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

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.

• Authors: Irene H Heijink, Harold G de Bruin, Maarten van den Berge, Lisa J C Bennink, Simone M Brandenburg, Reinoud Gosens, Antoon J van Oosterhout, Dirkje S Postma
• Journal: Thorax (Thorax) Vol. 68 Issue 8 Pg. 709-16 (Aug 2013) ISSN: 1468-3296 [Electronic] England
• PMID: 23370438 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• FZD2 protein, human
• Frizzled Receptors
• Proto-Oncogene Proteins
• RNA, Messenger
• WNT10B protein, human
• WNT4 protein, human
• WNT5B protein, human
• Wnt Proteins
• Wnt4 Protein

Topics

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