Abstract
Background
Glucocorticoids (GCs) are highly effective yet problematic agents against bronchopulmonary dysplasia (BPD). The dimeric trans-activation of GCs induces unfavorable effects, while monomeric trans-repression suppresses inflammation-related genes. Recently, non-steroidal-selective glucocorticoid-receptor agonists and modulators (SEGRAMs) with only the trans-repressive action have been designed.
Methods
Using a bleomycin (Bleo)-induced alveolar simplification newborn rat model (recapitulating arrested alveolarization during BPD), we evaluated the therapeutic effects of compound-A (CpdA), a SEGRAM. Sprague-Dawley rats were administered Bleo from postnatal day (PD) 0 to 10 and treated with dexamethasone (Dex) or CpdA from PD 0 to 13. The morphological changes and mRNA expression of inflammatory mediators, including interleukin (IL)-1β, C–X–C motif chemokine ligand 1 (CXCL1), and C–C motif chemokine 2 (CCL2) were investigated.
Results
Similar to the effects of Dex, CpdA exerted protective effects on morphological derangements and inhibited macrophage infiltration and production of pro-inflammatory mediators in Bleo-treated animals. The effects of CpdA were probably mediated by GC receptor (GR)-dependent trans-repression, because unlike the Dex-treated group, anti-inflammatory genes specifically induced by GR-dependent trans-activation (such as “glucocorticoid-induced leucine zipper, GILZ”) were not upregulated.
Conclusions
CpdA improved lung inflammation, inhibited the arrest of alveolar maturation, and restored histological and biochemical changes in a Bleo-induced alveolar simplification model.
Impact
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SEGRAMs have attracted widespread attention because they are expected to not exhibit unfavorable effects of GCs.
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Compound A, one of the SEGRAMs, improved lung morphometric changes and decreased lung inflammation in a bleomycin-induced arrested alveolarization, a newborn rat model representing one of the main features of BPD pathology.
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Compound A did not elicit bleomycin-induced poor weight gain, in contrast to dexamethasone treatment.
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SEGRAMs, including compound A, may be promising candidates for the therapy of BPD with less adverse effects compared with GCs.
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Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
The authors would like to thank Kazumi Honda and Yumiko Yoshimura for assistance with the biochemical analysis, and Yusuke Onishi and Yasuhiro Ogino for assistance with the immunohistochemical analysis.
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S.I., T.O., and J.S. conceived and designed the research. S.I., J.S., and S.K. performed experiments and acquired data. S.I. prepared the manuscript. T.O. revised and edited the manuscript. D.N. helped in executing the statistical analysis. S.Y., Y.H., and A.A. critically reviewed the manuscript for important intellectual content. All authors have approved the final manuscript and agreed to be accountable for all aspects of the work.
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Ishikawa, S., Ogihara, T., Yamaoka, S. et al. A glucocorticoid-receptor agonist ameliorates bleomycin-induced alveolar simplification in newborn rats. Pediatr Res 93, 1551–1558 (2023). https://doi.org/10.1038/s41390-022-02257-8
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DOI: https://doi.org/10.1038/s41390-022-02257-8
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