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Published on: October 19, 2013
Development of late pulmonary hypertension after antenatal inflammation in experimental bronchopulmonary dysplasia
Paula Dias Maia1,2, Gregory Seedorf3, Tania Gonzalez3
1Section of Neonatology, Department of Pediatrics, University of Colorado Anschutz School of Medicine and Children's Hospital Colorado, Aurora, CO, USA. paula.diasmaia@cuanschutz.edu.
Insights
Antenatal inflammation impairs early lung vascular growth, leading to pulmonary hypertension associated with bronchopulmonary dysplasia. This early injury precedes later structural changes and disease markers in infancy.
Area of Science:
- Neonatal research
- Pulmonary medicine
- Developmental biology
Background:
- Antenatal inflammation, such as chorioamnionitis, is a known risk factor for bronchopulmonary dysplasia (BPD) and associated pulmonary hypertension (BPD-PH) in preterm infants.
- The precise mechanisms linking antenatal stress to the development of BPD-PH and its progression during infancy remain unclear.
- This study investigates the hypothesis that antenatal inflammation disrupts lung alveolar and vascular development, predisposing infants to BPD-PH.
Purpose of the Study:
- To investigate the association between antenatal inflammation and temporal changes in lung structure and function.
- To determine how antenatal inflammation impacts the developing pulmonary circulation and contributes to BPD-PH.
- To elucidate the early developmental abnormalities that precede the onset of BPD-PH in infancy.
Main Methods:
- Fetal rats were exposed to intra-amniotic lipopolysaccharide (ETX) or saline (control) two days before term delivery.
- Lung structure, mechanics, and pulmonary hemodynamics were assessed using echocardiography at postnatal days 2, 7, and 14.
- Quantification of alveolar and vascular growth, pulmonary artery wall thickness, and right ventricular hypertrophy (RVH) was performed.
Main Results:
- Early postnatal exposure to ETX resulted in impaired alveolar and vascular growth by postnatal day 2, without significant RVH or definitive PH markers.
- By postnatal days 7-14, ETX-exposed pups exhibited echocardiographic evidence of PH and RVH, alongside sustained deficits in lung growth.
- Increased pulmonary artery wall thickness and worsened lung mechanics were observed in ETX-exposed pups throughout infancy.
Conclusions:
- Antenatal inflammation directly impairs pulmonary vascular growth shortly after birth, initiating early pulmonary vascular disease.
- This early vascular impairment precedes and contributes to the development of pulmonary hypertension and associated structural changes during infancy.
- These findings highlight antenatal inflammation as a critical disruptor of lung vascular development, increasing susceptibility to BPD-PH even without postnatal complications.
Background:
Antenatal 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.
Methods:
Fetal 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.
Results:
At 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.
Conclusions:
Antenatal 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.
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