Chronic Hypoxia in an EXTrauterine Environment for Neonatal Development Impairs Lung Development

Severe fetal hypoxia poses a significant risk to lung development, resulting in severe postnatal complications. Existing chronic hypoxia animal models lack the ability to achieve pathologically reduced fetal oxygen without compromising animal development, placental blood flow, or maternal health. Using an established model of isolated chronic hypoxia involving the Extrauterine Environment for Neonatal Development, we are able to investigate the direct impact of fetal hypoxia on lung development. Oxygen delivery to preterm fetal lambs (105-110 d gestational age) delivered by cesarean section was reduced, and animals were supported using the Extrauterine Environment for Neonatal Development through the canalicular or saccular stage of lung development. Fetal lambs in hypoxic conditions showed significant growth restriction compared with their normoxic counterparts. We also observed modest aberrant vascular remodeling in the saccular group after hypoxic conditions, with decreased macrovessel numbers and microvascular endothelial cell numbers and increased peripheral vessel muscularization. In addition, fetal hypoxia resulted in enlarged distal airspaces and decreased septal wall volume. Moreover, there was a reduction in mature SFTPB (surfactant protein B) and processed SFTPC protein expression concomitant with a decrease in alveolar type 2 cell number. These findings demonstrate that maternally independent fetal hypoxia predominantly affects distal airway development, alveolar type 2 cell number, and surfactant production, with mild effects on the vasculature.