Autophagy plays a role in FSTL1-induced epithelial mesenchymal transition and airway remodeling in asthma

Am J Physiol Lung Cell Mol Physiol. 2017 Jul 1;313(1):L27-L40. doi: 10.1152/ajplung.00510.2016. Epub 2017 May 4.


Asthma is a chronic disease related to airway hyperresponsiveness and airway remodeling. Airway remodeling is the important reason of refractory asthma and is associated with differentiation of airway epithelia into myofibroblasts via epithelial-mesenchymal transition (EMT) to increase the process of subepithelial fibrosis. There is growing evidence that autophagy modulates remodeling. However, the underlying molecular mechanisms of these effects are still unclear. In this study, we hypothesized that Follistatin-like 1 (FSTL1) promotes EMT and airway remodeling by intensifying autophagy. With the use of transmission electron microscopy (TEM), double-membrane autophagosomes were detected in the airways of patients and mice. More autophagosomes were in patients with asthma and OVA-challenged mice compared with healthy controls. The expression of FSTL1 and beclin-1 was upregulated in the airways of patients with asthma and OVA-challenged mice, accompanied by airway EMT and remodeling. In OVA-challenged Fstl1+/- mice, the degree of airway remodeling and autophagy was decreased compared with control mice. The effects of FSTL1 on autophagy and EMT were also tested in 16HBE cells in vitro. Additionally, inhibition of autophagy by using LY-294002 and siRNA-ATG5 reduced the FSTL1-induced EMT in 16HBE cells, as measured by E-cadherin, N-cadherin, and vimentin expression. In line herewith, administration of LY-294002 reduced the expression of autophagy, EMT, and airway remodeling markers in FSTL1-challenged WT mice. Taken together, our study suggests that FSTL1 may induce EMT and airway remodeling by activating autophagy. These findings may provide novel avenues for therapeutic research targeting the autophagy and FSTL1 pathway, which may be beneficial to patients with refractory asthma.

Keywords: EMT; FSTL1; airway remodeling; asthma; autophagy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Airway Remodeling* / drug effects
  • Animals
  • Asthma / complications
  • Asthma / pathology*
  • Asthma / physiopathology
  • Autophagosomes / metabolism
  • Autophagosomes / ultrastructure
  • Autophagy* / drug effects
  • Biomarkers / metabolism
  • Bronchoalveolar Lavage Fluid
  • Chromones / pharmacology
  • Disease Models, Animal
  • Epithelial-Mesenchymal Transition* / drug effects
  • Female
  • Follistatin-Related Proteins / blood
  • Follistatin-Related Proteins / genetics
  • Follistatin-Related Proteins / metabolism*
  • Humans
  • Lung / pathology
  • Lung / ultrastructure
  • Male
  • Mice, Inbred C57BL
  • Morpholines / pharmacology
  • Ovalbumin
  • Rats
  • Respiratory Hypersensitivity / complications
  • Respiratory Hypersensitivity / physiopathology
  • Up-Regulation / drug effects
  • Up-Regulation / genetics


  • Biomarkers
  • Chromones
  • Follistatin-Related Proteins
  • Fstl1 protein, mouse
  • Morpholines
  • FSTL1 protein, human
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Ovalbumin