All-trans retinoic acid (RA) is a potent modulator of lung development. Chorioamnionitis, which is frequently associated with preterm birth, causes fetal lung inflammation and improves lung function but also results in alveolar simplification and microvascular injury. Endotoxin-mediated chorioamnionitis reduces RA concentration in the fetal lung to 16% of control values. We hypothesized that administration of RA to the fetus before induction of chorioamnionitis would preserve septation of the distal airspaces. Time-mated ewes with singletons were assigned to receive a fetal intramuscular treatment with 20,000 IU of RA in olive oil (or olive oil only) 3 hr prior to intra-amniotic injection of endotoxin (20 mg, E. coli 055:135) or saline, at 124-day gestational age and 7 days after the fetal treatment. The right cranial lung lobe was processed for morphometric analysis. RA treatment did not affect chorioamnionitis-induced fetal and systemic inflammation or interleukin-8 concentrations in lung tissue. RA administration alone did not alter lung structure. Relative to control lungs (5 3 mL/kg), lung volume increased similarly with endotoxin (22 4 mL/kg) or RA plus endotoxin (20 3 mL/kg; P < 0.05). Alveolar wall thickness was 4.2 +/- 0.3 pm after endotoxin-induced chorioamnionitis, 6.0 +/- 0.4 mu m in controls (P < 0.05 versus endotoxin) and 5.5 +/- 0.2 mu m after RA and endotoxin (P < 0.05 versus control, n.s. versus endotoxin). The ratio of airspace versus tissue was 4.6 +/- 0.3 in endotoxin-induced chorioamnionitis, 2.1 +/- 0.3 in controls and 4.1 +/- 0.5 after RA and endotoxin. We conclude that fetal treatment with RA did not prevent inflammation-induced alveolar simplification.