Role of aberrant WNT signalling in the airway epithelial response to cigarette smoke in chronic obstructive pulmonary disease

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Abstract

Background WNT signalling is activated during lung tissue damage and inflammation. We investigated whether lung epithelial expression of WNT ligands, receptors (frizzled; FZD) or target genes is dysregulated on cigarette smoking and/or in chronic obstructive pulmonary disease (COPD).

Methods We studied this in human lung epithelial cell lines and primary bronchial epithelial cells (PBEC) from COPD patients and control (non-)smokers, at baseline and on cigarette smoke extract (CSE) exposure.

Results CSE significantly decreased WNT-4, WNT-10B and FZD2 and increased WNT-5B mRNA expression in 16HBE, but did not affect WNT-4 protein. The mRNA expression of WNT-4, but not other WNT ligands, was lower in PBEC from smokers than non-smokers and downregulated by CSE in PBEC from all groups, yet higher in PBEC from COPD patients than control smokers. Moreover, PBEC from COPD patients displayed higher WNT-4 protein expression than both smokers and non-smokers. Exogenously added WNT-4 significantly increased CXCL8/IL-8, IL-6, CCL5/RANTES, CCL2/MCP-1 and vascular endothelial growth factor (VEGF) secretion in 16HBE, but did not affect the canonical WNT target genes MMP-2, MMP-9, fibronectin, beta-catenin, Dickkopf and axin-2, and induced activation of the non-canonical signalling molecule p38. Moreover, WNT-4 potentiated the CSE-induced upregulation of IL-8 and VEGF.

Conclusions WNT-4 mRNA and protein levels are higher in PBEC from COPD patients than control (non-) smokers, while cigarette smoke downregulates airway epithelial WNT-4 mRNA, but not protein expression. As WNT-4 further increases CSE-induced pro-inflammatory cytokine release in bronchial epithelium, we propose that higher epithelial WNT-4 levels in combination with cigarette smoking may have important implications for the development of airway inflammation in COPD.

Original languageEnglish
Pages (from-to)709-716
Number of pages8
JournalThorax
Volume68
Issue number8
DOIs
Publication statusPublished - Aug-2013

Keywords

  • Adult
  • Aged
  • Cell Line
  • Epithelial Cells
  • Female
  • Frizzled Receptors
  • Gene Expression Regulation
  • Humans
  • Male
  • Middle Aged
  • Proto-Oncogene Proteins
  • Pulmonary Disease, Chronic Obstructive
  • RNA, Messenger
  • Respiratory Mucosa
  • Signal Transduction
  • Smoking
  • Wnt Proteins
  • Wnt4 Protein

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