required for the protective role of Nrf2 in EMT-mediated PF and provide an important therapeutic target for PF.
上皮间质转化（EMT）被认为是肺纤维化（PF）形成的关键事件。高迁移率族蛋白 B1（HMGB1）是 EMT 的新型介质。核因子红细胞 2 相关因子 2（Nrf2）是保护 PF 的关键转录因子。然而，Nrf2 和 HMGB1 在 EMT 介导的 PF 中的关系尚不清楚。建立了 Nrf2 敲除（Nrf2-/-）和野生型（WT）小鼠博莱霉素（BLM）诱导的 PF 以及大鼠 II 型肺泡上皮细胞系（RLE-6TN）和人肺泡上皮细胞系（A549）转化生长因子 β1（TGF-β1）诱导的 EMT，通过 Western blot 和免疫组织化学观察 Nrf2、HMGB1 和 EMT 之间的关系。与 WT 小鼠相比，BLM 诱导的 EMT 更严重，HMGB1 的表达增加更多。在体外，Nrf2 激活减弱了 TGF-β1 诱导的 EMT 和 ROS 产生，伴随着 HMGB1 的下调。相反，沉默 Nrf2 增强了 TGF-β1 诱导的 EMT 和 ROS 产生，同时增加了 HMGB1 的蛋白表达和释放。此外，HMGB1 激活加剧了 TGF-β1 诱导的 EMT，HMGB1 缺乏减轻了 TGF-β1 诱导的 EMT。此外，HMGB1 沉默减弱了 Nrf2 对 EMT 的保护作用。这些发现表明，HMGB1 的下调是 Nrf2 在 EMT 介导的 PF 中发挥保护作用所必需的，为 PF 提供了一个重要的治疗靶点。
