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Long-Term Effects of Neonatal Hyperoxia Exposure on Lung and Heart Health in a Murine Model: Role of Sex as a Biological Variable
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A2321 - Long-Term Effects of Neonatal Hyperoxia Exposure on Lung and Heart Health in a Murine Model: Role of Sex as a Biological Variable
Author Block: K. Lingappan, X. Dong; Pediatrics, Baylor College of Medicine, Houston, TX, United States.
Background: Male sex is considered an independent predictor for the development of bronchopulmonary dysplasia (BPD) after adjusting for other confounders. BPD is characterized by impaired alveolar secondary septation and vascular growth and these abnormalities may persist to adulthood leading to increased susceptibility to other chronic lung diseases. Exposure to high concentrations of oxygen (hyperoxia) in the neonatal period contributes to the development of BPD. Sex-specific differences in the long-term effects of neonatal hyperoxia exposure on lung and heart health and the underlying mechanisms have not been elucidated.
Methods: Neonatal male and female mice (C57BL/6) were exposed to hyperoxia (95% FiO2, PND 1-5: saccular stage of lung development) or room air and allowed to grow in room air till 6-8 weeks of postnatal age. Alveolarization (morphometric measurements including mean linear intercept and radial alveolar count), pulmonary vascularization (vWF positive vessel number by immunohistochemistry (IHC), inflammation (macrophage infiltration) were assessed at 6-8 weeks. Measurement of HIF-1 alpha and VEGF was done in lung and heart tissues from male and female mice at 6-8 weeks of age. Echocardiography was performed to assess pulmonary hypertension and pulmonary acceleration time (PAT) and ejection time (ET) were measured in the parasternal short-axis view by pulsed-wave Doppler of pulmonary artery flow.
Results: Neonatal hyperoxia exposure had persistent adverse effects on lung growth even in adulthood in this model. Hyperoxia exposed mice displayed alveolar simplification and arrest in pulmonary vascular development compared to mice maintained in room air. Alveolarization and angiogenesis was better preserved in hyperoxia-exposed female mice compared to similarly exposed male mice. Hyperoxia-exposed male mice showed increased macrophage infiltration in the lungs compared to females. Increased pulmonary hypertension was observed in hyperoxia-exposed animals at 6-8 weeks compared to room air controls. HIF-1 alpha and VEGF mRNA and protein expression was decreased in hyperoxia exposed animals and this was more significant in males.
Conclusions: Brief exposure to hyperoxia (PND 1-5) in the neonatal period can lead to long-term effects in lung growth persisting into adulthood and we present sex-specific differences in our model. Persistent changes in expression of crucial angiogenic genes such as HIF-1 alpha and VEGF may in part explain these differences. These results support the hypothesis that sex plays a crucial role in hyperoxia-mediated lung injury in this model.
Author Block: K. Lingappan, X. Dong; Pediatrics, Baylor College of Medicine, Houston, TX, United States.
Background: Male sex is considered an independent predictor for the development of bronchopulmonary dysplasia (BPD) after adjusting for other confounders. BPD is characterized by impaired alveolar secondary septation and vascular growth and these abnormalities may persist to adulthood leading to increased susceptibility to other chronic lung diseases. Exposure to high concentrations of oxygen (hyperoxia) in the neonatal period contributes to the development of BPD. Sex-specific differences in the long-term effects of neonatal hyperoxia exposure on lung and heart health and the underlying mechanisms have not been elucidated.
Methods: Neonatal male and female mice (C57BL/6) were exposed to hyperoxia (95% FiO2, PND 1-5: saccular stage of lung development) or room air and allowed to grow in room air till 6-8 weeks of postnatal age. Alveolarization (morphometric measurements including mean linear intercept and radial alveolar count), pulmonary vascularization (vWF positive vessel number by immunohistochemistry (IHC), inflammation (macrophage infiltration) were assessed at 6-8 weeks. Measurement of HIF-1 alpha and VEGF was done in lung and heart tissues from male and female mice at 6-8 weeks of age. Echocardiography was performed to assess pulmonary hypertension and pulmonary acceleration time (PAT) and ejection time (ET) were measured in the parasternal short-axis view by pulsed-wave Doppler of pulmonary artery flow.
Results: Neonatal hyperoxia exposure had persistent adverse effects on lung growth even in adulthood in this model. Hyperoxia exposed mice displayed alveolar simplification and arrest in pulmonary vascular development compared to mice maintained in room air. Alveolarization and angiogenesis was better preserved in hyperoxia-exposed female mice compared to similarly exposed male mice. Hyperoxia-exposed male mice showed increased macrophage infiltration in the lungs compared to females. Increased pulmonary hypertension was observed in hyperoxia-exposed animals at 6-8 weeks compared to room air controls. HIF-1 alpha and VEGF mRNA and protein expression was decreased in hyperoxia exposed animals and this was more significant in males.
Conclusions: Brief exposure to hyperoxia (PND 1-5) in the neonatal period can lead to long-term effects in lung growth persisting into adulthood and we present sex-specific differences in our model. Persistent changes in expression of crucial angiogenic genes such as HIF-1 alpha and VEGF may in part explain these differences. These results support the hypothesis that sex plays a crucial role in hyperoxia-mediated lung injury in this model.
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