title: Activation of the WNT/β-catenin pathway attenuates experimental emphysema.
abstract: BACKGROUND
  Chronic obstructive pulmonary disease (COPD) is a devastating disease, for which no causal therapy is available.
  
  
  OBJECTIVE
  To characterize WNT/β-catenin signaling in COPD in humans and elucidate its potential role as a preventive and therapeutic target in experimental emphysema in mice.
  
  
  METHODS
  The expression, localization, and activity of WNT/β-catenin signaling was assessed in 12 COPD and 12 transplant donor samples using quantitative reverse transcriptase polymerase chain reaction, immunohistochemistry, and Western blotting. The role of WNT/β-catenin signaling was assessed in elastase- and cigarette smoke-induced emphysema and therapeutic modulation thereof in elastase-induced emphysema in TOPGAL reporter and wild-type mice in vivo.
  
  
  RESULTS
  No differences in the mRNA expression profile of the main WNT/β-catenin signaling components were observed comparing COPD and donor lung homogenates. Immunohistochemical analysis revealed reduced numbers of nuclear β-catenin-positive alveolar epithelial cells in COPD. Similarly, WNT/β-catenin signaling was down-regulated in both experimental emphysema models. Preventive and therapeutic, WNT/β-catenin activation by lithium chloride attenuated experimental emphysema, as assessed by decreased airspace enlargement, improved lung function, reduced collagen content, and elevated expression of alveolar epithelial cell markers.
  
  
  CONCLUSIONS
  Decreased WNT/β-catenin signaling is involved in parenchymal tissue destruction and impaired repair capacity in emphysema. These data indicate a crucial role of WNT/β-catenin signaling in lung repair mechanisms in vivo, and highlight WNT/β-catenin activation as a future therapeutic approach for emphysema.
authors.affiliation: Department of Medicine, University of Giessen Lung Center, University of Giessen, Giessen, Germany
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Kneidinger
authors.forename: Ali Önder
authors.initials: AÖ
authors.lastname: Yildirim
authors.forename: Jens
authors.initials: J
authors.lastname: Callegari
authors.forename: Shinji
authors.initials: S
authors.lastname: Takenaka
authors.forename: Maria Magdalena
authors.initials: MM
authors.lastname: Stein
authors.forename: Rio
authors.initials: R
authors.lastname: Dumitrascu
authors.forename: Alexander
authors.initials: A
authors.lastname: Bohla
authors.forename: Ken R
authors.initials: KR
authors.lastname: Bracke
authors.forename: Rory E
authors.initials: RE
authors.lastname: Morty
authors.forename: Guy G
authors.initials: GG
authors.lastname: Brusselle
authors.forename: Ralph Theo
authors.initials: RT
authors.lastname: Schermuly
authors.forename: Oliver
authors.initials: O
authors.lastname: Eickelberg
authors.forename: Melanie
authors.initials: M
authors.lastname: Königshoff
mesh_terms: D000328:Adult; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000503:physiopathology*; D011656:Pulmonary Emphysema / Q000503:physiopathology*; D015398:Signal Transduction / Q000502:physiology*; D014019:Tissue Donors; D051153:Wnt Proteins / Q000378:metabolism*; D051155:Wnt1 Protein / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D051153:Wnt Proteins; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D051176:beta Catenin