Blockade of Pan-Fibroblast Growth Factor Receptors Mediates Bidirectional Effects in Lung Fibrosis

[Rationale] Fibroblast growth factors (FGF) are major factors associated with the pathogenesis of pulmonary fibrosis. Nintedanib, a tyrosine kinase inhibitor targeting several growth factor receptors including the FGF receptor (FGFR), has been approved for the treatment of idiopathic pulmonary fibrosis (IPF). On the other hand, recent reports suggest that FGF are required for epithelial recovery. In this study, we focused on FGF signaling to both fibroblasts and alveolar epithelial cells (AECs), and examined the effect of a pan-FGFR blocker on experimental pulmonary fibrosis in mice.
[Methods] The effects of BGJ398, a pan-FGFR inhibitor, on the migration and proliferation of fibroblasts and AECs were assessed using transwell migration or 3H-thymidine incorporation assays. The expression of FGFR was analyzed using immunoblot or flow cytometry. We also investigated the effect of BGJ398 on the pulmonary fibrosis induced by bleomycin in mice.
[Results] Both lung fibroblasts and AECs expressed FGFRs. BGJ398 significantly inhibited the proliferation and migration of lung fibroblasts stimulated with FGF2. BGJ398 also reduced the proliferation of AECs in response to FGF2. Although the administration of BGJ398 ameliorated pulmonary fibrosis in bleomycin-treated mice, it increased mortality due to alveolar injury and inhibition of AEC regeneration.
[Conclusions] These data suggest that the total inhibition of FGFR signaling can suppress lung fibrosis by inhibiting fibroblast activities, although alveolar injury is simultaneously caused.

内容要旨・審査要旨・論文本文の公開
本論文は，著者Shun Morizumiの学位論文として提出され，学位審査・授与の対象となっている。
Originally Published in: Shun Morizumi, Seidai Sato, Kazuya Koyama, Hiroyasu Okazaki, Yajuan Chen, Hisatsugu Goto, Kozo Kagawa, Hirohisa Ogawa, Haruka Nishimura, Hiroshi Kawano, Yuko Toyoda, Hisanori Uehara, Yasuhiko Nishioka. Blockade of Pan-Fibroblast Growth Factor Receptors Mediates Bidirectional Effects in Lung Fibrosis. American Journal of Respiratory Cell and Molecular Biology 2020; Volume 63, Issue 3: Pages 317-326.
The final publication is available at https://www.atsjournals.org/doi/10.1165/rcmb.2019-0090OC

Copyright © 2020 by the American Thoracic Society