MicroRNA-101 attenuates pulmonary fibrosis by inhibiting fibroblast proliferation and activation

Abstract

Aberrant proliferation and activation of lung fibroblasts contribute to the initiation and progression of idiopathic pulmonary fibrosis (IPF). However, the mechanisms responsible for the proliferation and activation of fibroblasts are not fully understood. The objective of this study was to investigate the role of miR-101 in the proliferation and activation of lung fibroblasts. miR-101 expression was determined in lung tissues from patients with IPF and mice with bleomycin-induced pulmonary fibrosis. The regulation of miR-101 and cellular signaling was investigated in pulmonary fibroblasts The role of miR-101 in pulmonary fibrosis was studied using adenovirus-mediated gene transfer in mice. The expression of miR-101 was down-regulated in fibrotic lungs from patients with IPF and bleomycin-treated mice. The down-regulation of miR-101 occurred via the E26 transformation-specific (ETS) transcription factor. miR-101 suppressed the WNT5a-induced proliferation of lung fibroblasts by inhibiting NFATc2 signaling via targeting Frizzled receptor 4/6 and the TGF-β-induced activation of lung fibroblasts by inhibition of SMAD2/3 signaling via targeting the TGF-β receptor 1. Adenovirus-mediated miR-101 gene transfer in the mouse lung attenuated bleomycin-induced lung fibrosis and improved lung function. Our data suggest that miR-101 is an anti-fibrotic microRNA and a potential therapeutic target for pulmonary fibrosis.

miRNAs in Lung Development and Diseases

“…Orotracheal administration of bleomycin following lenti-miR-9 treatment interrupted structural damage to the lungs, hence prevented pulmonary fibrosis in mice [69]. miR-101 decreased the mRNA and protein levels of TGFBR1, FZD4 and FZD6, and thus blocked NFATc2 and TGF-β1 signaling to attenuate fibroblast proliferation and activation [70].…”

Translational control of cardiac fibrosis

“…We found that targets of specific miRNAs or RBPs are significantly enriched in translationally but not transcriptionally regulated genes, revealing their post-transcriptional regulatory footprint during cardiac fibroblast activation. miR-101 was previously reported to inhibit cardiac fibrosis via the TGFβ1 pathway 29 , block fibroblast activation 30 and is reduced in the lung and serum of IPF patients 31 . We show that TGFβ1 stimulation results in a loss of anti-fibrotic miRNA-101 in atrial fibroblasts, which is significantly associated with an increase in ribosome occupancy on a select number of target transcripts ( Supplementary File 5 ).…”

The Role of miRNAs in Idiopathic Pulmonary Fibrosis

“…MicroRNAs (miRNAs) are short single-stranded RNA molecules of [19][20][21][22][23][24][25] nucleotides in length that mediate posttranscriptional gene silencing of target genes [5]. MiRNAs have been recognized as a distinct class of small regulatory RNAs in multiple species that regulate a wide variety of functions such as cell proliferation, differentiation, apoptosis, stress response, and immune response [6][7][8].…”

“…Profiling of miRNAs in the lung tissue from IPF patients was performed by different groups [18][19][20][21][22]. In IPF lungs, the expression of miR-21 and miR-155 was increased, whereas the expression of let-7a, miR-29, miR-30, and miR-101 was decreased [23][24][25]. MiR-21 expression was increased in the serum of IPF patients, and its levels correlated with a decrease in lung function [26].…”

“…However, little is known about miRNA functions in IPF; much of the functional data has been inferred from chemically induced mouse IPF models. In the lungs of mouse IPF models, miR-21, miR-9, and miR-155 were increased [19,21,30], and miR-26, miR-101, miR-139, miR-200, miR-326, miR-489, miR-503, and miR-708 were decreased [24,[31][32][33][34][35][36][37]. Furthermore, miR-21 expression was increased in myofibroblasts from IPF lungs, and its inhibition in mouse IPF models attenuated the disease severity [19].…”