2. Academic Validation
  3. Effects of DNA Methylase Inhibitors in a Murine Model of Severe BPD

Effects of DNA Methylase Inhibitors in a Murine Model of Severe BPD

  • Respir Physiol Neurobiol. 2023 Apr 7;104060. doi: 10.1016/j.resp.2023.104060.
Kathryn M Heyob 1,  Zahra Khuhro 1,  Aiman Q Khan 1,  Dorian Brown 1,  Trent E Tipple 2,  Lynette K Rogers 3
Affiliations

Affiliations

  • 1 Center for Perinatal Research, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio.
  • 2 Section of Neonatal-Perinatal Medicine, Department of Pediatrics, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
  • 3 Center for Perinatal Research, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio; Department of Pediatrics, The Ohio State University, Columbus, Ohio. Electronic address: Lynette.Rogers@NationwideChildrens.org.
PMID: 37031925 DOI: 10.1016/j.resp.2023.104060
Abstract

DNA methylation is necessary for developmental gene regulation, but adverse environments result in aberrant methylation and gene silencing. The current pilot study tested the hypothesis that treatment with DNA methylation inhibitors (decitabine; RG108) would improve alveolarization in a newborn murine model of severe bronchopulmonary dysplasia. Newborn mice exposed to maternal inflammation (LPS) and neonatal hyperoxia (85% O2) were treated with decitabine (p3, 0.1mg/kg; p2, 4, 6, 0.1mg/kg; or p2, 4, 6, 0.15mg/kg) or RG108 (p3, 0.0013mg/kg) delivered intranasally. Modest improvements in alveolarization were observed with decitabine, but no differences were observed with RG108. Attenuated phospho-SMAD2/3 levels and greater surfactant protein C protein levels compared to vehicle were observed with some tested doses. No detrimental side effects were observed with the doses used in this study. In summary, our pilot investigations identified a safe dose for intranasal administration of both methylation inhibitors and provides a foundation for further studies into methylation inhibitors in the context of neonatal lung injury.

Keywords

DNMT; RG108; TGFβ1; alveolarization.

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