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

https://doi.org/10.1016/j.ajpath.2017.12.004Get rights and content
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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.

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Supported by NIH grant K12 HD087023 (J.M.S.S.); National Institute of General Medical Sciences grant GM108807 (S.H.G.); National Heart, Lung, and Blood Institute grants K08HL133484 (J.T.B.), R01HL119503 (L.R.Y.), K08HL130595 (J.A.K.), P01HL92870 (T.S.B.), and R01HL085317 (T.S.B.); Department of Veterans Affairs grant BX002378 (T.S.B.); the Francis Family Foundation (J.A.K.); the Pulmonary Fibrosis Foundation (J.A.K.); and the Julia Carrell Stadler Chair in Pediatrics (S.H.G.). Experiments were performed, in part, through the use of the Vanderbilt University Cell Imaging Shared Resource, supported by NIH grants CA68485, DK20593, DK58404, and DK5963.

J.A.K. and S.H.G. contributed equally as senior authors.

Disclosures: None declared.

A guest editor acted as the Editor-in-Chief for this manuscript. No person at the University of Alabama at Birmingham was involved in the peer review process or final disposition of this article.

© 2018 American Society for Investigative Pathology. Published by Elsevier Inc.