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Isolation of Pulmonary Artery Smooth Muscle Cells from Neonatal Mice
Published on: October 19, 2013
Roxadustat attenuates hyperoxia-induced lung injury by upregulating proangiogenic factors in newborn mice
Liang-Ti Huang1, Hsiu-Chu Chou2, Chung-Ming Chen3
1Department of Pediatrics, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Insights
Roxadustat, an HIF stabilizer, reversed hyperoxia-induced lung injury in mice by promoting pulmonary angiogenesis. This study highlights roxadustat
Area of Science:
- Pulmonary Medicine
- Neonatology
- Developmental Biology
Background:
- Bronchopulmonary dysplasia (BPD) is a chronic lung disease in premature infants often linked to oxygen therapy and interrupted alveologenesis.
- Disrupted pulmonary angiogenesis is a key factor in BPD development, but underlying mechanisms remain unclear.
- Hypoxia-inducible factors (HIFs) regulate genes like vascular endothelial growth factor (VEGF), crucial for angiogenesis, yet their role in hyperoxia-induced lung injury is not fully understood.
Purpose of the Study:
- To investigate the effects of roxadustat, a known HIF stabilizer and promoter of angiogenesis, on pulmonary angiogenesis during hyperoxia exposure.
- To determine if roxadustat can mitigate the negative impacts of neonatal hyperoxia on lung development.
Main Methods:
- C57BL6 mouse pups were exposed to neonatal hyperoxia (85% O2).
- Pups received either phosphate-buffered saline or varying doses of roxadustat (5 or 10 mg/kg).
- Body weight, survival rates, and lung tissue were analyzed for histology and angiogenic factor expression on postnatal Day 7.
Main Results:
- Neonatal hyperoxia exposure significantly reduced body weight, survival rates, and expression of key angiogenic factors (von Willebrand factor, HIF-1α, VEGF, eNOS).
- Hyperoxia also increased the mean linear intercept, indicating impaired alveologenesis.
- Roxadustat administration effectively reversed these detrimental effects of hyperoxia.
Conclusions:
- Neonatal hyperoxia impairs pulmonary vascular development and reduces proangiogenic factor expression.
- Roxadustat promotes pulmonary angiogenesis in the context of hyperoxia by stabilizing HIF-1α and upregulating proangiogenic factors.
- These findings suggest roxadustat has significant potential for clinical and therapeutic applications in managing hyperoxia-induced lung injury.
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.
