title: Reduced Frizzled Receptor 4 Expression Prevents WNT/β-Catenin-driven Alveolar Lung Repair in Chronic Obstructive Pulmonary Disease.
abstract: Chronic obstructive pulmonary disease (COPD), in particular emphysema, is characterized by loss of parenchymal alveolar tissue and impaired tissue repair. Wingless and INT-1 (WNT)/β-catenin signaling is reduced in COPD; however, the mechanisms thereof, specifically the role of the frizzled (FZD) family of WNT receptors, remain unexplored.
  
  
  
  To identify and functionally characterize specific FZD receptors that control downstream WNT signaling in impaired lung repair in COPD.
  
  
  
  FZD expression was analyzed in lung homogenates and alveolar epithelial type II (ATII) cells of never-smokers, smokers, patients with COPD, and two experimental COPD models by quantitative reverse transcriptase-polymerase chain reaction, immunoblotting, and immunofluorescence. The functional effects of cigarette smoke on FZD4, WNT/β-catenin signaling, and elastogenic components were investigated in primary ATII cells in vitro and in three-dimensional lung tissue cultures ex vivo. Gain- and loss-of-function approaches were applied to determine the effects of FZD4 signaling on alveolar epithelial cell wound healing and repair, as well as on expression of elastogenic components.
  
  
  
  FZD4 expression was reduced in human and experimental COPD lung tissues as well as in primary human ATII cells from patients with COPD. Cigarette smoke exposure down-regulated FZD4 expression in vitro and in vivo, along with reduced WNT/β-catenin activity. Inhibition of FZD4 decreased WNT/β-catenin-driven epithelial cell proliferation and wound closure, and it interfered with ATII-to-ATI cell transdifferentiation and organoid formation, which were augmented by FZD4 overexpression. Moreover, FZD4 restoration by overexpression or pharmacological induction led to induction of WNT/β-catenin signaling and expression of elastogenic components in three-dimensional lung tissue cultures ex vivo.
  
  
  
  Reduced FZD4 expression in COPD contributes to impaired alveolar repair capacity.
authors.affiliation: 1 Helmholtz Zentrum Munich, Comprehensive Pneumology Center, Member of the German Center for Lung Research, Munich, Germany.
authors.forename: Wioletta
authors.identifier: 0000-0001-7618-0034
authors.initials: W
authors.lastname: Skronska-Wasek
authors.affiliation: 1 Helmholtz Zentrum Munich, Comprehensive Pneumology Center, Member of the German Center for Lung Research, Munich, Germany.
authors.forename: Kathrin
authors.identifier: 0000-0002-5577-4500
authors.initials: K
authors.lastname: Mutze
authors.affiliation: 1 Helmholtz Zentrum Munich, Comprehensive Pneumology Center, Member of the German Center for Lung Research, Munich, Germany.
authors.forename: Hoeke A
authors.initials: HA
authors.lastname: Baarsma
authors.affiliation: 2 Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
authors.forename: Ken R
authors.initials: KR
authors.lastname: Bracke
authors.affiliation: 1 Helmholtz Zentrum Munich, Comprehensive Pneumology Center, Member of the German Center for Lung Research, Munich, Germany.
authors.forename: Hani N
authors.initials: HN
authors.lastname: Alsafadi
authors.affiliation: 1 Helmholtz Zentrum Munich, Comprehensive Pneumology Center, Member of the German Center for Lung Research, Munich, Germany.
authors.forename: Mareike
authors.initials: M
authors.lastname: Lehmann
authors.affiliation: 1 Helmholtz Zentrum Munich, Comprehensive Pneumology Center, Member of the German Center for Lung Research, Munich, Germany.
authors.forename: Rita
authors.initials: R
authors.lastname: Costa
authors.affiliation: 3 Department of Pharmacy, University of Naples Federico II, Naples, Italy; and.
authors.forename: Mariano
authors.initials: M
authors.lastname: Stornaiuolo
authors.affiliation: 3 Department of Pharmacy, University of Naples Federico II, Naples, Italy; and.
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.affiliation: 2 Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
authors.forename: Guy G
authors.initials: GG
authors.lastname: Brusselle
authors.affiliation: 1 Helmholtz Zentrum Munich, Comprehensive Pneumology Center, Member of the German Center for Lung Research, Munich, Germany.
authors.forename: Darcy E
authors.initials: DE
authors.lastname: Wagner
authors.affiliation: 1 Helmholtz Zentrum Munich, Comprehensive Pneumology Center, Member of the German Center for Lung Research, Munich, Germany.
authors.forename: Ali Ö
authors.initials: AÖ
authors.lastname: Yildirim
authors.affiliation: 1 Helmholtz Zentrum Munich, Comprehensive Pneumology Center, Member of the German Center for Lung Research, Munich, Germany.|4 Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado, Denver, Aurora, Colorado.
authors.forename: Melanie
authors.identifier: 0000-0001-9414-5128
authors.initials: M
authors.lastname: Königshoff
mesh_terms: D000368:Aged; D056809:Alveolar Epithelial Cells / Q000378:metabolism*; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D051157:Frizzled Receptors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000235:genetics; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C402930:FZD4 protein, human; D051157:Frizzled Receptors; D051153:Wnt Proteins; D051176:beta Catenin
keywords: Frizzled 4 receptor; cigarette smoke; emphysema; regeneration; smoking