O29 Nrf2/HO-1 pathway alleviates epithelial-mesenchymal transition by inhibiting HMGB1 expression in pulmonary fibrosis

Abstract

Pulmonary fibrosis (PF) is a chronic, interstitial lung disease with unknown cause, characterized by the activation of accumulated myofibroblasts and deposition of extracellular matrix (ECM). Epithelial-mesenchymal transition (EMT) is considered to be one of the major hypotheses behind the formation of PF. High mobility group box1 (HMGB1) plays an important biological role in infection, inflammation, and immune responses. Nuclear factor E2-related factor 2 (Nrf2) is an important transcription factor for the regulation of oxidative stress. However, there is no direct evidence regarding the relationship between the Nrf2/HO-1 antioxidant system and HMGB1 in lung fibrosis. In our studies, the PF model was induced with bleomycin in both wild type (WT) mice and Nrf2 −/− mice. Rat type II alveolar epithelial cells (RLE-6TN) and the human alveolar epithelial cell line A549 were treated with the Nrf2 activator, sulforaphane, or transfected with Nrf2 and HMGB1 siRNAs to explore their relationship in TGF-β-induced PF. This research showed that bleomycin-induced fibrosis was more severe in Nrf2 −/− mice compared to WT mice. In the in vitro experiments, sulforaphane-treated cells had significantly attenuated TGF-β-induced epithelial-mesenchymal transition accompanied by downregulated expression of HMGB1. In contrast, silencing Nrf2 by siRNA enhanced TGFβ1-induced EMT with increased expression of HMGB1. However, when HMGB1 was silenced by siRNA, sulforaphane could not reduce the progression of EMT in either RLE-6TN cells or A549 cells. These findings suggest that the inhibitory effect of HMGB1 on EMT in PF is regulated by the Nrf2/HO-1 antioxidant pathway.