All trans-retinoic acid modulates hyperoxia-induced suppression of NF-kB-dependent Wnt signaling in alveolar A549 epithelial cells

PLoS One. 2022 Aug 10;17(8):e0272769. doi: 10.1371/journal.pone.0272769. eCollection 2022.


Introduction: Despite recent advances in perinatal medicine, bronchopulmonary dysplasia (BPD) remains the most common complication of preterm birth. Inflammation, the main cause for BPD, results in arrested alveolarization. All trans-retinoic acid (ATRA), the active metabolite of Vitamin A, facilitates recovery from hyperoxia induced cell damage. The mechanisms involved in this response, and the genes activated, however, are poorly understood. In this study, we investigated the mechanisms of action of ATRA in human lung epithelial cells exposed to hyperoxia. We hypothesized that ATRA reduces hyperoxia-induced inflammatory responses in A549 alveolar epithelial cells.

Methods: A549 cells were exposed to hyperoxia with or without treatment with ATRA, followed by RNA-seq analysis.

Results: Transcriptomic analysis of A549 cells revealed ~2,000 differentially expressed genes with a higher than 2-fold change. Treatment of cells with ATRA alleviated some of the hyperoxia-induced changes, including Wnt signaling, cell adhesion and cytochrome P450 genes, partially through NF-κB signaling.

Discussion/conclusion: Our findings support the idea that ATRA supplementation may decrease hyperoxia-induced disruption of the neonatal respiratory epithelium and alleviate development of BPD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alveolar Epithelial Cells / metabolism
  • Animals
  • Animals, Newborn
  • Bronchopulmonary Dysplasia* / complications
  • Bronchopulmonary Dysplasia* / etiology
  • Female
  • Humans
  • Hyperoxia* / metabolism
  • Infant, Newborn
  • Lung / metabolism
  • NF-kappa B / metabolism
  • Pregnancy
  • Premature Birth* / metabolism
  • Tretinoin / metabolism
  • Tretinoin / pharmacology
  • Wnt Signaling Pathway


  • NF-kappa B
  • Tretinoin

Grant support

This work was funded by a Pediatrics Research Discovery and Education Fund awarded to IA through the Neonatal-Perinatal Fellowship program, Department of Pediatrics, Penn State College of Medicine. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.