Roxadustat attenuates hyperoxia-induced lung injury by upregulating proangiogenic factors in newborn mice
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 ang...
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Elsevier
2021-07-01
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| Series: | Pediatrics and Neonatology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1875957221000541 |
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| author | Liang-Ti Huang Hsiu-Chu Chou Chung-Ming Chen |
| author_facet | Liang-Ti Huang Hsiu-Chu Chou Chung-Ming Chen |
| author_sort | Liang-Ti Huang |
| collection | DOAJ |
| description | 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-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. Conclusion: 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. |
| format | Article |
| id | doaj-art-66ff47151f3b469b902e17ad0cd812e3 |
| institution | DOAJ |
| issn | 1875-9572 |
| language | English |
| publishDate | 2021-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pediatrics and Neonatology |
| spelling | doaj-art-66ff47151f3b469b902e17ad0cd812e32025-08-20T03:18:15ZengElsevierPediatrics and Neonatology1875-95722021-07-0162436937810.1016/j.pedneo.2021.03.012Roxadustat attenuates hyperoxia-induced lung injury by upregulating proangiogenic factors in newborn miceLiang-Ti Huang0Hsiu-Chu Chou1Chung-Ming Chen2Department of Pediatrics, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei, TaiwanDepartment of Anatomy and Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, TaiwanDepartment of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Pediatrics, Taipei Medical University Hospital, Taipei, Taiwan; Corresponding author. Department of Pediatrics, Taipei Medical University Hospital, Taipei, 110, Taiwan.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-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. Conclusion: 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.http://www.sciencedirect.com/science/article/pii/S1875957221000541bronchopulmonary dysplasiahyperoxia-induced lung injuryhypoxia-inducible factorvascular endothelial growth factor |
| spellingShingle | Liang-Ti Huang Hsiu-Chu Chou Chung-Ming Chen Roxadustat attenuates hyperoxia-induced lung injury by upregulating proangiogenic factors in newborn mice Pediatrics and Neonatology bronchopulmonary dysplasia hyperoxia-induced lung injury hypoxia-inducible factor vascular endothelial growth factor |
| title | Roxadustat attenuates hyperoxia-induced lung injury by upregulating proangiogenic factors in newborn mice |
| title_full | Roxadustat attenuates hyperoxia-induced lung injury by upregulating proangiogenic factors in newborn mice |
| title_fullStr | Roxadustat attenuates hyperoxia-induced lung injury by upregulating proangiogenic factors in newborn mice |
| title_full_unstemmed | Roxadustat attenuates hyperoxia-induced lung injury by upregulating proangiogenic factors in newborn mice |
| title_short | Roxadustat attenuates hyperoxia-induced lung injury by upregulating proangiogenic factors in newborn mice |
| title_sort | roxadustat attenuates hyperoxia induced lung injury by upregulating proangiogenic factors in newborn mice |
| topic | bronchopulmonary dysplasia hyperoxia-induced lung injury hypoxia-inducible factor vascular endothelial growth factor |
| url | http://www.sciencedirect.com/science/article/pii/S1875957221000541 |
| work_keys_str_mv | AT liangtihuang roxadustatattenuateshyperoxiainducedlunginjurybyupregulatingproangiogenicfactorsinnewbornmice AT hsiuchuchou roxadustatattenuateshyperoxiainducedlunginjurybyupregulatingproangiogenicfactorsinnewbornmice AT chungmingchen roxadustatattenuateshyperoxiainducedlunginjurybyupregulatingproangiogenicfactorsinnewbornmice |