A Shared Pattern of β-Catenin Activation in Bronchopulmonary Dysplasia and Idiopathic Pulmonary Fibrosis.

Sucre JMS, Deutsch GH, Jetter CS, Ambalavanan N, Benjamin JT, Gleaves LA, Millis BA, Young LR, Blackwell TS, Kropski JA, Guttentag SH
Am J Pathol. 2018 188 (4): 853-862

PMID: 29355514 · PMCID: PMC5866104 · DOI:10.1016/j.ajpath.2017.12.004

Wnt/β-catenin signaling is necessary for normal lung development, and abnormal Wnt signaling contributes to the pathogenesis of both bronchopulmonary dysplasia (BPD) and idiopathic pulmonary fibrosis (IPF), fibrotic lung diseases that occur during infancy and aging, respectively. Using a library of human normal and diseased human lung samples, we identified a distinct signature of nuclear accumulation of β-catenin phosphorylated at tyrosine 489 and epithelial cell cytosolic localization of β-catenin phosphorylated at tyrosine 654 in early normal lung development and fibrotic lung diseases BPD and IPF. Furthermore, this signature was recapitulated in murine models of BPD and IPF. Image analysis of immunofluorescence colocalization demonstrated a consistent pattern of elevated nuclear phosphorylated β-catenin in the lung epithelium and surrounding mesenchyme in BPD and IPF, closely resembling the pattern observed in 18-week fetal lung. Nuclear β-catenin phosphorylated at tyrosine 489 associated with an increased expression of Wnt target gene AXIN2, suggesting that the observed β-catenin signature is of functional significance during normal development and injury repair. The association of specific modifications of β-catenin during normal lung development and again in response to lung injury supports the widely held concept that repair of lung injury involves the recapitulation of developmental programs. Furthermore, these observations suggest that β-catenin phosphorylation has potential as a therapeutic target for the treatment and prevention of both BPD and IPF.

Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

MeSH Terms (21)

A549 Cells Adult Animals Animals, Newborn Axin Protein beta Catenin Bronchopulmonary Dysplasia Cell Nucleus Epithelial Cells Female Fetus Humans Idiopathic Pulmonary Fibrosis Lung Mice, Inbred C57BL Phosphorylation Pregnancy Pregnancy Trimester, Second Protein Processing, Post-Translational Signal Transduction Tyrosine

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