Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 188, Issue 4, Pages 853-862Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2017.12.004
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Funding
- NIH [K12 HD087023, CA68485, DK20593, DK58404, DK5963]
- National Institute of General Medical Sciences grant [GM108807]
- National Heart, Lung, and Blood Institute [K08HL133484, R01HL119503, K08HL130595, P01HL92870, R01HL085317]
- Department of Veterans Affairs grant [BX002378]
- Francis Family Foundation
- Pulmonary Fibrosis Foundation
- Julia Carrell Stadler Chair in Pediatrics
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT [K12HD087023] Funding Source: NIH RePORTER
- NATIONAL CANCER INSTITUTE [P30CA068485] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL092906, K08HL130595, U01HL122626, R01HL059959, R01HL119503, T32HL094296, K08HL133484, P01HL092870, R01HL085317] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [P30DK058404, P30DK020593, P60DK020593] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM108807] Funding Source: NIH RePORTER
- Veterans Affairs [I01BX002378] Funding Source: NIH RePORTER
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Wnt/beta-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 beta-catenin phosphorylated at tyrosine 489 and epithelial cell cytosolic localization of beta-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 immunoftuorescence colocalization demonstrated a consistent pattern of elevated nuclear phosphorylated beta-catenin in the lung epithelium and surrounding mesenchyme in BPD and IPF, closely resembling the pattern observed in 18-week fetal Lung. Nuclear beta-catenin phosphorylated at tyrosine 489 associated with an increased expression of Wnt target gene AXIN2, suggesting that the observed beta-catenin signature is of functional significance during normal development and injury repair. The association of specific modifications of beta-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 beta-catenin phosphorylation has potential as a therapeutic target for the treatment and prevention of both BPD and IPF.
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