PT  - JOURNAL ARTICLE
AU  - Irene H Heijink
AU  - Harold G de Bruin
AU  - Maarten van den Berge
AU  - Lisa J C Bennink
AU  - Simone M Brandenburg
AU  - Reinoud Gosens
AU  - Antoon J van Oosterhout
AU  - Dirkje S Postma
TI  - Role of aberrant WNT signalling in the airway epithelial response to cigarette smoke in chronic obstructive pulmonary disease
AID  - 10.1136/thoraxjnl-2012-201667
DP  - 2013 Aug 01
TA  - Thorax
PG  - 709--716
VI  - 68
IP  - 8
4099  - http://thorax.bmj.com/content/68/8/709.short
4100  - http://thorax.bmj.com/content/68/8/709.full
SO  - Thorax2013 Aug 01; 68
AB  - 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.