Anti-fibrotic effect of iguratimod on pulmonary fibrosis by inhibiting the fibroblast–to-myofibroblast transition

Pulmonary fibrosis (PF) is a severe lung disease causing significant morbidity and mortality. PF pathogenesis is attributed to the fibroblast-to-myofibroblast transition (FMT) driven by the most potent pro-fibrogenic factor TGF-β1 activating the Smad3-dependent TGF-β1 canonical pathway. Iguratimod (IGU) is a novel anti-rheumatic drug that suppresses the secretion of inflammatory factors, but is also able to modulate the differentiation of multiple cells. Therefore, the aim of this work was to investigate the effect of IGU on FMT. PF mouse model was induced in C57BL/6 male mice by bleomycin. The effect of IGU was assessed through the evaluation of lung morphology by H&E and through the collagen accumulation in the lung by Masson staining. Primary human lung fibroblasts (pHLFs) were also used to evaluate the effect of IGU in vitro on TGF-β1-stimulated cells, and proliferation, migration and invasion were measured, together with genes and proteins involved in FMT. IGU attenuated bleomycin-induced PF in mice and improved the pathological changes in their lungs. In addition, IGU significantly inhibited proliferation, migration and invasion in TGF-β1-stimulated pHLFs without causing apoptosis. Moreover, IGU significantly reduced TGF-β1-induced increase of collagen I and III mRNA expression, thus reducing lung function impairment, and α-SMA, Smad2 and Smad3 phosphorylation, fibronectin expression and F-actin microfilament formation, thus attenuating FMT through the inhibition of the Smad3 pathway. Conclusions: Our results collectively revealed the beneficial effect of IGU on the inhibition of FMT, thus suggesting that it might act as an effective anti-fibrotic agent in preventing the progression of PF.