期刊
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
卷 50, 期 5, 页码 882-892出版社
AMER THORACIC SOC
DOI: 10.1165/rcmb.2013-0195OC
关键词
idiopathic pulmonary fibrosis; microRNAs; transforming growth factor-beta signaling
资金
- National Institutes of Health [R01 HL088029, HL056470]
- CSIR
- CSIR, India Task Force Project [BSC0116, MLP5501]
- Flight Attendants Medical Research Institute
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-b has been disappointing, and strategies to directly suppress TGF-beta 1 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-beta 1 regulation and to validate the role of miR-326 in pulmonary fibrosis. We show that hsa-miR-326 regulates TGF-beta 1 expression and that hsa-miR-326 levels are inversely correlated to TGF-beta 1 protein levels in multiple human cell lines. The increase in TGF-beta 1 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-beta 1 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-beta 1 expression and other profibrotic genes and could be useful in developing better therapeutic strategies for alleviating lung fibrosis.
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