Structural and transcriptomic response to antenatal corticosteroids in an Erk3-null mouse model of respiratory distress

Braden K. Pew, R. Alan Harris, Elena Sbrana, Milenka Cuevas Guaman, Cynthia Shope, Rui Chen, Sylvain Meloche, Kjersti Aagaard

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Background Neonatal respiratory distress syndrome in preterm infants is a leading cause of neonatal death. Pulmonary insufficiency-related infant mortality rates have improved with antenatal glucocorticoid treatment and neonatal surfactant replacement. However, the mechanism of glucocorticoid-promoted fetal lung maturation is not understood fully, despite decades of clinical use. We previously have shown that genetic deletion of Erk3 in mice results in growth restriction, cyanosis, and early neonatal lethality because of pulmonary immaturity and respiratory distress. Recently, we demonstrated that the addition of postnatal surfactant administration to antenatal dexamethasone treatment resulted in enhanced survival of neonatal Erk3-null mice. Objective To better understand the molecular underpinnings of corticosteroid-mediated lung maturation, we used high-throughput transcriptomic and high-resolution morphologic analysis of the murine fetal lung. We sought to examine the alterations in fetal lung structure and function that are associated with neonatal respiratory distress and antenatal glucocorticoid treatment. Study Design Dexamethasone (0.4 mg/kg) or saline solution was administered to pregnant dams on embryonic days 16.5 and 17.5. Fetal lungs were collected and analyzed by microCT and RNA-seq for differential gene expression and pathway interactions with genotype and treatment. Results from transcriptomic analysis guided further investigation of candidate genes with the use of immunostaining in murine and human fetal lung tissue. Results Erk3–/– mice exhibited atelectasis with decreased overall porosity and saccular space relative to wild type, which was ameliorated by glucocorticoid treatment. Of 596 differentially expressed genes (q < 0.05) that were detected by RNA-seq, pathway analysis revealed 36 genes (q < 0.05) interacting with dexamethasone, several with roles in lung development, which included corticotropin-releasing hormone and surfactant protein B. Corticotropin-releasing hormone protein was detected in wild-type and Erk3–/– lungs at E14.5, with significantly temporally altered expression through embryonic day 18.5. Antenatal dexamethasone attenuated corticotropin-releasing hormone at embryonic day 18.5 in both wild-type and Erk3–/– lungs (0.56-fold and 0.67-fold; P <.001). Wild type mice responded to glucocorticoid administration with increased pulmonary surfactant protein B (P =.003). In contrast, dexamethasone treatment in Erk3–/– mice resulted in decreased surfactant protein B (P =.012). In human validation studies, we confirmed that corticotropin-releasing hormone protein is present in the fetal lung at 18 weeks of gestation and increases in expression with progression towards viability (22 weeks of gestation; P <.01). Conclusion Characterization of whole transcriptome gene expression revealed glucocorticoid-mediated regulation of corticotropin-releasing hormone and surfactant protein B via Erk3-independent and -dependent mechanisms, respectively. We demonstrated for the first time the expression and temporal regulation of corticotropin-releasing hormone protein in midtrimester human fetal lung. This unique model allows the effects of corticosteroids on fetal pulmonary morphologic condition to be distinguished from functional gene pathway regulation. These findings implicate Erk3 as a potentially important molecular mediator of antenatal glucocorticoid action in promoting surfactant protein production in the preterm neonatal lung and expanding our understanding of key mechanisms of clinical therapy to improve neonatal survival.

Original languageEnglish (US)
Pages (from-to)384.e1-384.e89
JournalAmerican journal of obstetrics and gynecology
Volume215
Issue number3
DOIs
StatePublished - Sep 1 2016

Keywords

  • CRH
  • ERK3
  • SFTPB
  • antenatal glucocorticoid
  • fetal lung maturation

ASJC Scopus subject areas

  • Obstetrics and Gynecology

Fingerprint Dive into the research topics of 'Structural and transcriptomic response to antenatal corticosteroids in an Erk3-null mouse model of respiratory distress'. Together they form a unique fingerprint.

  • Cite this

    Pew, B. K., Harris, R. A., Sbrana, E., Guaman, M. C., Shope, C., Chen, R., Meloche, S., & Aagaard, K. (2016). Structural and transcriptomic response to antenatal corticosteroids in an Erk3-null mouse model of respiratory distress. American journal of obstetrics and gynecology, 215(3), 384.e1-384.e89. https://doi.org/10.1016/j.ajog.2016.04.043