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Published ahead of print on November 4, 2005, doi:10.1165/rcmb.2005-0277OC

Am. J. Respir. Cell Mol. Biol., Volume 34, Number 3, March 2006, 274-285

A more recent version of this article appeared on March 1, 2006
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Submitted on July 20, 2005
Revised on October 28, 2005

Beta-Catenin in the Fibroproliferative Response to Acute Lung Injury

Ivor S Douglas1*, Fernando Diaz del Valle2, Robert A Winn2, and Norbert F Voelkel2

1 Department of Medicine, Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, CO, USA; Department of Medicine, Denver Health Medical Center, Denver, CO, USA, 2 Department of Medicine, Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, CO, USA

* To whom correspondence should be addressed. E-mail: idouglas{at}dhha.org.

Resolution of alveolar epithelial/capillary membrane (ACM) damage after acute lung injury (ALI) requires coordinated and effective tissue repair to reestablish a functional ACM barrier. We hypothesized that signalling pathways important in lung alveolar bud ontogeny are activated in the recovery and remodeling phases after profound oxidant stress lung injury in a murine model. To test this, we characterized the expression of non-canonical {beta}-catenin pathway proteins E-cadherin, ILK-1 and {beta}-catenin in mice undergoing normoxic recovery after exposure to butylated hydroxytoluene (BHT, ionol) and concomitant sublethal (75% O2) hyperoxia. Mice developed early acute lung injury with subsequent inflammation, collagen deposition, interstitial cellular proliferation and lung architectural distortion. Reduced E-cadherin expression after 6 days of BHT and hyperoxia was accompanied by enhanced expression and nuclear localization of {beta}-catenin as well increased ILK-1 expression during subsequent normoxic recovery. This resulted in increased expression of the co-transcriptional regulators TCF-1 and -3 and Cyclin D1. Proliferation of MLE-12 cells in vitro following 8 hours of treatment with BHT quinone-methide and hyperoxia and 48 hours of normoxic recovery was enhanced 2.7-fold compared with vehicle-treated controls at the same time point. BHT/hyperoxia exposed mice treated with the pan-caspase inhibitor z-ASP had increased ALI and reduced survival despite the presence of TUNEL positive cells suggesting enhanced lung cell necrosis. {beta}-catenin expression was reduced in z-ASP cotreated lungs after BHT/hyperoxia. Non-canonical cadherin - {beta}-catenin axis is associated with fibroproliferative repair after BHT/hyperoxia exposure and may regulate epithelial proliferation and lung matrix remodeling and repair in response to lung injury.




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