A novel molecular mechanism of microRNA-21 inducing pulmonary fibrosis and human pulmonary fibroblast extracellular matrix through transforming growth factor 1-mediated SMADs activation

摘要

Pulmonary fibrosis (PF), characterized by the destruction of lung tissue architecture and the abnormal deposition of extracellular matrix (ECM) proteins, currently has no satisfactory treatment. The role of microRNA (miR)-21 in PF has been reported; the current study attempted to investigate a novel molecular mechanism by which miR-21 exerted its function. Consistent with previous studies, miR-21 inhibition reduced ECM protein levels in bleomycin (BLM)-induced mouse model of PF. In human pulmonary fibroblast (IMR-90), miR-21 inhibition reduced transforming growth factor 1 (TGF1)-induced ECM protein expression. Regarding a novel molecular mechanism, TGF1 combined withTGF1 receptor 1 (TGF1RI) to activate SMAD2/3, promote SMAD4 nucleus transformation, and thus regulate miR-21 expression and ECM. SMAD3 and SMADs complex could bind to the promoter region of miR-21 to promote miR-21 expression. In conclusion, miR-21 exerts promotive effects on BLM-induced PF and TGF1-induced ECM in IMR-90; TGF1 combines with TGF1RI to activate SMAD2/3, promote SMAD4 nucleus transformation, promote miR-21 expression, and thus to promote BLM-induced PF and TGF1-induced ECM in IMR-90 cells.