miR-31 is a negative regulator of fibrogenesis and pulmonary fibrosis.
Aberrant expression of miRNAs is closely associated with initiation and progression of pathological processes, including diabetes, cancer, and cardiovascular disease. However, the role of miRNAs in lung fibrosis is not well characterized. We sought to determine the role of miR-31 in regulating the fibrogenic, contractile, and migratory activities of lung fibroblasts and modulating of pulmonary fibrosis in vivo. In vivo lung fibrosis models and ex vivo cell culture systems were employed. Real-time PCR and Western blot analysis were used to determine gene expression levels. miR-31 mimics or inhibitors were transfected into pulmonary fibroblasts. Fibrogenic, contractile, and migratory activities of lung fibroblasts were determined. We found that miR-31 expression is reduced in the lungs of mice with experimental pulmonary fibrosis and in IPF fibroblasts. miR-31 inhibits the profibrotic activity of TGF-β1 in normal lung fibroblasts and diminishes the fibrogenic, contractile, and migratory activities of IPF fibroblasts. In these experiments, miR-31 was shown to directly target integrin α(5) and RhoA, two proteins that have been shown to regulate activation of fibroblasts. We found that levels of integrin α(5) and RhoA are up-regulated in fibrotic mouse lungs. Knockdown of integrin α(5) and RhoA attenuated fibrogenic, contractile, and migratory activities of IPF fibroblasts, in a manner similar to that observed with miR-31. We also found that introduction of miR-31 ameliorated experimental lung fibrosis in mice. Our data suggest that miR-31 is an important regulator of the pathological activities of lung fibroblasts and may be a potential target in the development of novel therapies to treat pathological fibrotic disorders, including pulmonary fibrosis.
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Shanzhong
S
Yang
Na
N
Xie
Huachun
H
Cui
Sami
S
Banerjee
Edward
E
Abraham
Victor J
VJ
Thannickal
Gang
G
Liu
D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002460:Cell Line; D017931:DNA Primers; D005347:Fibroblasts / Q000502:physiology; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics*; D039482:Integrin alpha5 / Q000378:metabolism; D008168:Lung / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D017931:DNA Primers; D039482:Integrin alpha5; C534612:MIRN31 microRNA, human; D035683:MicroRNAs; C539917:Mirn31 microRNA, mouse; D053773:Transforming Growth Factor beta1; D020742:rhoA GTP-Binding Protein