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miR-323a-3p regulates lung fibrosis by targeting multiple profibrotic pathways
Lingyin Ge, … , Cory M. Hogaboam, Peter Chen
Lingyin Ge, … , Cory M. Hogaboam, Peter Chen
Published December 8, 2016
Citation Information: JCI Insight. 2016;1(20):e90301. https://doi.org/10.1172/jci.insight.90301.
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Research Article Pulmonology

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

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Abstract

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.

Authors

Lingyin Ge, David M. Habiel, Phil M. Hansbro, Richard Y. Kim, Sina A. Gharib, Jeffery D. Edelman, Melanie Königshoff, Tanyalak Parimon, Rena Brauer, Ying Huang, Jenieke Allen, Dianhua Jiang, Adrianne A. Kurkciyan, Takako Mizuno, Barry R. Stripp, Paul W. Noble, Cory M. Hogaboam, Peter Chen

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Figure 2

miR-323a-3p antagomirs augment bleomycin-induced lung fibrosis.

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miR-323a-3p antagomirs augment bleomycin-induced lung fibrosis.
(A) Repr...
(A) Representative images of H&E- and trichrome-stained lungs 21 days after bleomycin injury (0.05 U/kg) from mice treated with miR-323a-3p antagomir or a scrambled control 5, 10, and 15 days after bleomycin injury. Scale bar: 100 μm. (B) Lungs were processed for measuring hydroxyproline levels. n = 5 (PBS control and antagomir), n = 7 (control bleomycin), n = 8 (mimic bleomycin), *P < 0.05, **P < 0.005 by 2-way ANOVA and post-hoc analysis.

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