Children with hypoplastic lung disease associated with congenital diaphragmatic hernia (CDH) continue to suffer significant morbidity and mortality secondary to progressive pulmonary disease. Recently published work from our lab demonstrated the potential of Roxadustat (FG-4592), a prolyl hydroxylase inhibitor, as a treatment for CDH-associated pulmonary hypoplasia. Treatment with Roxadustat led to significantly accelerated compensatory lung growth (CLG) through downregulation of pigment epithelium-derived factor (PEDF), an anti-angiogenic factor, rather than upregulation of vascular endothelial growth factor (VEGF). PEDF and its role in pulmonary development is a largely unexplored field. In this study, we sought to further evaluate the role of PEDF in accelerating CLG. PEDF-deficient mice demonstrated significantly increased lung volume, total lung capacity, and alveolarization compared to wild type controls following left pneumonectomy without increased VEGF expression. Furthermore, Roxadustat administration in PEDF-deficient mice did not further accelerate CLG. Human microvascular endothelial lung cells (HMVEC-L) and human pulmonary alveolar epithelial cells (HPAEC) similarly demonstrated decreased PEDF expression with Roxadustat administration. Additionally, downregulation of PEDF in Roxadustat-treated HMVEC-L and HPAEC, a previously unreported finding, speaks to the potential translatability of Roxadustat from small animal studies. Taken together, these findings further suggest that PEDF downregulation is the primary mechanism by which Roxadustat accelerates CLG. More importantly, these data highlight the critical role PEDF may have in pulmonary growth and development, a previously unexplored field.

中文翻译：

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色素上皮衍生因子的缺乏加速了代偿性肺生长模型中的肺生长和发育

患有与先天性膈疝（CDH）相关的发育不良肺病的儿童继续遭受继发于进行性肺病的显着发病率和死亡率。我们实验室最近发表的工作证明了 Roxadustat (FG-4592)（一种脯氨酰羟化酶抑制剂）作为治疗 CDH 相关肺发育不全的潜力。Roxadustat 治疗通过下调色素上皮衍生因子 (PEDF)（一种抗血管生成因子）而不是上调血管内皮生长因子 (VEGF)，显着加速了代偿性肺生长 (CLG)。PEDF 及其在肺发育中的作用是一个很大程度上尚未探索的领域。在这项研究中，我们试图进一步评估 PEDF 在加速 CLG 中的作用。PEDF 缺陷小鼠的肺容量显着增加，与野生型对照相比，左肺切除术后总肺容量和肺泡化，而 VEGF 表达没有增加。此外，在 PEDF 缺陷小鼠中使用 Roxadustat 并没有进一步加速 CLG。人类微血管内皮肺细胞 (HMVEC-L) 和人类肺泡上皮细胞 (HPAEC) 同样表现出使用 Roxadustat 降低 PEDF 表达。此外，先前未报道的发现，Roxadustat 处理的 HMVEC-L 和 HPAEC 中 PEDF 的下调说明了 Roxadustat 在小动物研究中的潜在可转化性。总之，这些发现进一步表明 PEDF 下调是 Roxadustat 加速 CLG 的主要机制。更重要的是，这些数据突出了 PEDF 在肺部生长和发育中可能发挥的关键作用，