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Dasatinib Suppresses TGFβ-Mediated Epithelial–Mesenchymal Transition in Alveolar Epithelial Cells and Inhibits Pulmonary Fibrosis

  • Interstitial Lung Disease
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Abstract

Purpose

Transforming growth factor β (TGFβ)-mediated epithelial–mesenchymal transition (EMT) of alveolar epithelial cells contributes to pulmonary fibrosis. Dasatinib (DAS), a potent and broad-spectrum tyrosine kinase inhibitor, has been widely studied as an anti-cancer agent. However, the therapeutic application of DAS for pulmonary fibrosis has not been clarified. Our purpose here is to investigate the effect of DAS on TGFβ1-induced EMT in human alveolar and bronchial epithelial cells in vitro and to evaluate the efficacy of DAS on lung fibrosis in vivo.

Methods

TGFβ1-stimulated human alveolar epithelial (A549) and bronchial epithelial (BEAS-2B) cells were treated with or without DAS in vitro. Murine pulmonary fibrosis model was generated by injection of bleomycin (BLM).

Results

A549 and BEAS-2B cells exposed to TGFβ1 underwent EMT, as indicated by downregulation of epithelial protein E-cadherin and induction of the mesenchymal proteins, fibronectin and type I and type IV collagen. These effects were dramatically suppressed by DAS treatment, which also prevented Smad2 and Smad3 phosphorylation. DAS inhibited TGFβ1-induced cell motility and migration. Furthermore, DAS administration significantly attenuated lung fibrosis in mice by histological analysis. Treatment with DAS also significantly reduced the levels of collagen and fibronectin and phosphorylation of Smad2 in the lung tissues of the murine model.

Conclusions

These findings suggest that DAS inhibited TGFβ-mediated EMT of alveolar and bronchial epithelial cells and attenuated BLM-induced lung fibrosis in mice by suppressing the TGFβ/Smad pathway. DAS may be a promising and novel anti-fibrotic agent for preventing lung fibrosis.

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Abbreviations

DAS:

Dasatinib

IPF:

Idiopathic pulmonary fibrosis

ECM:

Extracellular matrix

TGF:

Transforming growth factor

EMT:

Epithelial mesenchymal transition

BLM:

Bleomycin

HE:

Hematoxylin-Eosin

MT:

Masson-Trichrome

qPCR:

Quantitative polymerase chain reaction

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Acknowledgements

We appreciate the advice and expertise of Ms. Etsuko Kobayashi, Juntendo University Graduate School of Medicine.

Funding

This study was supported by JSPS KAKENHI Grant Number 26461200. This study was also funded by Research Grants from the Satoshi Okamoto Memorial Foundation of Pulmonary Fibrosis, Japan Research Foundation for Clinical Pharmacology, Mochida Memorial Foundation for Medical and Pharmaceutical Research, and Yokoyama Foundation for Clinical Pharmacology.

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Authors and Affiliations

  1. Department of Respiratory Medicine, Juntendo University, Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan

    Ryota Kanemaru, Fumiyuki Takahashi, Motoyasu Kato, Yoichiro Mitsuishi, Ken Tajima, Hiroaki Ihara, Moulid Hidayat, Aditya Wirawan, Yoshika Koinuma, Daisuke Hayakawa, Shigehiro Yagishita, Ryo Ko, Tadashi Sato, Norihiro Harada, Yuzo Kodama, Fariz Nurwidya, Shinichi Sasaki & Kazuhisa Takahashi

  2. Research Institute for Diseases of Old Ages, Juntendo University, Graduate School of Medicine, Tokyo, Japan

    Ryota Kanemaru, Fumiyuki Takahashi, Motoyasu Kato, Yoichiro Mitsuishi, Ken Tajima, Hiroaki Ihara, Moulid Hidayat, Aditya Wirawan, Yoshika Koinuma, Daisuke Hayakawa, Shigehiro Yagishita, Ryo Ko, Tadashi Sato, Norihiro Harada, Yuzo Kodama, Fariz Nurwidya, Shinichi Sasaki & Kazuhisa Takahashi

  3. Leading Center for the Development and Research of Cancer Medicine, Juntendo University, Graduate School of Medicine, Tokyo, Japan

    Kazuhisa Takahashi

  4. Link Genomics, Incorporated, Tokyo, Japan

    Shin-ichiro Niwa

Authors
  1. Ryota Kanemaru
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  2. Fumiyuki Takahashi
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  19. Kazuhisa Takahashi
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Corresponding author

Correspondence to Fumiyuki Takahashi.

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Conflict of interest

The authors declare no conflicts of interest for this work.

Ethical Approval

All animal experiments were carried out in accordance with the Fundamental Guidelines for Proper Conduct of Animal Experiment and Related Activities in Academic Research Institutions under the jurisdiction of the Ministry of Education, Culture, Sports, Science and Technology (Notice No. 71, 2006) and approved by the Committee for Animal Experimentation of Juntendo University with the Approval No. 290031.

Research Involving Human Participants

This article does not contain any studies with human participants performed by any of the authors.

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Kanemaru, R., Takahashi, F., Kato, M. et al. Dasatinib Suppresses TGFβ-Mediated Epithelial–Mesenchymal Transition in Alveolar Epithelial Cells and Inhibits Pulmonary Fibrosis. Lung 196, 531–541 (2018). https://doi.org/10.1007/s00408-018-0134-6

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  • DOI: https://doi.org/10.1007/s00408-018-0134-6

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