title: LPS-induced chorioamnionitis and antenatal corticosteroids modulate Shh signaling in the ovine fetal lung.
abstract: Chorioamnionitis and antenatal corticosteroids mature the fetal lung functionally but disrupt late-gestation lung development. Because Sonic Hedgehog (Shh) signaling is a major pathway directing lung development, we hypothesized that chorioamnionitis and antenatal corticosteroids modulated Shh signaling, resulting in an altered fetal lung structure. Time-mated ewes with singleton ovine fetuses received an intra-amniotic injection of lipopolysaccharide (LPS) and/or maternal intramuscular betamethasone 7 and/or 14 days before delivery at 120 days gestational age (GA) (term = 150 days GA). Intra-amniotic LPS exposure decreased Shh mRNA levels and Gli1 protein expression, which was counteracted by both betamethasone pre- or posttreatment. mRNA and protein levels of fibroblast growth factor 10 and bone morphogenetic protein 4, which are important mediators of lung development, increased 2-fold and 3.5-fold, respectively, 14 days after LPS exposure. Both 7-day and 14-day exposure to LPS changed the mRNA levels of elastin (ELN) and collagen type I alpha 1 (Col1A1) and 2 (Col1A2), which resulted in fewer elastin foci and increased collagen type I deposition in the alveolar septa. Corticosteroid posttreatment prevented the decrease in ELN mRNA and increased elastin foci and decreased collagen type I deposition in the fetal lung. In conclusion, fetal lung exposure to LPS was accompanied by changes in key modulators of lung development resulting in abnormal lung structure. Betamethasone treatment partially prevented the changes in developmental processes and lung structure. This study provides new insights into clinically relevant prenatal exposures and fetal lung development.
authors.affiliation: Department of Pediatrics, School for Oncology and Developmental Biology, School for Mental Health and Neuroscience, Maastricht University Medical Center, The Netherlands.
authors.forename: Jennifer J P
authors.initials: JJ
authors.lastname: Collins
authors.forename: Elke
authors.initials: E
authors.lastname: Kuypers
authors.forename: Ilias
authors.initials: I
authors.lastname: Nitsos
authors.forename: J
authors.initials: J
authors.lastname: Jane Pillow
authors.forename: Graeme R
authors.initials: GR
authors.lastname: Polglase
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Kemp
authors.forename: John P
authors.initials: JP
authors.lastname: Newnham
authors.forename: Jack P
authors.initials: JP
authors.lastname: Cleutjens
authors.forename: Suzanna G M
authors.initials: SG
authors.lastname: Frints
authors.forename: Suhas G
authors.initials: SG
authors.lastname: Kallapur
authors.forename: Alan H
authors.initials: AH
authors.lastname: Jobe
authors.forename: Boris W
authors.initials: BW
authors.lastname: Kramer
mesh_terms: D000818:Animals; D001623:Betamethasone / Q000494:pharmacology* / Q000627:therapeutic use; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D002821:Chorioamnionitis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D024042:Collagen Type I / Q000378:metabolism; D004549:Elastin / Q000378:metabolism; D005260:Female; D005333:Fetus / Q000187:drug effects / Q000196:embryology / Q000378:metabolism* / Q000473:pathology; D051526:Fibroblast Growth Factor 10 / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D018507:Gene Expression Regulation, Developmental; D005938:Glucocorticoids / Q000494:pharmacology* / Q000627:therapeutic use; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000196:embryology / Q000378:metabolism* / Q000473:pathology; D012756:Sheep; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D000071676:Zinc Finger Protein GLI1
chemical_list: D055415:Bone Morphogenetic Protein 4; D024042:Collagen Type I; D051526:Fibroblast Growth Factor 10; D005938:Glucocorticoids; D018840:HSP70 Heat-Shock Proteins; D053823:Hedgehog Proteins; D008070:Lipopolysaccharides; D015513:Oncogene Proteins; D015534:Trans-Activators; D000071676:Zinc Finger Protein GLI1; D004549:Elastin; D001623:Betamethasone