title: miR-21 mediates fibrogenic activation of pulmonary fibroblasts and lung fibrosis.
abstract: Uncontrolled extracellular matrix production by fibroblasts in response to tissue injury contributes to fibrotic diseases, such as idiopathic pulmonary fibrosis (IPF), a progressive and ultimately fatal process that currently has no cure. Although dysregulation of miRNAs is known to be involved in a variety of pathophysiologic processes, the role of miRNAs in fibrotic lung diseases is unclear. In this study, we found up-regulation of miR-21 in the lungs of mice with bleomycin-induced fibrosis and also in the lungs of patients with IPF. Increased miR-21 expression was primarily localized to myofibroblasts. Administration of miR-21 antisense probes diminished the severity of experimental lung fibrosis in mice, even when treatment was started 5-7 d after initiation of pulmonary injury. TGF-beta1, a central pathological mediator of fibrotic diseases, enhanced miR-21 expression in primary pulmonary fibroblasts. Increasing miR-21 levels promoted, whereas knocking down miR-21 attenuated, the pro-fibrogenic activity of TGF-beta1 in fibroblasts. A potential mechanism for the role of miR-21 in fibrosis is through regulating the expression of an inhibitory Smad, Smad7. These experiments demonstrate an important role for miR-21 in fibrotic lung diseases and also suggest a novel approach using miRNA therapeutics in treating clinically refractory fibrotic diseases, such as IPF.
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA. gliu@uab.edu
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.forename: Arnaud
authors.initials: A
authors.lastname: Friggeri
authors.forename: Yanping
authors.initials: Y
authors.lastname: Yang
authors.forename: Jadranka
authors.initials: J
authors.lastname: Milosevic
authors.forename: Qiang
authors.initials: Q
authors.lastname: Ding
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Thannickal
authors.forename: Naftali
authors.initials: N
authors.lastname: Kaminski
authors.forename: Edward
authors.initials: E
authors.lastname: Abraham
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016375:Antisense Elements (Genetics) / Q000235:genetics / Q000627:therapeutic use; D001761:Bleomycin / Q000494:pharmacology; D002460:Cell Line; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009841:Oligonucleotides / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology* / Q000628:therapy; D051899:Smad2 Protein / Q000378:metabolism; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000494:pharmacology
chemical_list: D000199:Actins; D016375:Antisense Elements (Genetics); D016326:Extracellular Matrix Proteins; D005353:Fibronectins; C524940:MIRN21 microRNA, human; C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; D009841:Oligonucleotides; C497782:SMAD2 protein, human; C497806:SMAD7 protein, human; D051899:Smad2 Protein; D051906:Smad7 Protein; D053773:Transforming Growth Factor beta1; C544013:alpha-smooth muscle actin, mouse; C477371:locked nucleic acid; D001761:Bleomycin; D003094:Collagen