Abstract

BackgroundChorioamnionitis 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.MethodsOvine 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.ResultsLPS 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.ConclusionChronic UP and subsequent LPS exposure increased pulmonary inflammation and decreased expression of angiogenic growth factors and receptors when compared to single hit-exposed animals.

Highlights

  • Preterm birth is frequently associated with chorioamnionitis, an inflammation of the chorion, amnion and placenta [1, 2]

  • We quantified the number of CD3-positive cell infiltrates in the ovine fetal lungs (Fig 2A) and found that chronic U. parvum exposure did not significantly raise the infiltrate number compared with the media group

  • The CD3-positive cell infiltrate count increased in the 2d LPS- and 7d LPS-treated animals compared with the saline group (Fig 2A, 2E and 2F)

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Summary

Introduction

Preterm birth is frequently associated with chorioamnionitis, an inflammation of the chorion, amnion and placenta [1, 2]. Dependent on the presence of additional postnatal factors such as ventilation and sepsis, a progressive pulmonary inflammatory response may be induced which promotes the development of bronchopulmonary dysplasia (BPD) [5]. BPD is characterized by alveolar simplification and impaired vascular growth [6, 7]. The vascular hypothesis implies that disruption of pulmonary angiogenesis during essential stages of fetal growth may impair alveolarization and contribute to the pulmonary hypoplasia that typifies BPD [10, 11]. 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

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