Therapeutic effects of eperisone on pulmonary fibrosis via preferential
suppression of fibroblast activity
Abstract
Background and purpose: 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. Experimental approach: 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). Key results:
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. Conclusion and implications:
Considering these results, we propose that eperisone may be safer and
more therapeutically beneficial for IPF patients than current therapies.