Tuberculosis and Respiratory Diseases

  • 제82권1호
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  • Pages.42-52
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  • 2019
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  • 1738-3536(pISSN)
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  • 2005-6184(eISSN)
대한결핵및호흡기학회 (The Korean Academy of Tuberculosis and Respiratory Diseases)
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The Effects of Retinoic Acid and MAPK Inhibitors on Phosphorylation of Smad2/3 Induced by Transforming Growth Factor β1

  • Lee, Sang Hoon (Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Institute of Chest Diseases, Severance Hospital, Younsei University Health System, Yonsei University College of Medicine) ;
  • Shin, Ju Hye (Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Institute of Chest Diseases, Severance Hospital, Younsei University Health System, Yonsei University College of Medicine) ;
  • Shin, Mi Hwa (Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Institute of Chest Diseases, Severance Hospital, Younsei University Health System, Yonsei University College of Medicine) ;
  • Kim, Young Sam (Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Institute of Chest Diseases, Severance Hospital, Younsei University Health System, Yonsei University College of Medicine) ;
  • Chung, Kyung Soo (Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Institute of Chest Diseases, Severance Hospital, Younsei University Health System, Yonsei University College of Medicine) ;
  • Song, Joo Han (Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Institute of Chest Diseases, Severance Hospital, Younsei University Health System, Yonsei University College of Medicine) ;
  • Kim, Song Yee (Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Institute of Chest Diseases, Severance Hospital, Younsei University Health System, Yonsei University College of Medicine) ;
  • Kim, Eun Young (Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Institute of Chest Diseases, Severance Hospital, Younsei University Health System, Yonsei University College of Medicine) ;
  • Jung, Ji Ye (Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Institute of Chest Diseases, Severance Hospital, Younsei University Health System, Yonsei University College of Medicine) ;
  • Kang, Young Ae (Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Institute of Chest Diseases, Severance Hospital, Younsei University Health System, Yonsei University College of Medicine) ;
  • Chang, Joon (Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Institute of Chest Diseases, Severance Hospital, Younsei University Health System, Yonsei University College of Medicine) ;
  • Park, Moo Suk (Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Institute of Chest Diseases, Severance Hospital, Younsei University Health System, Yonsei University College of Medicine)
  • 투고 : 2017.09.28
  • 심사 : 2018.03.23
  • 발행 : 2019.01.31
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초록

Background: Transforming growth factor ${\beta}$ (TGF-${\beta}$), retinoic acid (RA), p38 mitogen-activated protein kinase (MAPK), and MEK signaling play critical roles in cell differentiation, proliferation, and apoptosis. We investigated the effect of RA and the role of these signaling molecules on the phosphorylation of Smad2/3 (p-Smad2/3) induced by TGF-${\beta}1$. Methods: A549 epithelial cells and CCD-11Lu fibroblasts were incubated and stimulated with or without all-trans RA (ATRA) and TGF-${\beta}1$ and with MAPK or MEK inhibitors. The levels of p-Smad2/3 were analyzed by western blotting. For animal models, we studied three experimental mouse groups: control, bleomycin, and bleomycin+ATRA group. Changes in histopathology, lung injury score, and levels of TGF-${\beta}1$ and Smad3 were evaluated at 1 and 3 weeks. Results: When A549 cells were pre-stimulated with TGF-${\beta}1$ prior to RA treatment, RA completely inhibited the p-Smad2/3. However, when A549 cells were pre-treated with RA prior to TGF-${\beta}1$ stimulation, RA did not completely suppress the p-Smad2/3. When A549 cells were pre-treated with MAPK inhibitor, TGF-${\beta}1$ failed to phosphorylate Smad2/3. In fibroblasts, p38 MAPK inhibitor suppressed TGF-${\beta}1$-induced p-Smad2. In a bleomycin-induced lung injury mouse model, RA decreased the expression of TGF-${\beta}1$ and Smad3 at 1 and 3 weeks. Conclusion: RA had inhibitory effects on the phosphorylation of Smad induced by TGF-${\beta}1$ in vitro, and RA also decreased the expression of TGF-${\beta}1$ at 1 and 3 weeks in vivo. Furthermore, pre-treatment with a MAPK inhibitor showed a preventative effect on TGF-${\beta}1$/Smad phosphorylation in epithelial cells. As a result, a combination of RA and MAPK inhibitors may suppress the TGF-${\beta}1$-induced lung injury and fibrosis.

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