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1 Department of Pediatrics, University of Colorado Health Sciences Center, Denver, CO, USA
* To whom correspondence should be addressed. E-mail: vivek.balasubramaniam{at}uchsc.edu.
We have previously shown that neonatal mice deficient in endothelial nitric oxide synthase (eNOS -/-) are more susceptible to hypoxic inhibition of alveolar and vascular growth in the neonatal period. Although eNOS is downregulated in models of lung injury, the role of NO on lung growth during recovery of infant mice after neonatal lung injury is poorly understood. Therefore, we hypothesized that lung vascular and alveolar growth would remain impaired in eNOS -/- mice during recovery in room air, andthat NO therapy during the recovery from neonatal hypoxia would augment compensatory lung growth in the eNOS -/- mice. Litters of 1-day old mouse pups from eNOS +/- parents were placed in a hypobaric chamber at a simulated altitude of 12,300 ft (FIO2 = 0.16). After 10 days, pups were allowed to recover in either room air (HR group) or inhaled NO (10 ppm) (HiNO group) until 3 weeks of age. Mice were killed and lung tissue was collected for morphometric and molecular analysis. Morphometric analysis revealed that the eNOS -/- mice in the HR group had a persistently abnormal lung structure as compared to wild type mice, and assayed by and increase in mean linear intercept, and a reduction in radial alveolar counts, nodal point density and vessel density. Interestingly, lung morphologyof the eNOS +/- in the HR group was not different from wild type mice. Inhaled NO therapy during recovery from neonatal hypoxia stimulated compensatory lung growth in eNOS -/- mice, that resulted in a complete restoration of normal lung structure. In the HR group, the eNOS +/- mice had a 2 1/2 fold increase in lung VEGFR-2 protein as compared to wild type (p<0.05). In the HiNO group, the eNOS -/- had a 66% increase in lung VEGFR-2 protein as compared to eNOS -/- in the HR group (p<0.01). We conclude that genetic deficiency of eNOS leads to a persistent failure of lung alveolar growth during recovery from neonatal hypoxia, and that inhaled NO stimulates alveolar and vascular growth in eNOS -/- mice after neonatal hypoxia.
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