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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Actins / genetics
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Actins / metabolism
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Animals
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Antisense Elements (Genetics) / genetics
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Antisense Elements (Genetics) / therapeutic use
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Bleomycin / pharmacology
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Cell Line
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Collagen / genetics
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Collagen / metabolism
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Extracellular Matrix Proteins / genetics
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Extracellular Matrix Proteins / metabolism
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Fibroblasts / drug effects
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Fibroblasts / metabolism*
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Fibroblasts / pathology*
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Fibronectins / genetics
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Fibronectins / metabolism
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Gene Expression / drug effects
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Gene Expression / genetics
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Humans
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Idiopathic Pulmonary Fibrosis / genetics*
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Idiopathic Pulmonary Fibrosis / metabolism
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Idiopathic Pulmonary Fibrosis / pathology
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Lung / metabolism
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Lung / pathology
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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MicroRNAs / genetics
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MicroRNAs / metabolism*
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Oligonucleotides / genetics
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Phosphorylation / drug effects
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Pulmonary Fibrosis / chemically induced
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Pulmonary Fibrosis / genetics*
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Pulmonary Fibrosis / pathology*
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Pulmonary Fibrosis / therapy
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Smad2 Protein / metabolism
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Smad7 Protein / genetics
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Smad7 Protein / metabolism
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Transforming Growth Factor beta1 / genetics
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Transforming Growth Factor beta1 / pharmacology
Substances
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Actins
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Antisense Elements (Genetics)
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Extracellular Matrix Proteins
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Fibronectins
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MIRN21 microRNA, human
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MIRN21 microRNA, mouse
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MicroRNAs
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Oligonucleotides
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SMAD2 protein, human
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SMAD7 protein, human
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Smad2 Protein
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Smad7 Protein
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Transforming Growth Factor beta1
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alpha-smooth muscle actin, mouse
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locked nucleic acid
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Bleomycin
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Collagen