[Investigation of Drug-induced Lung Injury for the Development of a Novel Therapeutic Approach].

The development of serious lung diseases, such as pulmonary fibrosis, is associated with several drugs. A recent study has shown that the epithelial-mesenchymal transition (EMT) plays an essential role in the development of pulmonary fibrosis. However, the mechanisms underlying drug-induced EMT in alveolar epithelial cells have not been characterized. The present study showed that methotrexate (MTX), a drug known to cause lung injury, induced EMT-like phenotypic changes in an A549 cell model of the alveolar epithelium. We also found that the transforming growth factor (TGF)-β1-mediated signaling pathway was associated with MTX-induced EMT. In addition, our results showed that certain secreted factors and microRNAs, a class of small noncoding RNAs, may be involved in MTX-induced EMT. The effects of COA-Cl, a novel synthetic small molecule, on TGF-β1-induced EMT were evaluated to determine the therapeutic potential of COA-Cl against drug-induced lung injury. COA-Cl significantly suppressed TGF-β1-induced EMT-like phenotypic changes, as evidenced by the inhibition of EMT-related transcription factors. Furthermore, MTX-induced EMT was completely suppressed by co-treatment with folic acid. Thus, these compounds may be promising therapeutic agents against drug-induced lung injury. In conclusion, the present study elucidated mechanisms underlying drug-induced EMT and highlighted a potential novel therapeutic approach to drug-induced lung diseases.