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Published on: May 4, 2020
A glucocorticoid-receptor agonist ameliorates bleomycin-induced alveolar simplification in newborn rats
Shoichi Ishikawa1, Tohru Ogihara2, Shigeo Yamaoka1
1Division of Neonatology, Department of Pediatrics, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, Japan.
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:
SEGRAMs have attracted widespread attention because they are expected to not exhibit unfavorable effects of GCs. 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. Compound A did not elicit bleomycin-induced poor weight gain, in contrast to dexamethasone treatment. SEGRAMs, including compound A, may be promising candidates for the therapy of BPD with less adverse effects compared with GCs.
Insights
Selective glucocorticoid receptor modulators (SEGRAMs) like compound A show promise for treating bronchopulmonary dysplasia (BPD). Compound A improved lung inflammation and development in a rat model, offering a potentially safer alternative to traditional glucocorticoids.
Area of Science:
- Pulmonary Medicine
- Pharmacology
- Developmental Biology
Background:
- Glucocorticoids (GCs) are effective for bronchopulmonary dysplasia (BPD) but cause adverse effects via trans-activation.
- Selective glucocorticoid receptor agonists and modulators (SEGRAMs) offer trans-repression without trans-activation, potentially reducing side effects.
Purpose of the Study:
- To evaluate the therapeutic potential of compound A (CpdA), a SEGRAM, in a neonatal rat model of BPD.
- To compare the effects of CpdA with dexamethasone (Dex) in mitigating lung injury and inflammation.
Main Methods:
- A bleomycin (Bleo)-induced alveolar simplification model in newborn rats was used to mimic BPD.
- Rats were treated with Dex or CpdA, and lung morphology, inflammation markers (IL-1β, CXCL1, CCL2), and gene expression were analyzed.
Main Results:
- CpdA demonstrated protective effects, reducing lung morphological derangements and macrophage infiltration in Bleo-treated rats.
- CpdA inhibited pro-inflammatory mediators similar to Dex, but without upregulating GC-dependent trans-activation genes like GILZ.
- Unlike Dex, CpdA did not cause poor weight gain in the Bleo-induced model.
Conclusions:
- Compound A improved lung inflammation and alveolar maturation arrest in a BPD rat model.
- SEGRAMs, including CpdA, represent promising therapeutic candidates for BPD with a potentially improved safety profile over traditional GCs.
