miR-323a-3p regulates lung fibrosis by targeting multiple profibrotic pathways

Maladaptive epithelial repair from chronic injury is a common feature in fibrotic diseases, which in turn activates a pathogenic fibroblast response that produces excessive matrix deposition. Dysregulated microRNAs (miRs) can regulate expression of multiple genes and fundamentally alter cellular phe...

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Bibliographic Details
Published in:JCI insight 2016-12, Vol.1 (20), p.e90301-e90301
Main Authors: Ge, Lingyin, Habiel, David M, Hansbro, Phil M, Kim, Richard Y, Gharib, Sina A, Edelman, Jeffery D, Königshoff, Melanie, Parimon, Tanyalak, Brauer, Rena, Huang, Ying, Allen, Jenieke, Jiang, Dianhua, Kurkciyan, Adrianne A, Mizuno, Takako, Stripp, Barry R, Noble, Paul W, Hogaboam, Cory M, Chen, Peter
Format: Article
Language:English
Subjects:
Animals
Bleomycin
Bronchiolitis Obliterans - genetics
Bronchiolitis Obliterans - pathology
Cells, Cultured
Fibroblasts - cytology
Humans
Idiopathic Pulmonary Fibrosis - genetics
Idiopathic Pulmonary Fibrosis - pathology
Lung
Lung Transplantation
Mice
Mice, Inbred C57BL
MicroRNAs - genetics
Respiratory Mucosa - physiopathology
Signal Transduction
Transforming Growth Factors - metabolism
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Summary:Maladaptive epithelial repair from chronic injury is a common feature in fibrotic diseases, which in turn activates a pathogenic fibroblast response that produces excessive matrix deposition. Dysregulated microRNAs (miRs) can regulate expression of multiple genes and fundamentally alter cellular phenotypes during fibrosis. Although several miRs have been shown to be associated with lung fibrosis, the mechanisms by which miRs modulate epithelial behavior in lung fibrosis are lacking. Here, we identified miR-323a-3p to be downregulated in the epithelium of lungs with bronchiolitis obliterans syndrome (BOS) after lung transplantation, idiopathic pulmonary fibrosis (IPF), and murine bleomycin-induced fibrosis. Antagomirs for miR-323a-3p augment, and mimics suppress, murine lung fibrosis after bleomycin injury, indicating that this miR may govern profibrotic signals. We demonstrate that miR-323a-3p attenuates TGF-α and TGF-β signaling by directly targeting key adaptors in these important fibrogenic pathways. Moreover, miR-323a-3p lowers caspase-3 expression, thereby limiting programmed cell death from inducers of apoptosis and ER stress. Finally, we find that epithelial expression of miR-323a-3p modulates inhibitory crosstalk with fibroblasts. These studies demonstrate that miR-323a-3p has a central role in lung fibrosis that spans across murine and human disease, and downregulated expression by the lung epithelium releases inhibition of various profibrotic pathways to promote fibroproliferation.
ISSN:2379-3708
2379-3708
DOI:10.1172/jci.insight.90301