title: Cigarette smoke-induced epithelial expression of WNT-5B: implications for COPD.
abstract: Wingless/integrase-1 (WNT) signalling is associated with lung inflammation and repair, but its role in chronic obstructive pulmonary disease (COPD) pathogenesis is unclear. We investigated whether cigarette smoke-induced dysregulation of WNT-5B contributes to airway remodelling in COPD.We analysed WNT-5B protein expression in the lung tissue of COPD patients and (non)smoking controls, and investigated the effects of cigarette smoke exposure on WNT-5B expression in COPD and control-derived primary bronchial epithelial cells (PBECs). Additionally, we studied downstream effects of WNT-5B on remodelling related genes fibronectin, matrix metalloproteinase (MMP)-2, MMP-9 and SnaiI in BEAS-2B and air-liquid interface (ALI)-cultured PBECs.We observed that airway epithelial WNT-5B expression is significantly higher in lung tissue from COPD patients than controls. Cigarette smoke extract significantly increased mRNA expression of WNT-5B in COPD, but not control-derived PBECs. Exogenously added WNT-5B augmented the expression of remodelling related genes in BEAS-2B cells, which was mediated by transforming growth factor (TGF)-β/Smad3 signalling. In addition, WNT-5B upregulated the expression of these genes in ALI-cultured PBECs, particularly PBECs from COPD patients.Together, our results provide evidence that exaggerated WNT-5B expression upon cigarette smoke exposure in the bronchial epithelium of COPD patients leads to TGF-β/Smad3-dependent expression of genes related to airway remodelling.
authors.affiliation: University of Groningen, University Medical Center Groningen, Dept of Pathology and Medical Biology, Groningen, The Netherlands University of Groningen, University Medical Center Groningen, Dept of Pulmonology, Groningen, The Netherlands University of Groningen, University Medical Center Groningen GRIAC Research Institute, Groningen, The Netherlands h.i.heijink@umcg.nl.
authors.forename: Irene H
authors.initials: IH
authors.lastname: Heijink
authors.affiliation: University of Groningen, University Medical Center Groningen, Dept of Pathology and Medical Biology, Groningen, The Netherlands.
authors.forename: Harold G
authors.initials: HG
authors.lastname: de Bruin
authors.affiliation: University of Groningen, University Medical Center Groningen, Dept of Pathology and Medical Biology, Groningen, The Netherlands.
authors.forename: Robin
authors.initials: R
authors.lastname: Dennebos
authors.affiliation: University of Groningen, University Medical Center Groningen, Dept of Pathology and Medical Biology, Groningen, The Netherlands.
authors.forename: Marnix R
authors.initials: MR
authors.lastname: Jonker
authors.affiliation: University of Groningen, University Medical Center Groningen, Dept of Pathology and Medical Biology, Groningen, The Netherlands.
authors.forename: Jacobien A
authors.initials: JA
authors.lastname: Noordhoek
authors.affiliation: University of Groningen, University Medical Center Groningen, Dept of Pathology and Medical Biology, Groningen, The Netherlands University of Groningen, University Medical Center Groningen GRIAC Research Institute, Groningen, The Netherlands.
authors.forename: Corry-Anke
authors.initials: CA
authors.lastname: Brandsma
authors.affiliation: University of Groningen, University Medical Center Groningen, Dept of Pulmonology, Groningen, The Netherlands University of Groningen, University Medical Center Groningen GRIAC Research Institute, Groningen, The Netherlands.
authors.forename: Maarten
authors.initials: M
authors.lastname: van den Berge
authors.affiliation: University of Groningen, University Medical Center Groningen, Dept of Pulmonology, Groningen, The Netherlands University of Groningen, University Medical Center Groningen GRIAC Research Institute, Groningen, The Netherlands.
authors.forename: Dirkje S
authors.initials: DS
authors.lastname: Postma
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001980:Bronchi / Q000378:metabolism; D016022:Case-Control Studies; D016207:Cytokines / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism*; D005260:Female; D005353:Fibronectins; D006801:Humans; D007249:Inflammation; D008168:Lung / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D020545:Respiratory Mucosa / Q000166:cytology; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism; D012906:Smoke / Q000009:adverse effects*; D000071250:Snail Family Transcription Factors / Q000378:metabolism; D062789:Tobacco Products; D016212:Transforming Growth Factor beta / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*
chemical_list: D016207:Cytokines; C067625:FN1 protein, human; D005353:Fibronectins; C497790:SMAD3 protein, human; C000604407:SNAI1 protein, human; D051900:Smad3 Protein; D012906:Smoke; D000071250:Snail Family Transcription Factors; D016212:Transforming Growth Factor beta; C435831:WNT5B protein, human; D051153:Wnt Proteins; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9