Lung fibroblasts express a miR-19a-19b-20a sub-cluster to suppress TGF-β-associated fibroblast activation in murine pulmonary fibrosis

Lung fibroblastsplay a pivotal role in pulmonary fibrosis, a devastating lungdisease, by producing extracellular matrix. MicroRNAs (miRNAs) suppress numerous genes post-transcriptionally; however, the roles of miRNAs in activated fibroblastsin fibrotic lungsremain poorly understood. To elucidate these roles, we performed global miRNA-expression profiling of fibroblastsfrom bleomycin- and silica-induced fibrotic lungsand investigated the functions of miRNAs in activated lung fibroblasts. Clustering analysis of global miRNA-expression data identified miRNA signatures exhibiting increased expression during fibrosis progression. Among these signatures, we found that a miR-19a-19b-20a sub-cluster suppressed TGF-β-induced activation of fibroblastsin vitro. Moreover, to elucidate whether fibroblast-specific intervention against the sub-cluster modulates pathogenic activation of fibroblastsin fibrotic lungs, we intratracheally transferred the sub-cluster-overexpressing fibroblastsinto bleomycin-treated lungs. Global transcriptome analysis of the intratracheally transferred fibroblastsrevealed that the sub-cluster not only downregulated expression of TGF-β-associated pro-fibrotic genes, including Acta2, Col1a1, Ctgf, and Serpine1, but also upregulated expression of the anti-fibrotic genes Dcn, Igfbp5, and Mmp3in activated lung fibroblasts. Collectively, these findings indicated that upregulation of the miR-19a-19b-20a sub-cluster expression in lung fibroblastscounteracted TGF-β-associated pathogenic activation of fibroblastsin murine pulmonary fibrosis.