| First Author | Das S | Year | 2014 |
| Journal | Am J Respir Cell Mol Biol | Volume | 50 |
| Issue | 5 | Pages | 882-92 |
| PubMed ID | 24279830 | Mgi Jnum | J:232085 |
| Mgi Id | MGI:5775885 | Doi | 10.1165/rcmb.2013-0195OC |
| Citation | Das S, et al. (2014) MicroRNA-326 regulates profibrotic functions of transforming growth factor-beta in pulmonary fibrosis. Am J Respir Cell Mol Biol 50(5):882-92 |
| abstractText | Idiopathic pulmonary fibrosis (IPF) is a fatal disorder resulting from the progressive remodeling of lungs, with no known effective treatment. Although transforming growth factor (TGF)-beta has a well-established role in lung fibrosis, clinical experience with neutralizing antibodies to TGF-beta has been disappointing, and strategies to directly suppress TGF-beta1 secretion are needed. In this study we used a combination of in silico, in vitro, and in vivo approaches to identify microRNAs involved in TGF-beta1 regulation and to validate the role of miR-326 in pulmonary fibrosis.We show that hsa-miR-326 regulates TGF-beta1 expression and that hsa-miR-326 levels are inversely correlated to TGF-beta1 protein levels in multiple human cell lines. The increase in TGF-beta1 expression during the progression of bleomycin-induced lung fibrosis in mice was associated with loss of mmu-miR-326. Restoration of mmu-miR-326 levels by intranasal delivery of miR-326 mimics was sufficient to inhibit TGF-beta1 expression and attenuate the fibrotic response. Moreover, human IPF lung specimens had markedly diminished miR-326 expression as compared with nonfibrotic lungs. Additional targets of miR-326 controlling TGF-beta signaling and fibrosis-related pathways were identified, and miR-326 was found to down-regulate profibrotic genes, such as Ets1, Smad3, and matrix metalloproteinase 9, whereas it up-regulates antifibrotic genes, such as Smad7. Our results suggest for the first time that miR-326 plays a key role in regulating TGF-beta1 expression and other profibrotic genes and could be useful in developing better therapeutic strategies for alleviating lung fibrosis. |
