Extremely preterm fetal sheep lung responses to antenatal steroids and inflammation

Am J Obstet Gynecol. 2018 Mar;218(3):349.e1-349.e10. doi: 10.1016/j.ajog.2017.12.207. Epub 2017 Dec 21.

Abstract

Background: The efficacy of antenatal steroids for fetal lung maturation in the periviable period is not fully understood.

Objective: We sought to determine the lung maturational effects of antenatal steroids and inflammation in early gestation sheep fetuses, similar to the periviable period in human beings.

Study design: Date-mated ewes with singleton fetuses were randomly assigned to 1 of 4 treatment groups (n = 8/group): (1) maternal intramuscular injection of betamethasone; (2) intraamniotic lipopolysaccharide; (3) betamethasone + lipopolysaccharide; and (4) intraamniotic + intramuscular saline (controls). Fetuses were delivered surgically 48 hours later at 94 days' gestation (63% term gestation) for comprehensive evaluations of lung maturation, and lung and systemic inflammation.

Results: Relative to controls, first, betamethasone increased the fetal lung air space to mesenchymal area ratio by 47% but did not increase the messenger RNAs for the surfactant proteins-B and -C that are important for surfactant function or increase the expression of pro-surfactant protein-C in the alveolar type II cells. Second, betamethasone increased expression of 1 of the 4 genes in surfactant lipid synthetic pathways. Third, betamethasone increased genes involved in epithelium sodium channel transport, but not sodium-potassium adenosine triphosphatase or Aquaporin 5. Fourth, lipopolysaccharide increased proinflammatory genes in the lung but did not effectively recruit activated inflammatory cells. Last, betamethasone incompletely suppressed lipopolysaccharide-induced lung inflammation. In the liver, betamethasone when given alone increased the expression of serum amyloid A3 and C-reactive protein messenger RNAs.

Conclusion: Compared the more mature 125-day gestation sheep, antenatal steroids do not induce pulmonary surfactants during the periviable period, indicating a different response.

Keywords: chorioamnionitis; fetal inflammation; fetal lung maturation; respiratory distress syndrome; surfactant.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alveolar Epithelial Cells
  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Betamethasone / pharmacology*
  • C-Reactive Protein / genetics
  • Cell Count
  • Chorioamnionitis / chemically induced
  • Chorioamnionitis / drug therapy
  • Chorioamnionitis / genetics
  • Cytokines / genetics
  • Female
  • Gene Expression / drug effects*
  • Glutathione Peroxidase / genetics
  • Glutathione Peroxidase GPX1
  • Inflammation / chemically induced
  • Inflammation / drug therapy
  • Lipopolysaccharides
  • Lung / embryology*
  • Lung / metabolism
  • Male
  • Pregnancy
  • Premature Birth / drug therapy*
  • Prenatal Care
  • Protein Isoforms
  • Pulmonary Surfactant-Associated Protein B / genetics
  • Pulmonary Surfactant-Associated Protein C / genetics
  • RNA, Messenger / metabolism*
  • Random Allocation
  • Receptors, Glucocorticoid / genetics
  • Serum Amyloid A Protein / genetics
  • Sheep
  • Superoxide Dismutase / genetics
  • Vascular Endothelial Growth Factor A / genetics*

Substances

  • Anti-Inflammatory Agents
  • Cytokines
  • Lipopolysaccharides
  • Protein Isoforms
  • Pulmonary Surfactant-Associated Protein B
  • Pulmonary Surfactant-Associated Protein C
  • RNA, Messenger
  • Receptors, Glucocorticoid
  • Serum Amyloid A Protein
  • Vascular Endothelial Growth Factor A
  • C-Reactive Protein
  • Betamethasone
  • Glutathione Peroxidase
  • Superoxide Dismutase
  • superoxide dismutase 2
  • Glutathione Peroxidase GPX1