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Ge, L.* ; Habiel, D.M.* ; Hansbro, P.M.* ; Kim, R.Y.* ; Gharib, S.A.* ; Edelman, J.D.* ; Königshoff, M. ; Parimon, T.* ; Brauer, R.* ; Huang, Y.* ; Allen, J.* ; Jiang, D.* ; Kurkciyan, A.A.* ; Mizuno, T.* ; Stripp, B.R.* ; Noble, P.W.* ; Hogaboam, C.M.* ; Chen, P.*

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

JCI insight 1:e90301 (2016)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
ISSN (print) / ISBN 2379-3708
e-ISSN 2379-3708
Journal JCI insight
Quellenangaben Volume: 1, Issue: 20, Pages: , Article Number: e90301 Supplement: ,
Publisher Clarivate
Publishing Place Ann Arbor, Michigan
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Lung Health and Immunity (LHI)