Posttranslational modification of {beta}-catenin is associated with pathogenic fibroblastic changes in bronchopulmonary dysplasia

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.
Source: AJP: Lung Cellular and Molecular Physiology - Category: Respiratory Medicine Authors: Tags: RAPID REPORT Source Type: research