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1 Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
* To whom correspondence should be addressed. E-mail: suhas.kallapur{at}cchmc.org.
Chorio-amnionitis is associated with preterm delivery and bronchopulmonary dysplasia (BPD), characterized by impaired alveolar, pulmonary vascular development and vascular dysfunction. To study the vascular effects in a model of chorio-amnionitis, preterm lambs were exposed to 20mg intra-amniotic (IA) endotoxin or saline for 1, 2, 4 or 7d and delivered at 122d gestational age (Term=150d). This intra-amniotic endotoxin dose was previously shown to induce lung maturation. The effect of IA endotoxin on expression of endothelial proteins was evaluated. Muscularization of the media and collagen deposition in adventitia of small pulmonary arteries was used to assess vascular remodeling. Compared with controls, BALF protein content was increased 2d after IA endotoxin exposure. Vascular endothelial growth factor (VEGF) 165 isoform mRNA decreased 2-4d after IA endotoxin. VEGF, VEGF receptor- 2, endothelial nitric oxide synthase (eNOS), platelet endothelial cell adhesion molecule-1, and Tie-2 protein expression in the lung coordinately decreased 1-7d after IA endotoxin. IA endotoxin appeared to selectively decrease eNOS expression in the small pulmonary vessels compared with the large vessels. Medial smooth muscle hypertrophy and increased adventitial fibrosis were observed 4d and 7d after IA endotoxin. These results demonstrate that in the preterm lamb lung, antenatal inflammation inhibits endothelial cell protein expression followed by vascular remodeling changes in the small pulmonary arteries. Exposure to antenatal inflammation may cause vascular remodeling and contribute to the development of BPD.
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