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

Ge, L; Habiel, DM; Hansbro, PM; Kim, RY; Gharib, SA; Edelman, JD; Königshoff, M; Parimon, T; Brauer, R; Huang, Y; Allen, J; Jiang, D; Kurkciyan, AA; Mizuno, T; Stripp, BR; Noble, PW; Hogaboam, CM; Chen, P

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

Ge, L Habiel, DM Hansbro, PM Kim, RY Gharib, SA Edelman, JD Königshoff, M Parimon, T Brauer, R Huang, Y Allen, J Jiang, D Kurkciyan, AA Mizuno, T Stripp, BR Noble, PW Hogaboam, CM Chen, P

Permalink

Publisher:: AMER SOC CLINICAL INVESTIGATION INC
Publication Type:: Journal Article
Citation:: JCI insight, 2016, 1, (20), pp. e90301
Issue Date:: 2016-12-08

Closed Access

	Filename	Description	Size
	miR-323a-3p regulates lung fibrosis by targeting multiple profibrotic pathways.pdf	Published version	979.59 kB	Adobe PDF	View/Open

Copyright Clearance Process

Recently Added
In Progress
Closed Access

This item is closed access and not available.

Full metadata record

Field	Value	Language
dc.contributor.author	Ge, L
dc.contributor.author	Habiel, DM
dc.contributor.author	Hansbro, PM
dc.contributor.author	Kim, RY
dc.contributor.author	Gharib, SA
dc.contributor.author	Edelman, JD
dc.contributor.author	Königshoff, M
dc.contributor.author	Parimon, T
dc.contributor.author	Brauer, R
dc.contributor.author	Huang, Y
dc.contributor.author	Allen, J
dc.contributor.author	Jiang, D
dc.contributor.author	Kurkciyan, AA
dc.contributor.author	Mizuno, T
dc.contributor.author	Stripp, BR
dc.contributor.author	Noble, PW
dc.contributor.author	Hogaboam, CM
dc.contributor.author	Chen, P
dc.date.accessioned	2020-12-23T00:38:27Z
dc.date.available	2020-12-23T00:38:27Z
dc.date.issued	2016-12-08
dc.identifier.citation	JCI insight, 2016, 1, (20), pp. e90301
dc.identifier.issn	2379-3708
dc.identifier.issn	2379-3708
dc.identifier.uri	http://hdl.handle.net/10453/144935
dc.description.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.
dc.format	Electronic
dc.language	eng
dc.publisher	AMER SOC CLINICAL INVESTIGATION INC
dc.relation.ispartof	JCI insight
dc.relation.isbasedon	10.1172/jci.insight.90301
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject.mesh	Lung
dc.subject.mesh	Respiratory Mucosa
dc.subject.mesh	Cells, Cultured
dc.subject.mesh	Fibroblasts
dc.subject.mesh	Animals
dc.subject.mesh	Mice, Inbred C57BL
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Bronchiolitis Obliterans
dc.subject.mesh	Bleomycin
dc.subject.mesh	Transforming Growth Factors
dc.subject.mesh	MicroRNAs
dc.subject.mesh	Lung Transplantation
dc.subject.mesh	Signal Transduction
dc.subject.mesh	Idiopathic Pulmonary Fibrosis
dc.subject.mesh	Animals
dc.subject.mesh	Bleomycin
dc.subject.mesh	Bronchiolitis Obliterans
dc.subject.mesh	Cells, Cultured
dc.subject.mesh	Fibroblasts
dc.subject.mesh	Humans
dc.subject.mesh	Idiopathic Pulmonary Fibrosis
dc.subject.mesh	Lung
dc.subject.mesh	Lung Transplantation
dc.subject.mesh	Mice
dc.subject.mesh	Mice, Inbred C57BL
dc.subject.mesh	MicroRNAs
dc.subject.mesh	Respiratory Mucosa
dc.subject.mesh	Signal Transduction
dc.subject.mesh	Transforming Growth Factors
dc.title	miR-323a-3p regulates lung fibrosis by targeting multiple profibrotic pathways.
dc.type	Journal Article
utslib.citation.volume	1
utslib.location.activity	United States
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	/University of Technology Sydney
utslib.copyright.status	closed_access	*
dc.date.updated	2020-12-23T00:38:13Z
pubs.issue	20
pubs.publication-status	Published
pubs.volume	1
utslib.citation.issue	20

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.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/144935