title: miR-323a-3p regulates lung fibrosis by targeting multiple profibrotic pathways.
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.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Lingyin
authors.initials: L
authors.lastname: Ge
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Habiel
authors.affiliation: Priority Research Centre for Asthma and Respiratory Disease, Department of Microbiology and Immunology, School of Pharmacy and Biomedical Sciences, Faculty of Health and Hunter Medical Research Institute, University of Newcastle, Newcastle, Australia.
authors.forename: Phil M
authors.initials: PM
authors.lastname: Hansbro
authors.affiliation: Priority Research Centre for Asthma and Respiratory Disease, Department of Microbiology and Immunology, School of Pharmacy and Biomedical Sciences, Faculty of Health and Hunter Medical Research Institute, University of Newcastle, Newcastle, Australia.
authors.forename: Richard Y
authors.initials: RY
authors.lastname: Kim
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Sina A
authors.initials: SA
authors.lastname: Gharib
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Edelman
authors.affiliation: Comprehensive Pneumology Center, Ludwig Maximilians University, University Hospital Grosshadern, and Helmholtz Zentrum Munchen, Munich, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Königshoff
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Tanyalak
authors.initials: T
authors.lastname: Parimon
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Rena
authors.initials: R
authors.lastname: Brauer
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Jenieke
authors.initials: J
authors.lastname: Allen
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Dianhua
authors.initials: D
authors.lastname: Jiang
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Adrianne A
authors.initials: AA
authors.lastname: Kurkciyan
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Takako
authors.initials: T
authors.lastname: Mizuno
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Barry R
authors.initials: BR
authors.lastname: Stripp
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Noble
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Cory M
authors.initials: CM
authors.lastname: Hogaboam
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Chen
mesh_terms: D000818:Animals; D001761:Bleomycin; D001989:Bronchiolitis Obliterans / Q000235:genetics / Q000473:pathology; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics* / Q000473:pathology; D008168:Lung; D016040:Lung Transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D020545:Respiratory Mucosa / Q000503:physiopathology*; D015398:Signal Transduction; D015291:Transforming Growth Factors / Q000378:metabolism
chemical_list: C584442:MIRN323 microRNA, mouse; D035683:MicroRNAs; D001761:Bleomycin; D015291:Transforming Growth Factors