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KMID : 0383820160790040257
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Tuberculosis and Respiratory Diseases
2016 Volume.79 No. 4 p.257 ~ p.266
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Increased Cellular NAD+ Level through NQO1 Enzymatic Action Has Protective Effects on Bleomycin-Induced Lung Fibrosis in Mice
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Oh Gi-Su
Lee Su-Bin
Anjani Karna
Kim Hyung-Jin
AiHua Shen
Arpana Pandit
Lee Seung-Hoon
Yang Sei-Hoon
So Hong-Seob
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Abstract
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Background : Idiopathic pulmonary fibrosis is a common interstitial lung disease; it is a chronic, progressive, and fatal lung disease of unknown etiology. Over the last two decades, knowledge about the underlying mechanisms of pulmonary fibrosis has improved markedly and facilitated the identification of potential targets for novel therapies. However, despite the large number of antifibrotic drugs being described in experimental pre-clinical studies, the translation of these findings into clinical practices has not been accomplished yet. NADH:quinone oxidoreductase 1 (NQO1) is a homodimeric enzyme that catalyzes the oxidation of NADH to NAD+ by various quinones and thereby elevates the intracellular NAD+ levels. In this study, we examined the effect of increase in cellular NAD+ levels on bleomycin-induced lung fibrosis in mice.
Methods : C57BL/6 mice were treated with intratracheal instillation of bleomycin. The mice were orally administered with β-lapachone from 3 days before exposure to bleomycin to 1-3 weeks after exposure to bleomycin. Bronchoalveolar lavage fluid (BALF) was collected for analyzing the infiltration of immune cells. In vitro, A549 cells were treated with transforming growth factor β1 (TGF-β1) and β-lapachone to analyze the extracellular matrix (ECM) and epithelial-mesenchymal transition (EMT).
Results : β-Lapachone strongly attenuated bleomycin-induced lung inflammation and fibrosis, characterized by histological staining, infiltrated immune cells in BALF, inflammatory cytokines, fibrotic score, and TGF-β1, α-smooth muscle actin accumulation. In addition, β-lapachone showed a protective role in TGF-β1?induced ECM expression and EMT in A549 cells.
Conclusion : Our results suggest that β-lapachone can protect against bleomycin-induced lung inflammation and fibrosis in mice and TGF-β1?induced EMT in vitro, by elevating the NAD+/NADH ratio through NQO1 activation.
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KEYWORD
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Inflammation, Fibrosis, Transforming Growth Factor Beta1, Cell, NAD, Pulmonary Fibrosis, Mice, NQO1 Protein, Human
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