Protective and therapeutic effect of felodipine against bleomycin-induced pulmonary fibrosis in mice

Ken-Ichiro Tanaka,Shota Kurotsu,Tomoaki Ishihara,Tomomi Niino,Takahiro Takayama,Fumiya Tamura,Tohru Mizushima,Toshifumi Sugizaki,Masahiro Kawahara,Ayaka Takafuji,Yuki Kanda

doi:10.1038/s41598-017-03676-y

Ken-Ichiro Tanaka, Shota Kurotsu + Show 9 more

Open Access

https://doi.org/10.1038/s41598-017-03676-y

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Abstract

Idiopathic pulmonary fibrosis (IPF) involves alveolar epithelial injury and abnormal collagen production caused by activated fibroblasts; transforming growth factor (TGF)-β1 is implicated in this activation. In this study, we screened for chemicals capable of inhibiting TGF-β1-induced collagen production in cultured fibroblasts from medicines already in clinical use. We selected felodipine based on its extent of collagen production inhibition, clinical safety profile, and other pharmacological activity. Felodipine is a dihydropyridine Ca2+ channel blocker that has been used clinically to treat patients with high blood pressure. Felodipine suppressed collagen production within LL29 cells in the presence of TGF-β1, but not in its absence. Intratracheal administration of felodipine prevented bleomycin-induced pulmonary fibrosis, alteration of lung mechanics and respiratory dysfunction. Felodipine also improved pulmonary fibrosis, as well as lung and respiratory function when administered after fibrosis development. Furthermore, administration of felodipine suppressed a bleomycin-induced increase in activated fibroblasts in the lung. We also found other dihydropyridine Ca2+ channel blockers (nifedipine and benidipine) inhibited collagen production in vitro and partially prevented bleomycin-induced pulmonary fibrosis, alteration of lung mechanics and respiratory dysfunction in vivo. We propose that these Ca2+ channel blockers may be therapeutically beneficial for IPF patients.

Highlights

Idiopathic pulmonary fibrosis (IPF) is a progressive and devastating chronic lung condition with poor prognosis; mean length of survival from time of diagnosis is 2.8–4.2 years[1, 2]
We propose that dihydropyridine Ca2+ channel blockers may be therapeutically beneficial for IPF patients
From a library of medicines already in clinical use, we screened for compounds capable of inhibiting collagen production in the presence of Transforming growth factor (TGF)-β1 without affecting cell viability in NIH3T3, HFL1, WI-38 and IMR-90 cells

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF) is a progressive and devastating chronic lung condition with poor prognosis; mean length of survival from time of diagnosis is 2.8–4.2 years[1, 2]. Chemicals capable of suppressing TGF-β1-induced production of collagen represent good candidates to treat IPF patients. Both pirfenidone and nintedanib have been reported to suppress collagen production in activated fibroblasts[13,14,15]. We screened for small molecules capable of inhibiting TGF-β1-induced collagen production in cultured fibroblasts and identified felodipine from a library of medicines already in clinical use. Administration of felodipine, a dihydropyridine Ca2+ channel blocker previously used clinically to treat patients with high blood pressure[20], showed both preventive and therapeutic effects against bleomycin-induced pulmonary fibrosis. We propose that dihydropyridine Ca2+ channel blockers may be therapeutically beneficial for IPF patients

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