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

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.

• Authors: 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
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 183 Issue 6 Pg. 723-33 (Mar 15 2011) ISSN: 1535-4970 [Electronic] United States
• PMID: 20889911 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Wnt Proteins
• Wnt1 Protein
• Wnt1 protein, mouse
• beta Catenin

Topics

• Adult
• Animals
• Disease Models, Animal
• Female
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Middle Aged
• Pulmonary Disease, Chronic Obstructive (physiopathology)
• Pulmonary Emphysema (physiopathology)
• Signal Transduction (physiology)
• Tissue Donors
• Wnt Proteins (metabolism)
• Wnt1 Protein (metabolism)
• beta Catenin (metabolism)