Induction of EMT-like phenotypes by an active metabolite of leflunomide and its contribution to pulmonary fibrosis

T. Namba, K. I. Tanaka, Y. Ito, Tatsuya Hoshino, M. Matoyama, N. Yamakawa, Y. Isohama, A. Azuma, T. Mizushima

研究成果: Article査読

33 被引用数 (Scopus)

抄録

Drug-induced interstitial lung disease (ILD), particularly pulmonary fibrosis, is a serious clinical concern and myofibroblasts have been suggested to have a major role, with it recently being revealed that some of these myofibroblasts are derived from lung epithelial cells through epithelial-mesenchymal transition (EMT). In this study, we examined the EMT-inducing abilities of drugs known to induce ILD clinically. EMT-like phenotypes were induced by A771726, an active metabolite of leflunomide having an inhibitory effect on dihydroorotate dehydrogenase (DHODH). Smad-interacting protein 1 (a transcription factor regulating EMT) and the Notch-signaling pathway but not transforming growth factor-Β was shown to be involved in A771726-induced EMT-like phenotypes. When the cultures were supplemented with exogenous uridine, the A771726-induced EMT-like phenotypes and activation of the Notch-signaling pathway disappeared. Similarly, an A771726 analog without inhibitory activity on DHODH produced no induction, suggesting that this process is mediated through the inhibition of DHODH. In vivo, administration of leflunomide stimulated bleomycin-induced EMT-like phenomenon in pulmonary tissue, and exacerbated bleomycin-induced pulmonary fibrosis, both of which were suppressed by coadministration of uridine. Taken together, these findings suggest that leflunomide-dependent exacerbation of bleomycin-induced pulmonary fibrosis is mediated by stimulation of EMT of lung epithelial cells, providing the first evidence that drug-induced pulmonary fibrosis involves EMT of these cells.

本文言語English
ページ(範囲)1882-1895
ページ数14
ジャーナルCell Death and Differentiation
17
12
DOI
出版ステータスPublished - 2010 12月

ASJC Scopus subject areas

  • 分子生物学
  • 細胞生物学

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