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  • Activation of the WNT/β-catenin pathway attenuates experimental emphysema.

Activation of the WNT/β-catenin pathway attenuates experimental emphysema.

American journal of respiratory and critical care medicine (2010-10-05)
Nikolaus Kneidinger, Ali Önder Yildirim, Jens Callegari, Shinji Takenaka, Maria Magdalena Stein, Rio Dumitrascu, Alexander Bohla, Ken R Bracke, Rory E Morty, Guy G Brusselle, Ralph Theo Schermuly, Oliver Eickelberg, Melanie Königshoff
ABSTRACT

Chronic obstructive pulmonary disease (COPD) is a devastating disease, for which no causal therapy is available. 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. 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. 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. 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.

MATERIALS
Product Number
Brand
Product Description

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Anti-Prosurfactant Protein C (proSP-C) Antibody, serum, Chemicon®
Sigma-Aldrich
Anti-Active-β-Catenin (Anti-ABC) Antibody, clone 8E7, clone 8E7, Upstate®, from mouse
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Monoclonal Anti-Actin, α-Smooth Muscle, clone 1A4, ascites fluid