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Am J Respir Crit Care Med. 2011 Mar 15;183(6):723-33. doi: 10.1164/rccm.200910-1560OC. Epub 2010 Oct 1.

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

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1
Department of Medicine, University of Giessen Lung Center, University of Giessen, Giessen, Germany

Abstract

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 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.

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 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.

Comment in

PMID:
20889911
DOI:
10.1164/rccm.200910-1560OC
[Indexed for MEDLINE]
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