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Thorax doi:10.1136/thoraxjnl-2012-201667
  • Airway pathology
  • Original article

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

  1. Dirkje S Postma2,3
  1. 1Department of Pathology and Medical Biology, Lab of Allergology and Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
  2. 2Department of Pulmonology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
  3. 3GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
  4. 4Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands
  1. Correspondence to Dr Irene H Heijink, Pathology and Medical Biology, Lab of Allergology and Pulmonary Diseases, University of Groningen, EA52, University Medical Center Groningen, Hanzeplein 1, Groningen NL-9713 GZ, The Netherlands; h.i.heijink{at}umcg.nl
  • Received 24 January 2012
  • Revised 9 January 2013
  • Accepted 10 January 2013
  • Published Online First 31 January 2013

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, β-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.

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