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Downregulation of HMGB1 is required for the protective role of Nrf2 in EMT‐mediated PF
Author(s) -
Gao Jian
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.07547
Subject(s) - hmgb1 , western blot , epithelial–mesenchymal transition , myofibroblast , chemistry , downregulation and upregulation , cancer research , fibrosis , pulmonary fibrosis , a549 cell , extracellular matrix , transforming growth factor , immunohistochemistry , inflammation , microbiology and biotechnology , immunology , cell , pathology , biology , medicine , biochemistry , gene
Aim Pulmonary fibrosis (PF) is an interstitial lung disease 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 in 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 are no direct evidences regarding the relationship between Nrf2 and HMGB1 in PF. Methods PF animal model was established by intratracheal injection of bleomycin. Histological morphology of the lungs were reflected by H&E staining and Masson staining. The expressions of Nrf2, HMGB1 and EMT associated markers were determined by Western blot or immunohistochemistry. In vitro, the effect of Nrf2, HMGB1 and the relationship between them in TGF‐β1‐induced EMT were determined by western blot , coupled using respective pharmacological activators or transfection with siRNA. Results EMT was aggravated and the expression of HMGB1 was significantly elevated in Nrf2−/− mice compared with WT mice exposed to BLM. Moreover, the uptake of exogenous Nrf2 or ablation of HMGB1 ameliorated TGF‐β1‐induced EMT in rat type II alveolar epithelial cell line (RLE‐6TN) and human alveolar epithelial cell line(A549). In contrast, Nrf2 deficiency or HMGB1 activation aggravated TGF‐β1‐induced EMT. Furthermore, inhibition of HMGB1 diminished the protective effect of Nrf2 on EMT. Conclusion These findings suggest that the inhibitory effect of HMGB1 on EMT in PF is regulated by Nrf2 and provides a new strategy of clinical treatment for PF. Support or Funding Information This work was supported by the National Natural Science Foundation of China( No.: 8197141254, 81274172, 81473267, 81503330 and 81503129 ).