title: Systemic interleukin-2 administration improves lung function and modulates chorioamnionitis-induced pulmonary inflammation in the ovine fetus.
abstract: Chorioamnionitis, an inflammatory reaction of the fetal membranes to microbes, is an important cause of preterm birth and associated with inflammation-driven lung injury. However, inflammation in utero overcomes immaturity of the premature lung by inducing surfactant lipids and lung gas volume. Previously, we found that lipopolysaccharide (LPS)-induced chorioamnionitis resulted in pulmonary inflammation with increased effector T cells and decreased regulatory T cell (Treg) numbers. Because Tregs are crucial for immune regulation, we assessed the effects of interleukin (IL)-2-driven selective Treg expansion on the fetal lung in an ovine chorioamnionitis model. Instrumented fetuses received systemic prophylactic IL-2 treatment [118 days gestational age (dGA)] with or without subsequent exposure to intra-amniotic LPS (122 dGA). Following delivery at 129 dGA (term 147 dGA), pulmonary and systemic inflammation, morphological changes, lung gas volume, and phospholipid concentration were assessed. IL-2 pretreatment increased the FoxP3(+)/CD3(+) ratio, which was associated with reduced CD3-positive cells in the fetal lungs of LPS-exposed animals. Prophylactic IL-2 treatment did not prevent pulmonary accumulation of myeloperoxidase- and PU.1-positive cells or elevation of bronchoalveolar lavage fluid IL-8 and systemic IL-6 concentrations in LPS-exposed animals. Unexpectedly, IL-2 treatment improved fetal lung function of control lambs as indicated by increased disaturated phospholipids and improved lung gas volume. In conclusion, systemic IL-2 treatment in utero preferentially expanded Tregs and improved lung gas volume and disaturated phospholipids. These beneficial effects on lung function were maintained despite the moderate immunomodulatory effects of prophylactic IL-2 in the course of chorioamnionitis.
authors.forename: Monique G M
authors.initials: MG
authors.lastname: Willems
authors.affiliation: Department of Pediatrics, Maastricht University Medical Center, Maastricht, The Netherlands; School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands; and.
authors.forename: Daan R M G
authors.initials: DR
authors.lastname: Ophelders
authors.affiliation: Department of Pediatrics, Maastricht University Medical Center, Maastricht, The Netherlands; School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands; and.
authors.forename: Maria
authors.initials: M
authors.lastname: Nikiforou
authors.affiliation: Department of Pediatrics, Maastricht University Medical Center, Maastricht, The Netherlands; School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands; and.
authors.forename: Reint K
authors.initials: RK
authors.lastname: Jellema
authors.affiliation: Department of Pediatrics, Maastricht University Medical Center, Maastricht, The Netherlands;
authors.forename: Anke
authors.initials: A
authors.lastname: Butz
authors.affiliation: Department of BioMedical Engineering, Maastricht University Medical Center, Maastricht, The Netherlands; CARIM School for Cardiovascular Diseases, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Tammo
authors.initials: T
authors.lastname: Delhaas
authors.affiliation: Department of Pediatrics, Maastricht University Medical Center, Maastricht, The Netherlands; GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands; School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands; and.
authors.forename: Boris W
authors.initials: BW
authors.lastname: Kramer
authors.affiliation: Department of Pediatrics, Maastricht University Medical Center, Maastricht, The Netherlands; GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands; tim.wolfs@maastrichtuniversity.nl.
authors.forename: Tim G A M
authors.initials: TG
authors.lastname: Wolfs
mesh_terms: D000818:Animals; D002821:Chorioamnionitis / Q000188:drug therapy*; D005260:Female; D005333:Fetus / Q000187:drug effects*; D005865:Gestational Age; D007376:Interleukin-2 / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D011014:Pneumonia / Q000150:complications / Q000188:drug therapy* / Q000276:immunology; D011247:Pregnancy; D012756:Sheep
chemical_list: D007376:Interleukin-2; D008070:Lipopolysaccharides
keywords: chorioamnionitis; interleukin-2; lung function; pulmonary inflammation; regulatory T cells