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Abstract

Introduction: Bronchopulmonary dysplasia (BPD) complicated by pulmonary hypertension (PH) worsens clinical outcomes in former preterm infants, though the factors that predispose to BPD associated with PH are not clear. Studies suggest that excess generation of reactive oxygen species that exceeds the antioxidant capacity is central to the pathogenesis of neonatal alveolar and pulmonary vascular disease. Methods: Wild-type mice (WT), and mice lacking EC-SOD (KO) received intraperitoneal bleo (2 units per kilogram) or saline three times weekly during weeks 0–3 of life. At week 4, right ventricular systolic pressures (RVSP) were measured and lungs were inflation fixed for morphometric analysis, including radial alveolar counts (RAC), mean linear intercepts (MLI), and nodal point density (NPD), and immunohistochemistry (IHC), or flash frozen for protein content by western blot (WB). Results: Lack of EC-SOD impaired alveolar development at week 4, characterized by lower RAC and NPD and increased MLI, and augmented bleo-induced disruption of alveolar development. Bleo also decreased EC-SOD expression in WT mice. Although KO mice had higher RVSP than WT at 4 weeks, bleo treatment did not cause a further increase in RVSP in KO or WT mice. Altered VEGF or serotonin (5-HT) signaling did not account for the impaired lung development in KO mice at baseline or after bleo. No differences were observed between KO and WT mice in VEGF, VEGFR2, or eNOS expression, or in the 5-HT signaling pathway, including 5-HT, tryptophan hydroxylase, 5-HT transporter or 5-HT receptors, 5-HT2a or 5-HT2b. Conclusions: We propose that EC-SOD activity preserves normal lung and vascular development, and insufficient EC-SOD activity predisposes to worse outcomes in neonatal lung diseases. Further studies are needed to determine the mechanisms responsible for worsened lung and pulmonary vascular development in the neonatal lung in the setting of insufficient EC-SOD.