Therapeutic effects of eperisone on pulmonary fibrosis via preferential suppression of fibroblast activity

Abstract

Although the exact pathogenesis of idiopathic pulmonary fibrosis (IPF) is still unknown, the transdifferentiation of fibroblasts into myofibroblasts and the production of extracellular matrix components such as collagen, triggered by alveolar epithelial cell injury, are important mechanisms of IPF development. In the lungs of IPF patients, apoptosis is less likely to be induced in fibroblasts than in alveolar epithelial cells, and this process is involved in the pathogenesis of IPF. We used a library containing approved drugs to screen for drugs that preferentially reduce cell viability in LL29 cells (lung fibroblasts from an IPF patient) compared with A549 cells (human alveolar epithelial cell line). After screening, we selected eperisone, a central muscle relaxant used in clinical practice. Eperisone showed little toxicity in A549 cells and preferentially reduced the percentage of viable LL29 cells, while pirfenidone and nintedanib did not have this effect. Eperisone also significantly inhibited transforming growth factor-β1-dependent transdifferentiation of LL29 cells into myofibroblasts. In an in vivo study using ICR mice, eperisone inhibited bleomycin (BLM)-induced pulmonary fibrosis, respiratory dysfunction, and fibroblast activation. In contrast, pirfenidone and nintedanib were less effective than eperisone in inhibiting BLM-induced pulmonary fibrosis under this experimental condition. Finally, we showed that eperisone did not induce adverse effects in the liver and gastrointestinal tract in the BLM-induced pulmonary fibrosis model. Considering these results, we propose that eperisone may be safer and more therapeutically beneficial for IPF patients than current therapies.

Time course of histopathology of bleomycin-induced pulmonary fibrosis using an intratracheal sprayer in mice

“…In this study, we chose the mice, the most common animal species for bleomycin model generation [ 9 ]. Previously approved antifibrotic agents have used C57BL/6 mice [ 18 ] or ICR mice [ 19 ] for nintedanib and ICR mice [ 19 , 20 ] for pirfenidone as bleomycin models. It is known that there are strain differences in fibrosis formation after bleomycin administration in mice [ 21 ].…”

Ergothioneine Prevents Neuronal Cell Death Caused by the Neurotoxin 6-Hydroxydopamine

“…Cell viability was measured as in our previous studies [20,21]. Briefly, GT1-7 cells were seeded onto 96-well culture plates at a concentration of 3.0 × 10 4 cells/well in a 200 µL culture medium.…”

Advances in common in vitro cellular models of pulmonary fibrosis

“…17 Frequently used as an in vitro model for lung epithelial cell injury and EMT progression, A549 cells have been studied because of their involvement in inducing direct or indirect transformation of AECs into fibroblasts/myofibroblasts, resulting in excessive ECM deposition and extensive lung tissue remodeling, processes associated with the development of IPF. 18 Valproic acid, an antiepileptic drug possessing anti-inflammatory and antioxidant properties, can induce apoptosis in cancer cells. Chen et al 19 conducted an in vitro assay where they induced EMT in A549 cells through transforming growth factor-b1 (TGF-b1) stimulation and showed that valproic acid inhibited EMT, thereby alleviating PF in AECs in a time-and dosage-dependent manner.…”