Development of late pulmonary hypertension after antenatal inflammation in experimental bronchopulmonary dysplasia.

backgroundAntenatal inflammation due to chorioamnionitis is strongly associated with the development of bronchopulmonary dysplasia (BPD) and BPD-associated pulmonary hypertension (BPD-PH) after preterm birth. However, mechanisms linking antenatal stress with temporal changes in the pulmonary circulation leading to BPD-PH during infancy are incompletely understood. We hypothesized that antenatal inflammation impairs lung alveolar and vascular growth that precedes and increases susceptibility for the development of late BPD-PH.

methodsFetal rats received intra-amniotic ETX or saline 2 days before term delivery. We quantified temporal changes in lung structure, mechanics, and pulmonary hemodynamics by echocardiogram at postnatal days 2 (P2), P7, and P14.

resultsAt P2, ETX-exposed pups showed decreased alveolar and vascular growth, without evidence of right ventricular hypertrophy (RVH). Though echocardiography revealed increased interventricular septal flattening, other markers of PH were not different between groups. By P7-P14, echo revealed changes in metrics of PH and RVH. We found sustained reduction of pulmonary vascular and alveolar growth, increased pulmonary artery wall thickness, and worsened lung mechanics in ETX-exposed pups during infancy.

conclusionsAntenatal inflammation impairs lung vascular growth shortly after birth and causes early pulmonary vascular disease, which precedes sequential changes in pulmonary artery remodeling and echocardiogram markers of PH during the postnatal period, even in the absence of postnatal injury. IMPACT: No published preclinical studies have investigated the association between antenatal inflammation (AI) and temporal changes in structure and function of the developing lung circulation that lead to pulmonary hypertension (PH) associated with bronchopulmonary dysplasia (BPD; BPD-PH), despite strong epidemiologic links. We demonstrate that AI causes early abnormalities of pulmonary alveolar and vascular growth, preceding changes in pulmonary mechanics and echocardiographic metrics of PH, which increase over time during infancy without adverse postnatal exposures. These findings support the growing evidence that AI disrupts lung vascular development and that early pulmonary vascular disease increases susceptibility to BPD and BPD-PH in infancy.