Activation of the WNT/β-catenin pathway attenuates experimental emphysema.
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.
Kneidinger
Nikolaus
N
Department of Medicine, University of Giessen Lung Center, University of Giessen, Giessen, Germany
Yildirim
Ali Önder
AÖ
Callegari
Jens
J
Takenaka
Shinji
S
Stein
Maria Magdalena
MM
Dumitrascu
Rio
R
Bohla
Alexander
A
Bracke
Ken R
KR
Morty
Rory E
RE
Brusselle
Guy G
GG
Schermuly
Ralph Theo
RT
Eickelberg
Oliver
O
Königshoff
Melanie
M
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*
D051153:Wnt Proteins; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D051176:beta Catenin