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Published ahead of print on November 4, 2005, doi:10.1165/rcmb.2005-0277OC
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American Journal of Respiratory Cell and Molecular Biology. Vol. 34, pp. 274-285, 2006
© 2006 American Thoracic Society
DOI: 10.1165/rcmb.2005-0277OC

beta-Catenin in the Fibroproliferative Response to Acute Lung Injury

Ivor S. Douglas, Fernando Diaz del Valle, Robert A. Winn and Norbert F. Voelkel

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

Correspondence and requests for reprints should be addressed to Ivor S. Douglas, M.D., Univ. of Colorado at Denver & Health Sciences Center, Pulmonary Sciences & Critical Care Medicine SOM 5226, C-272, Denver, CO 80262. E-mail: idouglas{at}dhha.org

Resolution of alveolar epithelial/capillary membrane damage after acute lung injury requires coordinated and effective tissue repair to reestablish a functional alveolar epithelial/capillary membrane barrier. We hypothesized that signaling 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 noncanonical beta-catenin pathway proteins E-cadherin, integrin-linked kinase–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 d of BHT and hyperoxia was accompanied by enhanced expression and nuclear localization of beta-catenin and increased integrin-linked kinase-1 expression during subsequent normoxic recovery. This resulted in increased expression of the cotranscriptional regulators TCF-1 and -3 and cyclin D1. Proliferation of murine lung epithelial-12 cells in vitro after 8 h of treatment with BHT quinone-methide and hyperoxia and 48 h of normoxic recovery was enhanced 2.7-fold compared with vehicle-treated control mice at the same time point. BHT/hyperoxia-exposed mice treated with the pan-caspase inhibitor z-ASP had increased acute lung injury and reduced survival despite the presence of TUNEL-positive cells, suggesting enhanced lung cell necrosis. beta-Catenin expression was reduced in z-ASP–co-treated lungs after BHT/hyperoxia. The noncanonical 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.

Key Words: beta-catenin • E-cadherin • lung injury repair • cell junctions • caspase




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