title: Noncanonical WNT-5A signaling impairs endogenous lung repair in COPD.
abstract: Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide. One main pathological feature of COPD is the loss of functional alveolar tissue without adequate repair (emphysema), yet the underlying mechanisms are poorly defined. Reduced WNT-β-catenin signaling is linked to impaired lung repair in COPD; however, the factors responsible for attenuating this pathway remain to be elucidated. Here, we identify a canonical to noncanonical WNT signaling shift contributing to COPD pathogenesis. We demonstrate enhanced expression of noncanonical WNT-5A in two experimental models of COPD and increased posttranslationally modified WNT-5A in human COPD tissue specimens. WNT-5A was increased in primary lung fibroblasts from COPD patients and induced by COPD-related stimuli, such as TGF-β, cigarette smoke (CS), and cellular senescence. Functionally, mature WNT-5A attenuated canonical WNT-driven alveolar epithelial cell wound healing and transdifferentiation in vitro. Lung-specific WNT-5A overexpression exacerbated airspace enlargement in elastase-induced emphysema in vivo. Accordingly, inhibition of WNT-5A in vivo attenuated lung tissue destruction, improved lung function, and restored expression of β-catenin-driven target genes and alveolar epithelial cell markers in the elastase, as well as in CS-induced models of COPD. We thus identify a novel essential mechanism involved in impaired mesenchymal-epithelial cross talk in COPD pathogenesis, which is amenable to therapy.
authors.affiliation: Comprehensive Pneumology Center, Research Unit Lung Repair and Regeneration, Helmholtz Center Munich, Ludwig Maximilians University Munich, University Hospital Grosshadern, 81377 Munich, Germany.
authors.forename: Hoeke A
authors.initials: HA
authors.lastname: Baarsma
authors.affiliation: Comprehensive Pneumology Center, Research Unit Lung Repair and Regeneration, Helmholtz Center Munich, Ludwig Maximilians University Munich, University Hospital Grosshadern, 81377 Munich, Germany.
authors.forename: Wioletta
authors.identifier: 0000-0001-7618-0034
authors.initials: W
authors.lastname: Skronska-Wasek
authors.affiliation: Comprehensive Pneumology Center, Research Unit Lung Repair and Regeneration, Helmholtz Center Munich, Ludwig Maximilians University Munich, University Hospital Grosshadern, 81377 Munich, Germany.
authors.forename: Kathrin
authors.identifier: 0000-0002-5577-4500
authors.initials: K
authors.lastname: Mutze
authors.affiliation: Comprehensive Pneumology Center, Research Unit Lung Repair and Regeneration, Helmholtz Center Munich, Ludwig Maximilians University Munich, University Hospital Grosshadern, 81377 Munich, Germany.
authors.forename: Florian
authors.identifier: 0000-0003-3727-207X
authors.initials: F
authors.lastname: Ciolek
authors.affiliation: Comprehensive Pneumology Center, Research Unit Lung Repair and Regeneration, Helmholtz Center Munich, Ludwig Maximilians University Munich, University Hospital Grosshadern, 81377 Munich, Germany.
authors.forename: Darcy E
authors.identifier: 0000-0003-3794-1309
authors.initials: DE
authors.lastname: Wagner
authors.affiliation: Comprehensive Pneumology Center, Research Unit Lung Repair and Regeneration, Helmholtz Center Munich, Ludwig Maximilians University Munich, University Hospital Grosshadern, 81377 Munich, Germany.
authors.forename: Gerrit
authors.initials: G
authors.lastname: John-Schuster
authors.affiliation: Comprehensive Pneumology Center, Research Unit Lung Repair and Regeneration, Helmholtz Center Munich, Ludwig Maximilians University Munich, University Hospital Grosshadern, 81377 Munich, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Heinzelmann
authors.affiliation: University of Giessen Lung Center, 35392 Giessen, Germany.
authors.forename: Andreas
authors.identifier: 0000-0002-2187-0975
authors.initials: A
authors.lastname: Günther
authors.affiliation: Department of Respiratory Medicine, Ghent University Hospital, 9000 Ghent, Belgium.
authors.forename: Ken R
authors.identifier: 0000-0001-5906-4605
authors.initials: KR
authors.lastname: Bracke
authors.affiliation: Inserm U955, Equipe 4, 94000 Créteil, France.
authors.forename: Maylis
authors.initials: M
authors.lastname: Dagouassat
authors.affiliation: Inserm U955, Equipe 4, 94000 Créteil, France.
authors.forename: Jorge
authors.initials: J
authors.lastname: Boczkowski
authors.affiliation: Department of Respiratory Medicine, Ghent University Hospital, 9000 Ghent, Belgium.
authors.forename: Guy G
authors.initials: GG
authors.lastname: Brusselle
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, 3000 Rotterdam, Netherlands.
authors.forename: Ron
authors.initials: R
authors.lastname: Smits
authors.affiliation: Comprehensive Pneumology Center, Research Unit Lung Repair and Regeneration, Helmholtz Center Munich, Ludwig Maximilians University Munich, University Hospital Grosshadern, 81377 Munich, Germany.
authors.forename: Oliver
authors.identifier: 0000-0001-7170-0360
authors.initials: O
authors.lastname: Eickelberg
authors.affiliation: Comprehensive Pneumology Center, Research Unit Lung Repair and Regeneration, Helmholtz Center Munich, Ludwig Maximilians University Munich, University Hospital Grosshadern, 81377 Munich, Germany.
authors.forename: Ali Ö
authors.initials: AÖ
authors.lastname: Yildirim
authors.affiliation: Comprehensive Pneumology Center, Research Unit Lung Repair and Regeneration, Helmholtz Center Munich, Ludwig Maximilians University Munich, University Hospital Grosshadern, 81377 Munich, Germany melanie.koenigshoff@ucdenver.edu.
authors.forename: Melanie
authors.identifier: 0000-0001-9414-5128
authors.initials: M
authors.lastname: Königshoff
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004646:Emphysema / Q000209:etiology; D005260:Female; D008168:Lung / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology / Q000503:physiopathology*; D012907:Smoking / Q000009:adverse effects; D060449:Wnt Signaling Pathway / Q000502:physiology*; D000071818:Wnt-5a Protein / Q000502:physiology*; D051176:beta Catenin / Q000502:physiology
chemical_list: C085389:WNT5A protein, human; D000071818:Wnt-5a Protein; D051176:beta Catenin