Beta-catenin in the fibroproliferative response to acute lung injury.
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.
Douglas
Ivor S
IS
Department of Medicine, Pulmonary Sciences & Critical Care Medicine, Univ. of Colorado Health Sciences Center, Denver, CO 80262, USA. idouglas@dhha.org
Diaz del Valle
Fernando
F
Winn
Robert A
RA
Voelkel
Norbert F
NF
D000818:Animals; D017209:Apoptosis; D001216:Asparagine / Q000031:analogs & derivatives / Q000494:pharmacology; D002084:Butylated Hydroxytoluene; D015820:Cadherins / Q000378:metabolism; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D003094:Collagen / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009336:Necrosis; D018384:Oxidative Stress; D010100:Oxygen / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D012128:Respiratory Distress Syndrome / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D051176:beta Catenin / Q000378:metabolism*; D000099200:Scaffold Protein ILK
D001216:Asparagine; D002084:Butylated Hydroxytoluene; D015820:Cadherins; D061945:Caspase Inhibitors; D020169:Caspases; D003094:Collagen; D019938:Cyclin D1; D010100:Oxygen; D017346:Protein Serine-Threonine Kinases; D051176:beta Catenin; D000099200:Scaffold Protein ILK; C117865:benzyloxycarbonyl-asparagine