Therapeutic potential of all-trans retinoic acid to attenuate pulmonary hypoplasia in an experimental rat model of congenital diaphragmatic hernia

Florian Michael Friedmacher

Research output: ThesisDoctoral Thesis

Abstract

Congenital diaphragmatic hernia (CDH) is a prenatal defect in the integrity of the developing diaphragm, which results in pulmonary hypoplasia (PH) with alveolar immaturity. PH leads to life-threatening respiratory insufficiency at birth, thus remaining a major cause of neonatal mortality in CDH. Lipid-containing interstitial fibroblasts (LIFs) are crucial for fetal lung growth by stimulating alveolarization and surfactant phospholipid production in alveolar epithelial cells type II (AECII), which in turn increases alveolar maturation. Thymocyte antigen 1 (Thy-1) is a strongly expressed cell surface protein in LIFs, which plays a key role in alveolar lipid homeostasis by upregulating adipocyte differentiation-related protein (Adrp). Adrp is necessary for the intracellular uptake of neutral lipids into LIFs and their transport to AECII. Furthermore, LIFs express leptin (Lep), which binds to its receptor (Lep-R) on AECII, thus stimulating de novo synthesis and secretion of surfactant proteins. As Thy-1-/- knockout animals show a phenotype similar to PH in human CDH with impaired alveolar development and reduced proliferation of LIFs, the first objective of this study was to identify disruptions in Thy-1 signaling in hypoplastic rat lungs with toxicological induced CDH, which may have an adverse effect on the expression and lipid content of pulmonary LIFs. In addition, as it has been demonstrated that retinoids positively affect the proliferation of LIFs and expression of Lep and Lep-R in developing rat lungs, the second objective was to investigate if prenatal administration of all-trans retinoic acid (ATRA) may have the potential to attenuate PH in this rodent CDH model by improving fetal alveolarization and surfactant production. This study revealed that disruption of the Thy-1/Adrp signaling cascade in hypoplastic rat lungs leads to a reduction of pulmonary LIFs with significantly fewer cytoplasmatic lipid inclusions and impaired alveolar mesenchymal cell differentiation, which may contribute to decreased alveolar development and PH in the nitrofen-induced CDH model. Prenatal treatment with ATRA may therefore have a therapeutic potential in attenuating CDH-associated PH by increasing the overall number of LIFs and lipid droplets through an upregulation of Adrp transcripts and corresponding protein expression, and consequently enhances Lep-mediated surfactant phospholipid synthesis, which in turn stimulates fetal alveolarization, distal airway maturation and de novo surfactant production.
Original languageEnglish
Supervisors/Advisors
  • Rintala, Risto, Supervisor
  • Pakarinen, Mikko Petteri, Supervisor
Place of PublicationHelsinki
Publisher
Print ISBNs978-951-51-5345-6
Electronic ISBNs978-951-51-5346-3
Publication statusPublished - 2019
MoE publication typeG5 Doctoral dissertation (article)

Bibliographical note

M1 - 132 s. + liitteet

Fields of Science

  • Hernias, Diaphragmatic, Congenital
  • +prevention & control
  • Lung
  • +embryology
  • Pulmonary Alveoli
  • Alveolar Epithelial Cells
  • Pulmonary Surfactants
  • Retinoids
  • Fibroblasts
  • +drug effects
  • Thy-1 Antigens
  • Lipid Droplets
  • Lipids
  • Leptin
  • Cell Proliferation
  • Adipocytes
  • Cell Differentiation
  • Rats
  • Phenyl Ethers
  • Respiratory Insufficiency
  • 3123 Gynaecology and paediatrics

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