Ethan Lee
Faculty Member
Last active: 8/24/2020

Hyperoxia Injury in the Developing Lung Is Mediated by Mesenchymal Expression of Wnt5A.

Sucre JMS, Vickers KC, Benjamin JT, Plosa EJ, Jetter CS, Cutrone A, Ransom M, Anderson Z, Sheng Q, Fensterheim BA, Ambalavanan N, Millis B, Lee E, Zijlstra A, Königshoff M, Blackwell TS, Guttentag SH
Am J Respir Crit Care Med. 2020 201 (10): 1249-1262

PMID: 32023086 · PMCID: PMC7233334 · DOI:10.1164/rccm.201908-1513OC

Bronchopulmonary dysplasia (BPD) is a leading complication of preterm birth that affects infants born in the saccular stage of lung development at <32 weeks of gestation. Although the mechanisms driving BPD remain uncertain, exposure to hyperoxia is thought to contribute to disease pathogenesis. To determine the effects of hyperoxia on epithelial-mesenchymal interactions and to define the mediators of activated Wnt/β-catenin signaling after hyperoxia injury. Three hyperoxia models were used: A three-dimensional organotypic coculture using primary human lung cells, precision-cut lung slices (PCLS), and a murine hyperoxia model. Comparisons of normoxia- and hyperoxia-exposed samples were made by real-time quantitative PCR, RNA hybridization, quantitative confocal microscopy, and lung morphometry. Examination of an array of Wnt ligands in the three-dimensional organotypic coculture revealed increased mesenchymal expression of . Inhibition of Wnt5A abrogated the BPD transcriptomic phenotype induced by hyperoxia. In the PCLS model, Wnt5A inhibition improved alveolarization following hyperoxia exposure, and treatment with recombinant Wnt5a reproduced features of the BPD phenotype in PCLS cultured in normoxic conditions. Chemical inhibition of NF-κB with BAY11-7082 reduced expression in the PCLS hyperoxia model and mouse hyperoxia model, with improved alveolarization in the PCLS model. Increased mesenchymal Wnt5A during saccular-stage hyperoxia injury contributes to the impaired alveolarization and septal thickening observed in BPD. Precise targeting of Wnt5A may represent a potential therapeutic strategy for the treatment of BPD.

MeSH Terms (20)

Alveolar Epithelial Cells Animals Bronchopulmonary Dysplasia Coculture Techniques Fibroblasts Gene Expression Profiling Gene Expression Regulation, Developmental Humans Hyperoxia In Situ Hybridization Lung Mesenchymal Stem Cells Mice Microscopy, Confocal NF-kappa B Nitriles Organ Culture Techniques Real-Time Polymerase Chain Reaction Sulfones Wnt-5a Protein

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