Role of aberrant WNT signalling in the airway epithelial response to cigarette smoke in chronic obstructive pulmonary disease.
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.
Department of Pathology and Medical Biology, Lab of Allergology and Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. h.i.heijink@umcg.nl
Irene H
IH
Heijink
Harold G
HG
de Bruin
Maarten
M
van den Berge
Lisa J C
LJ
Bennink
Simone M
SM
Brandenburg
Reinoud
R
Gosens
Antoon J
AJ
van Oosterhout
Dirkje S
DS
Postma
D000328:Adult; D000368:Aged; D002460:Cell Line; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D051157:Frizzled Receptors / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008875:Middle Aged; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics*; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D012907:Smoking / Q000009:adverse effects*; D051153:Wnt Proteins / Q000096:biosynthesis / Q000235:genetics*; D060528:Wnt4 Protein / Q000096:biosynthesis / Q000235:genetics
C489742:FZD2 protein, human; D051157:Frizzled Receptors; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C491119:WNT10B protein, human; C555581:WNT4 protein, human; C435831:WNT5B protein, human; D051153:Wnt Proteins; D060528:Wnt4 Protein
Airway Epithelium; COPD - Mechanisms; COPD Pathology