Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive, life-threatening lung disease characterized by the proliferation of myofibroblasts and deposition of extracellular matrix that results in irreversible distortion of the lung structure and the formation of focal fibrosis. The molecular mechanism of IPF is not fully understood, and there is no satisfactory treatment. However, most studies suggest that abnormal activation of transforming growth factor-β1 (TGF-β1) can promote fibroblast activation and epithelial to mesenchymal transition (EMT) to induce pulmonary fibrosis. Deglycosylated azithromycin (Deg-AZM) is a compound we previously obtained by removing glycosyls from azithromycin; it was demonstrated to exert little or no antibacterial effects. Here, we discovered a new function of Deg-AZM in pulmonary fibrosis. In vivo experiments showed that Deg-AZM could significantly reduce bleomycin-induced pulmonary fibrosis and restore respiratory function. Further study revealed the anti-inflammatory and antioxidant effects of Deg-AZM in vivo. In vitro experiments showed that Deg-AZM inhibited TGF-β1 signaling, weakened the activation and differentiation of lung fibroblasts, and inhibited TGF-β1-induced EMT in alveolar epithelial cells. In conclusion, our findings show that Deg-AZM exerts antifibrotic effects by inhibiting TGF-β1-induced myofibroblast activation and EMT.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fibrous interstitial lung disease with unknown etiology [1]
hematoxylin and eosin (H&E) staining was performed to evaluate the degree of pulmonary fibrosis
Masson’s trichrome staining (Figure 2C) and hydroxyproline (HYP) analysis revealed serious collagen deposition in the model group, and Deglycosylated azithromycin (Deg-AZM) treatment reduced the collagen content, especially for the high dose group (~43% decreased compared to BLM group, Figure 2D). These results demonstrate that Deg-AZM can attenuate bleomycininduced pulmonary fibrosis
Summary
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fibrous interstitial lung disease with unknown etiology [1]. Much of the pathogenesis of IPF remains to be elucidated, the major paradigm is that aberrant injury-associated remodeling of epithelial cells induces myofibroblast activation through multiple cytokines and inflammatory factors, and these myofibroblasts in turn produce excessive ECM and promote fibrogenesis [4,5,6,7]. Among these cytokines, transforming growth factor-β1 (TGF-β1) is the strongest profibrotic mediator because it simultaneously contributes to epithelial cell injury and myofibroblast differentiation. Inhibiting TGF-β1-induced fibroblast activation and EMT may be an effective strategy for IPF treatment
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