一种糖皮质激素受体激动剂可改善新生大鼠博来霉素诱导的肺泡简化。
A glucocorticoid-receptor agonist ameliorates bleomycin-induced alveolar simplification in newborn rats.
机构信息
Division of Neonatology, Department of Pediatrics, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, Japan.
Department of Pathology, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, Japan.
出版信息
Pediatr Res. 2023 May;93(6):1551-1558. doi: 10.1038/s41390-022-02257-8. Epub 2022 Sep 6.
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.
背景
糖皮质激素（GCs）是治疗支气管肺发育不良（BPD）的高效药物，但存在问题。GC 的二聚体转录激活会产生不利影响，而单体转录抑制则会抑制炎症相关基因。最近，设计了仅具有转录抑制作用的非甾体选择性糖皮质激素受体激动剂和调节剂（SEGRAMs）。
方法
我们使用博来霉素（Bleo）诱导的肺泡简化新生大鼠模型（模拟 BPD 期间肺泡化停止），评估了 SEGRAM 化合物 A（CpdA）的治疗效果。新生大鼠从出生后第 0 天（PD）至 10 天接受 Bleo 治疗，并从 PD 0 至 13 天接受地塞米松（Dex）或 CpdA 治疗。研究了炎症介质白细胞介素（IL）-1β、C-X-C 基序趋化因子配体 1（CXCL1）和 C-C 基序趋化因子 2（CCL2）的形态变化和 mRNA 表达。
结果
与 Dex 的作用相似，CpdA 对形态异常具有保护作用，并抑制 Bleo 处理动物的巨噬细胞浸润和促炎介质的产生。CpdA 的作用可能是通过 GC 受体（GR）依赖性转录抑制介导的，因为与 Dex 处理组不同，GR 依赖性转录激活特异性诱导的抗炎基因（如“糖皮质激素诱导亮氨酸拉链，GILZ”）并未上调。
结论
CpdA 改善了肺炎症，抑制了肺泡成熟的停滞，并在博来霉素诱导的肺泡简化模型中恢复了组织学和生化变化。
影响
SEGRAMs 因其有望避免 GC 的不利影响而受到广泛关注。SEGRAM 之一的 CpdA 改善了博来霉素诱导的肺泡化停止新生大鼠模型中的肺形态变化和减少肺炎症，该模型代表了 BPD 病理的主要特征之一。与地塞米松治疗不同，CpdA 没有引起博来霉素诱导的体重增加不良。与 GCs 相比，包括 CpdA 在内的 SEGRAMs 可能是治疗 BPD 的有前途的候选药物，具有较少的不良反应。
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