Effects of DNA methylase inhibitors in a murine model of severe BPD

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 muri...

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Veröffentlicht in:Respiratory physiology & neurobiology 2023-07, Vol.313, p.104060-104060, Article 104060
Hauptverfasser: Heyob, Kathryn M., Khuhro, Zahra, Khan, Aiman Q., Brown, Dorian, Tipple, Trent E., Rogers, Lynette K.
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Sprache:eng
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Zusammenfassung: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, 0.1 mg/kg; p2, 4, 6, 0.1 mg/kg; or p2, 4, 6, 0.15 mg/kg) or RG108 (p3, 0.0013 mg/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. •Infants with BPD have higher levels of methylated DNA.•DNA methylation inhibitors were tested in an animal model of BPD.•Modest improvement in alveolarization and matrix remodeling were observed.•Decitabine treatment was associated with increased SPC expression.•Safe intranasal doses of decitabine and RG108 were identified.
ISSN:1569-9048
1878-1519
1878-1519
DOI:10.1016/j.resp.2023.104060