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bioRxiv · 10.1101/2021.04.28.441723

A selective glucocorticoid receptor modulator attenuates lung inflammation and improves alveolarization in a neonatal rat model of bronchopulmonary dysplasia.

Ishikawa, S.·Ogihara, T.·Yamaoka, S.·Shinohara, J.·Kawabata, S.·Hirose, Y.·Ashida, A.
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Abstract

BackgroundBronchopulmonary dysplasia (BPD) is a major problem for extremely preterm infants. Glucocorticoids effectively treat BPD; however, they have many side effects. Compound A (Cpd A) is a nonsteroidal Selective Glucocorticoid Receptor Modulator (SEGRM) that acts as a glucocorticoid receptor ligand without inducing the expression of glucocorticoid-response element-driven genes. Cpd A reportedly has anti-inflammatory properties with fewer side effects than glucocorticoids. MethodsUsing a bleomycin (Bleo)-induced BPD model, we evaluated the therapeutic effects of Cpd A. 0-day-old Sprague-Dawley rats were administered Bleo for 10 days and treated with dexamethasone (Dex) or Cpd A from day 0 to 13. We evaluated lung pathology by histology and the mRNA levels of interleukin (IL)-1{beta}, transforming growth factor (TGF)-{beta}1 and chemokines, CXCL1 and CCL2. ResultsBleo-treated mice had lungs with impaired alveolarization. Dex and Cpd A treatments improved the alveolar structure, attenuating the lung injury. Bleo-exposed lungs had increased inflammatory cells recruitment and inflammatory mediator mRNA levels. Cpd A treatment reduced inflammatory cells infiltration and CXCL1, CCL2 and TGF-{beta}1 expression. ConclusionCpd A improved lung inflammation and alveolar maturation arrest, and restored histological and biochemical changes in a model of BPD. SEGRMs, including Cpd A, are promising candidates for the therapy of BPD. Impact Statement{circ} What is the key message of your article? Compound A decreased lung inflammation and improved lung morphometric changes in Bleomycin-exposed lungs. {circ}What does it add to the existing literature? Compound A has anti-inflammatory effects in an experimental model of BPD. {circ}What is the impact? SEGRMs, including Cpd A, may be promising candidates for the therapy of BPD.

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Ishikawa, S., Ogihara, T., Yamaoka, S., Shinohara, J., Kawabata, S., Hirose, Y., Ashida, A.. 2021-04-28. A selective glucocorticoid receptor modulator attenuates lung inflammation and improves alveolarization in a neonatal rat model of bronchopulmonary dysplasia.. https://doi.org/10.1101/2021.04.28.441723

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