Ibuprofen-induced ductus closure improves pulmonary mechanics and increases alveolar surface area in premature baboons compared with baboons with a persistent patent ductus arteriosus (PDA). Ibuprofen-treatment has no effect on the expression of genes that regulate pulmonary inflammation but does increase the expression of alpha-ENaC (the transepithelial sodium channel that is critical for alveolar water clearance). Although ligation eliminates the PDA, it does not improve pulmonary mechanics or increase alveolar surface area. We used preterm baboons (delivered at 67% of term gestation and ventilated for 14 d) to study whether the lack of beneficial effects, after PDA ligation, might be due to alterations in pulmonary gene expression. We found no differences in ventilation or oxygenation indices between animals that were ligated (n = 7) on day of life 6 and those that had a persistent PDA (n = 12) during the entire 14 d study. In contrast with no intervention, PDA ligation produced a significant increase in the expression of genes involved with pulmonary inflammation (COX-2, TNF-α, and CD14) and a significant decrease in alpha-ENaC sodium channel expression. We speculate that these changes may decrease the rate of alveolar fluid clearance and contribute to the lack of improvement in pulmonary mechanics after PDA ligation.