Tuberculosis and Respiratory Diseases

The Korean Academy of Tuberculosis and Respiratory Diseases (대한결핵및호흡기학회)
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Increased Cellular NAD+ Level through NQO1 Enzymatic Action Has Protective Effects on Bleomycin-Induced Lung Fibrosis in Mice

  • Oh, Gi-Su (Department of Microbiology, Center for Metabolic Function Regulation, Wonkwang University School of Medicine) ;
  • Lee, Su-Bin (Department of Microbiology, Center for Metabolic Function Regulation, Wonkwang University School of Medicine) ;
  • Karna, Anjani (Department of Microbiology, Center for Metabolic Function Regulation, Wonkwang University School of Medicine) ;
  • Kim, Hyung-Jin (Department of Microbiology, Center for Metabolic Function Regulation, Wonkwang University School of Medicine) ;
  • Shen, AiHua (Department of Microbiology, Center for Metabolic Function Regulation, Wonkwang University School of Medicine) ;
  • Pandit, Arpana (Department of Microbiology, Center for Metabolic Function Regulation, Wonkwang University School of Medicine) ;
  • Lee, SeungHoon (Department of Microbiology, Center for Metabolic Function Regulation, Wonkwang University School of Medicine) ;
  • Yang, Sei-Hoon (Department of Internal Medicine, Wonkwang University School of Medicine) ;
  • So, Hong-Seob (Department of Microbiology, Center for Metabolic Function Regulation, Wonkwang University School of Medicine)
  • Received : 2015.12.10
  • Accepted : 2016.05.26
  • Published : 2016.10.05
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Abstract

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 ${\beta}$-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 ${\beta}1$ (TGF-${\beta}1$) and ${\beta}$-lapachone to analyze the extracellular matrix (ECM) and epithelial-mesenchymal transition (EMT). Results: ${\beta}$-Lapachone strongly attenuated bleomycin-induced lung inflammation and fibrosis, characterized by histological staining, infiltrated immune cells in BALF, inflammatory cytokines, fibrotic score, and TGF-${\beta}1$, ${\alpha}$-smooth muscle actin accumulation. In addition, ${\beta}$-lapachone showed a protective role in TGF-${\beta}1$-induced ECM expression and EMT in A549 cells. Conclusion: Our results suggest that ${\beta}$-lapachone can protect against bleomycin-induced lung inflammation and fibrosis in mice and TGF-${\beta}1$-induced EMT in vitro, by elevating the $NAD^+$/NADH ratio through NQO1 activation.

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References

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