Rationale: Chronic obstructive pulmonary disease (COPD) is a devastating and poorly understood disease. Currently, no causal therapy for COPD is available. The objectives of this study were, to characterize WNT/beta-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/beta-catenin signaling was assessed in 12 human COPD and 12 transplant donor

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... es using quantitative RT-PCR, immunohistochemistry, and Western blotting. The role of WNT/beta-catenin signaling was assessed in elastase-induced emphysema and therapeutic modulation thereof was assessed in elastase-induced emphysema in TOPGAL reporter and wild type mice in vivo. Measurements and Main Results: WNT/beta-catenin signaling components were largely expressed in alveolar epithelium in human COPD lungs. In COPD, no activation was observed and immunohistochemical analysis revealed reduced nuclear beta-catenin staining. Similarly, WNT/beta-catenin signaling was downregulated in the experimental emphysema model. Preventive, as well as therapeutic, WNT/beta-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 upon WNT activation.Conclusion: Decreased WNT/beta-catenin signaling is involved in parenchymal tissue destruction and impaired repair capacity in emphysema. These data indicate a crucial role of WNT/beta-catenin signaling in lung repair mechanisms in vivo, and highlight WNT/beta-catenin activation as a future therapeutic approach for emphysema.