Fetal lung transcriptome patterns in an ex vivo compression model of diaphragmatic hernia

Zachary D. Fox, Guihua Jiang, Kenneth K.Y. Ho, Kendal A. Walker, Allen P. Liu, Shaun M. Kunisaki

Research output: Contribution to journalArticlepeer-review

Abstract

Background: The purpose of this study was to employ a novel ex vivo lung model of congenital diaphragmatic hernia (CDH) to determine how a mechanical compression affects early pulmonary development. Methods: Day-15 whole fetal rat lungs (n = 6-12/group) from nitrofen-exposed and normal (vehicle only) dams were explanted and cultured ex vivo in compression microdevices (0.2 or 0.4 kPa) for 16 h to mimic physiologic compression forces that occur in CDH in vivo. Lungs were evaluated with significance set at P < 0.05. Results: Nitrofen-exposed lungs were hypoplastic and expressed lower levels of surfactant protein C at baseline. Although compression alone did not alter the α-smooth muscle actin (ACTA2) expression in normal lungs, nitrofen-exposed lungs had significantly increased ACTA2 transcripts (0.2 kPa: 2.04 ± 0.15; 0.4 kPa: 2.22 ± 0.11; both P < 0.001). Nitrofen-exposed lungs also showed further reductions in surfactant protein C expression at 0.2 and 0.4 kPa (0.53 ± 0.04, P < 0.01; 0.69 ± 0.23, P < 0.001; respectively). Whereas normal lungs exposed to 0.2 and 0.4 kPa showed significant increases in periostin (POSTN), a mechanical stress–response molecule (1.79 ± 0.10 and 2.12 ± 0.39, respectively; both P < 0.001), nitrofen-exposed lungs had a significant decrease in POSTN expression (0.4 kPa: 0.67 ± 0.15, P < 0.001), which was confirmed by immunohistochemistry. Conclusions: Collectively, these pilot data in a model of CDH lung hypoplasia suggest a primary aberration in response to mechanical stress within the nitrofen lung, characterized by an upregulation of ACTA2 and a downregulation in SPFTC and POSTN. This ex vivo compression system may serve as a novel research platform to better understand the mechanobiology and complex regulation of matricellular dynamics during CDH fetal lung development.

Original languageEnglish (US)
Pages (from-to)411-420
Number of pages10
JournalJournal of Surgical Research
Volume231
DOIs
StatePublished - Nov 2018
Externally publishedYes

Keywords

  • Congenital diaphragmatic hernia
  • Lung development
  • Mechanical compression
  • Periostin
  • Pulmonary hypoplasia

ASJC Scopus subject areas

  • Surgery

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