miR-34a Inhibits Lung Fibrosis by Inducing Lung Fibroblast Senescence

Am J Respir Cell Mol Biol. 2017 Feb;56(2):168-178. doi: 10.1165/rcmb.2016-0163OC.


Cellular senescence has been implicated in diverse pathologies. However, there is conflicting evidence regarding the role of this process in tissue fibrosis. Although dysregulation of microRNAs is a key mechanism in the pathogenesis of lung fibrosis, it is unclear whether microRNAs function by regulating cellular senescence in the disease. In this study, we found that miR-34a demonstrated greater expression in the lungs of patients with idiopathic pulmonary fibrosis and in mice with experimental pulmonary fibrosis, with its primary localization in lung fibroblasts. More importantly, miR-34a was up-regulated significantly in both human and mouse lung myofibroblasts. We found that mice with miR-34a ablation developed more severe pulmonary fibrosis than did wild-type animals after fibrotic lung injury. Mechanistically, we found that miR-34a induced a senescent phenotype in lung fibroblasts because this microRNA increased senescence-associated β-galactosidase activity, enhanced expression of senescence markers, and decreased cell proliferative capacities. Consistently, we found that primary lung fibroblasts from fibrotic lungs of miR-34a-deficient mice had a diminished senescent phenotype and enhanced resistance to apoptosis as compared with those from wild-type animals. We also identified multiple miR-34a targets that likely mediated its activities in inducing senescence in lung fibroblasts. In conclusion, our data suggest that miR-34a functions through a negative feedback mechanism to restrain fibrotic response in the lungs by promoting senescence of pulmonary fibroblasts.

Keywords: cellular senescence; lung fibrosis; microRNA; pulmonary fibroblast.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cell Differentiation / drug effects
  • Cellular Senescence* / drug effects
  • Cellular Senescence* / genetics
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Fibroblasts / pathology*
  • Gene Knockdown Techniques
  • Humans
  • Idiopathic Pulmonary Fibrosis / genetics*
  • Idiopathic Pulmonary Fibrosis / pathology*
  • Lung / pathology*
  • Mice, Inbred C57BL
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Myofibroblasts / metabolism
  • Myofibroblasts / pathology
  • Transforming Growth Factor beta1 / pharmacology
  • Up-Regulation / drug effects
  • Up-Regulation / genetics


  • MIRN34 microRNA, human
  • MIRN34a microRNA, mouse
  • MicroRNAs
  • Transforming Growth Factor beta1