Abstract
MicroRNAs are involved in diverse biological and pathological processes. Here, we studied the potential role of miRNAs in the in vivo pathogenesis of chronic obstructive pulmonary disease (COPD) using βENaC-overexpressing (βENaC-Tg) mouse model. We performed miRNA array analysis in lung tissue of βENaC-Tg and wild-type (WT) mice. Differentially expressed miRNAs were validated by qRT-PCR and their functional importance was determined by bioinformatics analysis and in luciferase reporter assays. Tissue specific localization was performed by in situ hybridization using locked nucleic acid-modified DNA probe. Direct functional studies were performed by knockdown of miRNA expression in the lungs of βENaC-Tg mice using antagomirs. The effects of knockdown were studied by lung histology, pulmonary function testing using flexiVent system and analysis of inflammatory cells in bronchoalveolar lavage. We demonstrate that miR-148b is upregulated in the lungs of βENaC-Tg mice and predominantly localized in the conducting airways. Luciferase reporter assay in Hela cells suggests Mig-6 (mitogen inducible gene-6), a protein previously shown in normal lung development, as a potential target of miR-148b. Knockdown of miR-148b in the lung of βENaC-Tg mice results in reduced emphysema and decreased numbers of neutrophils compared to WT mice. Moreover, we observed upregulation of miR-148b in bronchial brushing of cystic fibrosis and COPD lung tissue from human. Taken together, these results indicate that dysregulation of miR-148b expression may play an important role in the pathogenesis of COPD and may serve as a novel therapeutic target.
Supported by BMBF (82DZL00401).
- © 2013 ERS