Downregulation of HMGB1 is required for the protective role of Nrf2 in EMT‐mediated PF

Abstract

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.