To determine the separate and interactive effects of fetal
inflammation and neonatal
hyperoxia on the developing lung, we hypothesized that: 1) antenatal
endotoxin (ETX) causes sustained abnormalities of infant lung structure; and 2) postnatal
hyperoxia augments the adverse effects of antenatal ETX on infant lung growth. Escherichia coli ETX or saline (SA) was injected into amniotic sacs in pregnant Sprague-Dawley rats at 20 days of gestation. Pups were delivered 2 days later and raised in room air (RA) or moderate
hyperoxia (O₂, 80% O₂ at Denver's altitude, ∼65% O₂ at sea level) from birth through 14 days of age. Heart and lung tissues were harvested for measurements. Intra-amniotic ETX caused
right ventricular hypertrophy (RVH) and decreased lung
vascular endothelial growth factor (
VEGF) and
VEGF receptor-2 (VEGFR-2)
protein contents at birth. In ETX-exposed rats (ETX-RA), alveolarization and vessel density were decreased, pulmonary vascular wall thickness percentage was increased, and RVH was persistent throughout the study period compared with controls (SA-RA). After antenatal ETX, moderate
hyperoxia increased lung
VEGF and VEGFR-2
protein contents in ETX-O₂ rats and improved their alveolar and vascular structure and RVH compared with ETX-RA rats. In contrast, severe
hyperoxia (≥95% O₂ at Denver's altitude) further reduced lung vessel density after intra-amniotic ETX exposure. We conclude that intra-amniotic ETX induces fetal
pulmonary hypertension and causes persistent abnormalities of lung structure with sustained
pulmonary hypertension in infant rats. Moreover, moderate postnatal
hyperoxia after antenatal ETX restores lung growth and prevents
pulmonary hypertension during infancy.