Roxadustat attenuates hyperoxia-induced lung injury by upregulating proangiogenic factors in newborn mice
Roxadustat attenuates hyperoxia-induced lung injury by upregulating proangiogenic factors in newborn mice
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DOI：
10.1016/j.pedneo.2021.03.012
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发表时间：
2021-07-07
影响因子：
2.1
通讯作者：
Chen, Chung-Ming
中科院分区：
文献类型：
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作者：
Huang, Liang-Ti;Chou, Hsiu-Chu;Chen, Chung-Ming
背景：需要氧气治疗呼吸窘迫综合征的早产儿经常发展为支气管肺发育不良，这是一种以肺泡发育中断为特征的慢性肺部疾病。血管生成中断抑制肺泡生成；然而，破坏血管生成影响肺发育的机制尚不清楚。缺氧诱导因子（hif）是一种转录因子，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，在高氧诱导的肺损伤中，HIF对血管生成的调节尚不完全清楚。因此，我们探索了罗沙司他的作用，一种HIF稳定剂，已被证明可以促进血管生成，在高氧暴露下调节肺血管生成。方法：在室内空气和85% O2环境中饲养C57BL6小鼠幼鼠，分别注射磷酸缓冲生理盐水或5 mg/kg、10 mg/kg罗胥他。记录各组小鼠的日体重和存活率。在出生后第7天切除肺进行组织学和血管生成因子表达分析。结果：新生儿暴露于高氧环境下，体重下降；存活率;von Willebrand因子、HIF-1a、雷帕霉素靶蛋白、VEGF和内皮型一氧化氮合酶的表达均增加，平均线性截距值升高。罗沙司他逆转了这些作用。结论：高氧可抑制肺血管发育及促血管生成因子的表达。罗沙司他通过稳定HIF-1a和上调促血管生成因子的表达，促进高氧暴露时肺血管生成，显示其临床和治疗应用潜力。台湾儿科协会2021版权所有爱思唯尔台湾有限责任公司出版。
Background: 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.Methods: C57BL6 mice pups reared in room air and 85% O2 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.Results: Exposure to neonatal hyperoxia reduced body weight; survival rate; and expressions of von Willebrand factor, HIF-1a, 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.Conclusion: Hyperoxia suppressed pulmonary vascular development and the expression of proangiogenic factors. Roxadustat promoted pulmonary angiogenesis on hyperoxia exposure by stabilizing HIF-1a and upregulating the expression of proangiogenic factors, indicating its potential in clinical and therapeutic applications. Copyright (C) 2021, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC.