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

Chaoqun Huang,Xiao Xiao,Ye Yang,Amorite Mishra,Yurong Liang,Xiangming Zeng,Xiaoyun Yang,Dao Xu,Michael R Blackburn,Craig A Henke,Lin Liu

doi:10.1074/jbc.m117.805747

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 in vitro The role of miR-101 in pulmonary fibrosis in vivo 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.

Highlights

Aberrant proliferation and activation of lung fibroblasts contribute to the initiation and progression of idiopathic pulmonary fibrosis (IPF)
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-␤-induced activation of lung fibroblasts by inhibition of SMAD2/3 signaling via targeting the TGF-␤ receptor 1
Idiopathic pulmonary fibrosis (IPF)2 is a lethal fibrotic lung disease characterized by enhanced fibroblast proliferation, collagen synthesis, extracellular matrix deposition, and alveolar epithelial type II cell hyperplasia

Summary

Introduction

Aberrant proliferation and activation of lung fibroblasts contribute to the initiation and progression of idiopathic pulmonary fibrosis (IPF). 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. Idiopathic pulmonary fibrosis (IPF) is a lethal fibrotic lung disease characterized by enhanced fibroblast proliferation, collagen synthesis, extracellular matrix deposition, and alveolar epithelial type II cell hyperplasia. Whether restoration of let-7 can prevent or reverse pulmonary fibrosis in animal models is unknown Another down-regulated miRNA in IPF is miR-29, which is localized in interstitial cells and regulates fibrotic genes in fibroblasts in vitro [12]. Because the expression of many miRNAs is altered in IPF, these studies underscore the need for further investigations to identify critical miRNAs that regulate key pathways for pulmonary fibrosis

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