Abstract
Idiopathic pulmonary fibrosis is a progressive fatal disease characterized by interstitial remodeling, with high lethality and a lack of effective medical therapies. Tetrandrine has been proposed to present anti-fibrotic effects, but the efficacy and mechanisms have not been systematically evaluated. We sought to study the potential therapeutic effects and mechanisms of tetrandrine against lung fibrosis. The anti-fibrotic effects of tetrandrine were evaluated in bleomycin-induced mouse models and TGF-β1-stimulated murine lung fibroblasts. We performed Chromatin Immunoprecipitation (ChIP), Immunoprecipitation (IP), and mRFP-GFP-MAP1LC3B adenovirus construct to investigate the novel mechanisms of tetrandrine-induced autophagy. Tetrandrine decreased TGF-β1-induced expression of α-smooth muscle actin, fibronectin, vimentin, and type 1 collagen and proliferation in fibroblasts. Tetrandrine restored TGF-β1-induced impaired autophagy flux, accompanied by enhanced interaction of SQSTM1 and MAP1LC3-Ⅱ. ChIP studies revealed that tetrandrine induced autophagy via increasing binding of NRF2 and SQSTM1 promoter. Furthermore, tetrandrine inhibited TGF-β1-induced phosphorylation of mTOR by reducing activation of Rheb. In vivo tetrandrine suppressed the bleomycin-induced expression of fibrotic markers and improved pulmonary function. Our data suggest that protective effect of tetrandrine against lung fibrosis might be through promoting Rheb-mTOR and NRF2-SQSTM1 mediated autophagy. Tetrandrine may thus be potentially employed as a novel therapeutic medicine against IPF.
Highlights
Idiopathic pulmonary fibrosis is a prototype of chronic, progressive, and fibrotic lung disease, characterized by repetitive injury of the lung epithelium, activation and proliferation of fibroblasts, and accumulation of extracellular matrix (King et al, 2011; Hutchinson et al, 2015)
We provide evidences that Treatment of Pulmonary FibrosisTetrandrine (TET) can resolve pulmonary fibrosis through inhibiting myofibroblast differentiation, proliferation, and extracellular matrix (ECM) deposition
We found that TET can enhance the interaction of SQSTM1 with MAP1LC3-II and ubiquitinated proteins due to NRF2-mediated SQSTM1 transcription and Ras homolog enriched in the brain gene (Rheb)-mTOR signaling activation, dramatically inducing SQSTM1selective autophagy and directly leading to Col-I degradation in lysosome (Figure 10)
Summary
Idiopathic pulmonary fibrosis is a prototype of chronic, progressive, and fibrotic lung disease, characterized by repetitive injury of the lung epithelium, activation and proliferation of (myo) fibroblasts, and accumulation of extracellular matrix (King et al, 2011; Hutchinson et al, 2015). Despite this high unmet clinical need, only two anti-fibrotics drugs, Pirfenidone and nintedanib, have been approved to be effective in slowing down the decline of lung function in IPF patients. The mechanism underlying the protective effects of TET on lung fibrosis remains unclear
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