LPS-induced chorioamnionitis and antenatal corticosteroids modulate Shh signaling in the ovine fetal lung

Am J Physiol Lung Cell Mol Physiol. 2012 Nov 1;303(9):L778-87. doi: 10.1152/ajplung.00280.2011. Epub 2012 Sep 7.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Betamethasone / pharmacology*
  • Betamethasone / therapeutic use
  • Bone Morphogenetic Protein 4 / genetics
  • Bone Morphogenetic Protein 4 / metabolism
  • Cell Proliferation
  • Chorioamnionitis / drug therapy
  • Chorioamnionitis / immunology
  • Chorioamnionitis / metabolism*
  • Collagen Type I / metabolism
  • Elastin / metabolism
  • Female
  • Fetus / drug effects
  • Fetus / embryology
  • Fetus / metabolism*
  • Fetus / pathology
  • Fibroblast Growth Factor 10 / genetics
  • Fibroblast Growth Factor 10 / metabolism
  • Gene Expression
  • Gene Expression Regulation, Developmental
  • Glucocorticoids / pharmacology*
  • Glucocorticoids / therapeutic use
  • HSP70 Heat-Shock Proteins / metabolism
  • Hedgehog Proteins / metabolism*
  • Lipopolysaccharides / pharmacology*
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism
  • Pregnancy
  • Pulmonary Alveoli / drug effects
  • Pulmonary Alveoli / embryology
  • Pulmonary Alveoli / metabolism*
  • Pulmonary Alveoli / pathology
  • Sheep
  • Signal Transduction
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Zinc Finger Protein GLI1

Substances

  • Bone Morphogenetic Protein 4
  • Collagen Type I
  • Fibroblast Growth Factor 10
  • Glucocorticoids
  • HSP70 Heat-Shock Proteins
  • Hedgehog Proteins
  • Lipopolysaccharides
  • Oncogene Proteins
  • Trans-Activators
  • Zinc Finger Protein GLI1
  • Elastin
  • Betamethasone