Involvement of epithelial-mesenchymal transition in methotrexate-induced pulmonary fibrosis

• Ohbayashi Masayuki

  Division of Clinical Pharmacy, Department of Pharmacotherapeutics, School of Pharmacy, Showa University

• Kubota Satoshi

  Division of Clinical Pharmacy, Department of Pharmacotherapeutics, School of Pharmacy, Showa University

• Kawase Aya

  Division of Clinical Pharmacy, Department of Pharmacotherapeutics, School of Pharmacy, Showa University

• Kohyama Noriko

  Division of Clinical Pharmacy, Department of Pharmacotherapeutics, School of Pharmacy, Showa University

• Kobayashi Yasuna

  Division of Clinical Pharmacy, Department of Pharmacotherapeutics, School of Pharmacy, Showa University

• Yamamoto Toshinori

  Division of Clinical Pharmacy, Department of Pharmacotherapeutics, School of Pharmacy, Showa University

Abstract

Epithelial-mesenchymal transition (EMT) plays a pivotal event in the development of pulmonary fibrosis. We have previously reported that methotrexate (MTX)-induced alveolar epithelial cell injury followed by pulmonary fibrosis as a result of the recruitment and proliferation of myofibroblasts. However, there is no data concerning whether EMT occurs in MTX-induced pulmonary fibrosis. In the present study, therefore, we investigated the expression of EMT markers such as E-cadherin, α-SMA, and vimentin by immunofluorescence analysis in mouse lung tissues after administration of MTX. We found that vimentin and α-SMA-positive cells of the MTX-induced pulmonary fibrosis were increased; on the other hand, E-cadherin was decreased, indicating that epithelial cells act as the main source of mesenchymal expansion. These results exhibited the down-regulation of E-cadherin expression and the up-regulation of α-smooth muscle actin (α-SMA) in primary mouse alveolar epithelial cells (MAECs) and A549 cell lines. Additionally, MTX-induced A549 cells exhibited an EMT-like phenotype accompanied by the elevation of the expression of interleukin-6 (IL-6) and transforming growth factor (TGF)-β1, as well as an enhancement of migration. All of these findings suggest that MTX-induced pulmonary fibrosis occurs via EMT.

Journal

• The Journal of Toxicological Sciences

  The Journal of Toxicological Sciences 39 (2), 319-330, 2014

  The Japanese Society of Toxicology

Keywords

• Methotrexate
• Pulmonary toxicity
• Epithelial mesenchymal transition
• Alveolar epithelial cell

Details

• CRID: 1390282679882400256
• NII Article ID: 130004903994
• NII Book ID: AN00002808
• DOI: 10.2131/jts.39.319
• COI: 1:STN:280:DC%2BC2crltlCnsA%3D%3D
• ISSN: 18803989
• ISSN: 03881350
• NDL BIB ID: 025456440
• PubMed: 24646714
• Web Site: https://ndlsearch.ndl.go.jp/books/R000000004-I025456440
• Web Site: https://www.jstage.jst.go.jp/article/jts/39/2/39_319/_pdf
• Web Site: https://search.jamas.or.jp/link/ui/2015061884
• Text Lang: en
• Data Source:
  • JaLC
  • NDL
  • Crossref
  • PubMed
  • CiNii Articles
  • KAKEN
• Abstract License Flag: Disallowed