• Sucre Jennifer M S JM Mildred Stahlman Division of Neonatology, Department of Pediatrics, Vanderbilt University, Nashville, Tennessee; jennifer.sucre@vanderbilt.edu., Preethi Vijayaraj, Cody J Aros, Dan Wilkinson, Manash Paul, Bruce Dunn, Susan H Guttentag, and Brigitte N Gomperts.
• Mildred Stahlman Division of Neonatology, Department of Pediatrics, Vanderbilt University, Nashville, Tennessee; jennifer.sucre@vanderbilt.edu.
• Am. J. Physiol. Lung Cell Mol. Physiol. 2017 Feb 1; 312 (2): L186-L195.

AbstractBronchopulmonary dysplasia (BPD) is a common complication of premature birth. The histopathology of BPD is characterized by an arrest of alveolarization with fibroblast activation. The Wnt/β-catenin signaling pathway is important in early lung development. When Wnt signaling is active, phosphorylation of β-catenin by tyrosine kinases at activating sites, specifically at tyrosine 489 (Y489), correlates with nuclear localization of β-catenin. We examined fetal lung tissue, lung tissue from term newborns, and lung tissue from infants who died with BPD; we found nuclear β-catenin phosphorylation at Y489 in epithelial and mesenchymal cells in fetal tissue and BPD tissue, but not in the lungs of term infants. Using a 3D human organoid model, we found increased nuclear localization of β-catenin phosphorylated at Y489 (p-β-cateninY489) after exposure to alternating hypoxia and hyperoxia compared with organoids cultured in normoxia. Exogenous stimulation of the canonical Wnt pathway in organoids was sufficient to cause nuclear localization of p-β-cateninY489 in normoxia and mimicked the pattern of α-smooth muscle actin (α-SMA) expression seen with fibroblastic activation from oxidative stress. Treatment of organoids with a tyrosine kinase inhibitor prior to cyclic hypoxia-hyperoxia inhibited nuclear localization of p-β-cateninY489 and prevented α-SMA expression by fibroblasts. Posttranslational phosphorylation of β-catenin is a transient feature of normal lung development. Moreover, the persistence of p-β-cateninY489 is a durable marker of fibroblast activation in BPD and may play an important role in BPD disease pathobiology.Copyright © 2017 the American Physiological Society.

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