Idebenone has preventative and therapeutic effects on pulmonary fibrosis via preferential suppression of fibroblast activity

Toshifumi Sugizaki,Tohru Mizushima,Ayaka Takafuji,Masahiro Kawahara,Kaoru Mogushi,Mikako Shimoda,Yuuki Hino,Daisuke Kobayashi,Teita Asano,Ken-Ichiro Tanaka

doi:10.1038/s41420-019-0226-y

Abstract

Alveolar epithelial injury induced by reactive oxygen species (ROS) and abnormal collagen production by activated fibroblasts (myofibroblasts) is involved in the onset and exacerbation of idiopathic pulmonary fibrosis (IPF). Compared with alveolar epithelial cells, lung fibroblasts, especially myofibroblasts, exhibit an apoptosis-resistance phenotype (apoptosis paradox) that appears to be involved in IPF pathogenesis. Thus, we screened for chemicals eliciting preferential cytotoxicity of LL29 cells (lung fibroblasts from an IPF patient) compared with A549 cells (human lung alveolar epithelial cell line) from medicines already in clinical use. We identified idebenone, a synthetic analogue of coenzyme Q10 (CoQ10, an antioxidant) that has been used clinically as a brain metabolic stimulant. Idebenone induced cell growth inhibition and cell death in LL29 cells at a lower concentration than in A549 cells, a feature that was not observed for other antioxidant molecules (such as CoQ10) and two IPF drugs (pirfenidone and nintedanib). Administration of idebenone prevented bleomycin-induced pulmonary fibrosis and increased pulmonary ROS levels. Importantly, idebenone also improved pulmonary fibrosis and lung function when administered after the development of fibrosis, whereas administration of CoQ10 similarly prevented bleomycin-induced pulmonary fibrosis, but had no effect after its development. Administration of idebenone, but not CoQ10, suppressed bleomycin-induced increases in lung myofibroblasts. In vitro, treatment of LL29 cells with idebenone, but not CoQ10, suppressed TGF-β–induced collagen production. These results suggest that in addition to antioxidant activity, idebenone exerts inhibitory activity on the function of lung fibroblasts, with the former activity being preventative and the latter therapeutic for bleomycin-induced fibrosis. Thus, we propose that idebenone may be more therapeutically beneficial for IPF patients than current treatments.

Highlights

Idiopathic pulmonary fibrosis (IPF) is a progressive and devastating chronic lung disease with an poorOfficial journal of the Cell Death Differentiation AssociationSugizaki et al Cell Death Discovery (2019)5:146IPF appears to be triggered by lung epithelial injury resulting from increased production of reactive oxygen species (ROS) and the subsequent repair and remodelling process, such as collagen synthesis, induced to address this injury
LL29 or A549 cells were exposed to each drug for 24 h and viable cell numbers were determined by the MTT method
Amongst drugs that showed lower IC50 values for LL29 cells than for A549 cells, we selected idebenone based on the extent of difference of IC50 values between these two types of cells, clinical safety, and other pharmacological activity

Summary

Introduction

In IPF patients this process is excessively stimulated, resulting in abnormal fibrosis (abnormal wound repair and remodelling) characterised by collagen deposition[7,8]. As ROS can stimulate collagen synthesis, it is believed that ROS play a pivotal role in IPF pathogenesis. Supporting this notion, a number of antioxidant molecules, such as N-acetylcysteine (NAC) and superoxide dismutase (SOD), have shown beneficial effects in IPF patients and animal models of IPF, such as bleomycin-induced pulmonary fibrosis[9,10]. Compounds that suppress myofibroblast production or inhibit myofibroblast activity are good candidates for drugs to treat IPF patients Both pirfenidone and nintedanib reportedly suppress the transdifferentiation of fibroblasts into myofibroblasts and collagen production in activated fibroblasts[13,14,15]

Methods

Results

Conclusion