Effects of other drugs on BLM-induced pulmonary fibrosis
Using the same experimental approach as in Figure 3, we examined the effect of pirfenidone and nintedanib on BLM-dependent pulmonary fibrosis. The dose of pirfenidone (200 mg/kg) was 20 times the initial clinical dose (600 mg/day) used in Japan (Song et al., 2020), and the same dose of nintedanib (30 mg/kg) that had shown triple kinase inhibition in previous animal studies was used (Wollin, Maillet, Quesniaux, Holweg, & Ryffel, 2014). As shown in Supplementary Figure S1A–S1C, BLM-dependent collagen deposition and increased hydroxyproline levels in the lung were not suppressed by oral administration of pirfenidone or nintedanib. Nintedanib or pirfenidone administration tended to improve the BLM-dependent deterioration of respiratory function, but the effect was not statistically significant (Supplementary Figure S1D).
We next analyzed the effect of tolperisone, a structural analogue of eperisone with central muscle relaxant properties (Tekes, 2014), on BLM-dependent pulmonary fibrosis. As shown in Supplementary Figure S2A–S2C, oral administration of tolperisone suppressed BLM-dependent collagen deposition and increased hydroxyproline levels in the lung similar to eperisone administration. In addition, tolperisone significantly improved the BLM-dependent increase in total elastance and tissue elastance and the decrease in FVC (Supplementary Figure S2D). These results indicate that preferential suppression of fibroblast activity is important to prevent BLM-dependent exacerbation of lung fibrosis.