Department of Pediatrics, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Department of Anatomy and Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Pediatr Neonatol. 2021 Jul;62(4):369-378. doi: 10.1016/j.pedneo.2021.03.012. Epub 2021 Mar 24.
Premature infants who require oxygen therapy for respiratory distress syndrome often develop bronchopulmonary dysplasia, a chronic lung disease characterized by interrupted alveologenesis. Disrupted angiogenesis inhibits alveologenesis; however, the mechanisms through which disrupted angiogenesis affects lung development are poorly understood. Hypoxia-inducible factors (HIFs) are transcription factors that activate multiple oxygen-sensitive genes, including those encoding for vascular endothelial growth factor (VEGF). However, the HIF modulation of angiogenesis in hyperoxia-induced lung injury is not fully understood. Therefore, we explored the effects of roxadustat, an HIF stabilizer that has been shown to promote angiogenesis, in regulating pulmonary angiogenesis on hyperoxia exposure.
C57BL6 mice pups reared in room air and 85% O were injected with phosphate-buffered saline or 5 mg/kg or 10 mg/kg roxadustat. Their daily body weight and survival rate were recorded. Their lungs were excised for histology and angiogenic factor expression analyses on postnatal Day 7.
Exposure to neonatal hyperoxia reduced body weight; survival rate; and expressions of von Willebrand factor, HIF-1α, phosphor mammalian target of rapamycin, VEGF, and endothelial nitric oxide synthase and increased the mean linear intercept values in the pups. Roxadustat administration reversed these effects.
Hyperoxia suppressed pulmonary vascular development and the expression of proangiogenic factors. Roxadustat promoted pulmonary angiogenesis on hyperoxia exposure by stabilizing HIF-1α and upregulating the expression of proangiogenic factors, indicating its potential in clinical and therapeutic applications.
需要氧疗治疗呼吸窘迫综合征的早产儿常发展为支气管肺发育不良，这是一种以肺泡发生中断为特征的慢性肺部疾病。血管生成中断会抑制肺泡发生；然而，血管生成中断影响肺发育的机制尚未完全阐明。缺氧诱导因子（HIFs）是转录因子，可激活多种氧敏感基因，包括编码血管内皮生长因子（VEGF）的基因。然而，HIF 对高氧诱导的肺损伤中血管生成的调节作用尚不完全清楚。因此，我们探讨了罗沙司他（一种已被证明可促进血管生成的 HIF 稳定剂）在调节高氧暴露时肺血管生成中的作用。
在常氧和 85%氧气中饲养的 C57BL6 幼鼠接受磷酸盐缓冲盐水或 5mg/kg 或 10mg/kg 罗沙司他注射。记录它们的每日体重和存活率。在出生后第 7 天，取出它们的肺进行组织学和血管生成因子表达分析。
暴露于新生高氧中会降低幼鼠的体重、存活率；降低血管性血友病因子、HIF-1α、磷酸化哺乳动物雷帕霉素靶蛋白、VEGF 和内皮型一氧化氮合酶的表达，并增加它们的平均线性截距值。罗沙司他的给药逆转了这些效应。
高氧抑制肺血管发育和促血管生成因子的表达。罗沙司他通过稳定 HIF-1α 和上调促血管生成因子来促进高氧暴露时的肺血管生成，表明其在临床和治疗应用中的潜力。
