Low-dose cadmium exposure induces peribronchiolar fibrosis through site-specific phosphorylation of vimentin

Am J Physiol Lung Cell Mol Physiol. 2017 Jul 1;313(1):L80-L91. doi: 10.1152/ajplung.00087.2017. Epub 2017 Apr 27.

Abstract

Exposure to cadmium (Cd) has been associated with development of chronic obstructive lung disease (COPD). The mechanisms and signaling pathways whereby Cd causes pathological peribronchiolar fibrosis, airway remodeling, and subsequent airflow obstruction remain unclear. We aimed to evaluate whether low-dose Cd exposure induces vimentin phosphorylation and Yes-associated protein 1 (YAP1) activation leading to peribronchiolar fibrosis and subsequent airway remodeling. Our data demonstrate that Cd induces myofibroblast differentiation and extracellular matrix (ECM) deposition around small (<2 mm in diameter) airways. Upon Cd exposure, α-smooth muscle actin (α-SMA) expression and the production of ECM proteins, including fibronectin and collagen-1, are markedly induced in primary human lung fibroblasts. Cd induces Smad2/3 activation and the translocation of both Smad2/3 and Yes-associated protein 1 (YAP1) into the nucleus. In parallel, Cd induces AKT and cdc2 phosphorylation and downstream vimentin phosphorylation at Ser39 and Ser55, respectively. AKT and cdc2 inhibitors block Cd-induced vimentin fragmentation and secretion in association with inhibition of α-SMA expression, ECM deposition, and collagen secretion. Furthermore, vimentin silencing abrogates Cd-induced α-SMA expression and decreases ECM production. Vimentin-deficient mice are protected from Cd-induced peribronchiolar fibrosis and remodeling. These findings identify two specific sites on vimentin that are phosphorylated by Cd and highlight the functional significance of vimentin phosphorylation in YAP1/Smad3 signaling that mediates Cd-induced peribronchiolar fibrosis and airway remodeling.

Keywords: cadmium; chronic obstructive lung disease; fibrosis; phosphorylation; vimentin.

MeSH terms

  • Actins / metabolism
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Bronchioles / pathology*
  • CDC2 Protein Kinase / metabolism
  • Cadmium / adverse effects*
  • Cell Differentiation / drug effects
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Collagen / metabolism
  • Extracellular Matrix / drug effects
  • Extracellular Matrix / metabolism
  • Fibrosis
  • Gene Silencing / drug effects
  • Humans
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Biological
  • Myofibroblasts / drug effects
  • Myofibroblasts / metabolism
  • Myofibroblasts / pathology
  • Phosphoproteins / metabolism
  • Phosphorylation / drug effects
  • Phosphoserine / metabolism
  • Protein Kinase C / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Smad Proteins / metabolism
  • Transcription Factors
  • Vimentin / metabolism*

Substances

  • ACTA2 protein, human
  • Actins
  • Adaptor Proteins, Signal Transducing
  • Phosphoproteins
  • Protein Kinase Inhibitors
  • Smad Proteins
  • Transcription Factors
  • Vimentin
  • YAP1 protein, human
  • Cadmium
  • Phosphoserine
  • Collagen
  • Protein Kinase C
  • CDC2 Protein Kinase