Pulmonary vascular changes in extremely preterm sheep after intra-amniotic exposure to Ureaplasma parvum and lipopolysaccharide

• Published in: PloS one 2017-06, Vol.12 (6), p.e0180114-e0180114
• Main Authors: Willems, Monique G M, Kemp, Matthew W, Fast, Laura A, Wagemaker, Nick M M, Janssen, Leon E W, Newnham, John P, Payne, Matt S, Spiller, Owen B, Kallapur, Suhas G, Jobe, Alan H, Delhaas, Tammo, Kramer, Boris W, Wolfs, Tim G A M
• Format: Article
• Language: English
• Subjects: Alveoli; Angiogenesis; Angiopoietin; Animal development; Animals; Biology and Life Sciences; Biomedical engineering; Blood Vessels - drug effects; Blood Vessels - microbiology; CD3 antigen; Chorioamnionitis; Complications and side effects; Cytokines; Developmental biology; Developmental stages; Dysplasia; Exposure; Female; Fetuses; Fibrosis; Genetic aspects; Growth factors; Hospitals; Inflammation; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Lung - blood supply; Lungs; Maternal Exposure; Medicine and Health Sciences; Memory; Microorganisms; Models, Animal; Newborn babies; Oncology; Pediatrics; Peroxidase; Physiological aspects; Pregnancy; Premature birth; Pulmonary hypertension; Receptors; Research and analysis methods; Rodents; Sepsis; Sheep; Sheep - embryology; Sheep - growth & development; Simplification; Ureaplasma - physiology; Vascular endothelial growth factor; Vascular endothelial growth factor receptors; Water pollution effects; Womens health
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0180114

Chorioamnionitis can induce pulmonary inflammation and promote bronchopulmonary dysplasia development, distinguished by alveolar simplification and impaired vascular growth. Chorioamnionitis is more common during the extremely preterm canalicular lung stage (crucial for vascular development); and increases the risk for subsequent sepsis. We hypothesized that single/combined exposure to chronic and/or acute inflammation induces pulmonary inflammatory responses and vascular changes. Ovine fetuses were intra-amniotically exposed to chronic Ureaplasma parvum (UP) at 24 days (d) before extreme preterm delivery at 94d (term 147d) and/or to lipopolysaccharide (LPS) 7 or 2d before delivery. Pulmonary inflammation, vascular remodeling and angiogenic factors were assessed. LPS exposure increased CD3-positive and myeloperoxidase-positive cells. Combined UP-LPS exposure increased pulmonary inflammation compared with 2d LPS or UP groups. The UP+2d LPS group had an increased adventitial fibrosis score when compared with UP-treated animals. A reduced wall-to-lumen ratio was found in the 7d LPS animals when compared to the 2d LPS-treated animals. Exposure to UP+2d LPS reduced VEGF and VEGFR-2 levels compared with 2d LPS-treated animals. Angiopoietin-1 (Ang1) and tunica interna endothelial cell kinase 2 (Tie-2) levels were decreased after UP+7d LPS as well as after 7d LPS, but not with UP alone. Chronic UP and subsequent LPS exposure increased pulmonary inflammation and decreased expression of angiogenic growth factors and receptors when compared to single hit-exposed animals.