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

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 beta 1 (TGF-beta 1)-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-beta 1-induced EMT and ROS production accompanied by the downregulation of HMGB1. In contrast, silencing Nrf2 enhanced TGF-beta 1-induced EMT and ROS production along with increased the protein expression and the release of HMGB1. Moreover, HMGB1 activation aggravated TGF-beta 1-induced EMT and HMGB1 deficiency alleviated TGF-beta 1-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.