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Activation of the WNT/β-catenin pathway attenuates experimental emphysema.
Am. J. Respir. Crit. Care Med. 183, 723-733 (2011)
RATIONALE: Chronic obstructive pulmonary disease (COPD) is a devastating disease, for which no causal therapy is available. OBJECTIVES: 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 RT-PCR, 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. MEASUREMENTS AND MAIN 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 !-catenin-positive alveolar epithelial cells in COPD. Similarly, WNT/β-catenin signaling was downregulated in both experimental emphysema models. Preventive, as well as 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. CONCLUSION: 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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter COPD; emphysema; WNT; lung development
ISSN (print) / ISBN 1073-449X
Quellenangaben Band: 183, Heft: 6, Seiten: 723-733
Verlag American Thoracic Society
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Lung Biology (ILBD)