1. Academic Validation
  2. Attenuation of pulmonary fibrosis in type I collagen-targeted reporter mice with ALK-5 inhibitors

Attenuation of pulmonary fibrosis in type I collagen-targeted reporter mice with ALK-5 inhibitors

  • Pulm Pharmacol Ther. 2019 Feb;54:31-38. doi: 10.1016/j.pupt.2018.11.005.
Hideki Terashima 1 Misato Aonuma 2 Hiroshi Tsuchida 3 Kotaro Sugimoto 4 Mika Yokoyama 5 Mikio Kato 5
Affiliations

Affiliations

  • 1 Biomarker Research Department, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: terashima.hideki.jw@daiichisankyo.co.jp.
  • 2 Discovery Science and Technology Department, Daiichi Sankyo Novare Co., Ltd, 1-16-3 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
  • 3 Department of Pathology, University of Washington, 850 Republican St, Seattle, WA 98109, USA.
  • 4 Medical Science Department, Medical Affairs Division, Daiichi Sankyo Co., Ltd, 3-5-1, Nihonbashi Honcho, Chuo-ku, Tokyo 103-8426, Japan.
  • 5 End-Organ Disease Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease, and consequently, effective antifibrotic drugs are strongly desired. Although we have previously reported a validated Col1a1-Luc Tg rat model for fibrosis, there are only a few mouse models that enable the evaluation of fibrosis in a short time period and with high sensitivity. Therefore, we generated a Col1a1-internal ribosome entry site (IRES)-Luc knock-in (KI) mouse in which the IRES-luciferase gene construct was inserted into the 3'-UTR of the type I collagen alpha 1 gene (Col1a1). There was a high correlation between luciferase activity and hydroxyproline content in the KI mice, which is similar to the result that we have previously reported for the Col1a1-Luc Tg rat model. In a bleomycin (BLM)-induced lung fibrosis model, luciferase activity in the lung showed a significant increase 3 days after BLM treatment, while only a slight increase was observed in the hydroxyproline content. An ALK-5 inhibitor-R-268712-was effective in inhibiting the luciferase activity in both the in vivo BLM-induced lung fibrosis model and in vitro primary mouse lung fibroblasts. This suggests that fibroblasts are the major collagen-producing cells in lung fibrosis. In human lung fibroblasts, TGF-β stimulation induced α-smooth muscle actin as observed by immunostaining, suggesting that myofibroblast transdifferentiation (MTD) plays an important role in lung fibrosis. Together, these results indicated that ALK-5 inhibitors might affect lung fibrosis mainly via the inhibition of MTD. Thus, the Col1a1-IRES-Luc KI mouse might be useful for the evaluation of antifibrotic effects and their underlying mechanisms.

Keywords

ALK-5; Bleomycin; Collagen; Fibrosis; Knock-in; TGF-β.

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