Rationale: 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.Objectives: To determine the effects of hyperoxia on epithelial-mesenchymal interactions and to define the mediators of activated Wnt/β-catenin signaling after hyperoxia injury.Methods: Three hyperoxia models were used: A three-dimensional organotypic coculture using primary human lung cells, precision-cut lung slices (PCLS), and a murine in vivo hyperoxia model. Comparisons of normoxia- and hyperoxia-exposed samples were made by real-time quantitative PCR, RNA in situ hybridization, quantitative confocal microscopy, and lung morphometry.Measurements and Main Results: Examination of an array of Wnt ligands in the three-dimensional organotypic coculture revealed increased mesenchymal expression of WNT5A. 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 Wnt5a expression in the PCLS hyperoxia model and in vivo mouse hyperoxia model, with improved alveolarization in the PCLS model.Conclusions: 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.

中文翻译：

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Wnt5A 的间充质表达介导了发育中肺中的高氧损伤。

理由：支气管肺发育不良 (BPD) 是早产的主要并发症，会影响出生于小于 32 周的肺发育囊状阶段的婴儿。虽然驱动 BPD 的机制仍不确定，但认为暴露于高氧有助于疾病的发病机制。 : 使用了三种高氧模型：使用原代人肺细胞、精确切割的肺切片 (PCLS) 和小鼠体内高氧模型的三维器官共培养。通过实时定量 PCR、RNA 原位杂交、定量共聚焦显微镜和肺形态测定法对常氧和高氧暴露样品进行比较。测量和主要结果：检查三维器官共培养中的一系列 Wnt 配体显示 WNT5A 的间充质表达增加。Wnt5A 的抑制消除了由高氧诱导的 BPD 转录组表型。在 PCLS 模型中，Wnt5A 抑制改善了高氧暴露后的肺泡化，并且重组 Wnt5a 处理再现了在常氧条件下培养的 PCLS 中 BPD 表型的特征。用 BAY11-7082 化学抑制 NF-κB 降低了 PCLS 高氧模型和体内小鼠高氧模型中 Wnt5a 的表达，改善了 PCLS 模型中的肺泡形成。在 BPD 中观察到间隔增厚。