Abstract
Abstract
Background: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 a critical transcription factor for the regulation of oxidative stress. However, there are no direct evidences regarding the molecular mechanism of Nrf2,HMGB1 and the relationship between them in EMT-mediated PF.
Methods: PF animal model was established by intratracheal injection of bleomycin(BLM). Histological morphology of the lungs was reflected by HE 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 transforming growth factor &beta1(TGF&beta1) 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 knockout mice compared with WT mice exposed to BLM. Moreover, the uptake of exogenous Nrf2 or ablation of HMGB1 ameliorated TGF&beta1 induced EMT in rat alveolar epithelial cell line(RLE-6TN) and human alveolar epithelial cell line(A549). In contrast, Nrf2 deficiency or HMGB1 activation aggravated TGF&beta1 induced EMT. Furthermore, inhibition of HMGB1 diminished the protective effect of Nrf2 on EMT.
Conclusion: These findings suggest that the stimulative effect of HMGB1 on EMT in PF is regulated by Nrf2 and provide a new strategy of clinical treatment for PF.
Keywords: Pulmonary fibrosis, Nuclear factor E2 related factor 2, High mobility group box1
Corresponding to:
Prof. Jian Gao, PhD,
Second Affiliated Hospital of Dalian Medical University,
467 Zhongshan Road,
Dalian, Liaoning, 116023, China
Tel: 0411-84663471
Fax: 0411-84672130
Email: gaojianayfy@163.com
