Abstract
Background
Bronchopulmonary dysplasia (BPD) remains a frequent complication following preterm birth, affecting respiratory health throughout life. Transcriptome analysis in a preterm rabbit model for BPD revealed dysregulation of key genes for inflammation, vascular growth and lung development in animals exposed to hyperoxia, which could be prevented by simvastatin.
Methods
Preterm rabbits were randomized to either normoxia (21% O2) or hyperoxia (95% O2) and within each condition to treatment with 5 mg/kg simvastatin daily or control. Lung function, structure and mRNA-expression was assessed on day 7.
Results
Simvastatin partially prevented the effect of hyperoxia on lung function, without altering alveolar structure or inflammation. A trend towards a less fibrotic phenotype was noted in simvastatin-treated pups, and airways were less muscularized. Most importantly, simvastatin completely prevented hyperoxia-induced arterial remodeling, in association with partial restoration of VEGFA and VEGF receptor 2 (VEGFR2) expression. Simvastatin however decreased survival in pups exposed to normoxia, but not to hyperoxia.
Conclusion
Repurposing of simvastatin could be an advantageous therapeutic strategy for bronchopulmonary dysplasia and other developmental lung diseases with pulmonary vascular disease. The increased mortality in the treated normoxia group however limits the translational value at this dose and administration route.
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Acknowledgements
We would like to thank Katrien Luyten and Rita Van Bree for their technical assistance with immunohistochemistry and qPCR respectively. We would also like to thank Prof. Tania Roskams and Prof. Dietmar Thal for their help with the explorative search for liver and muscle toxicity. T.S. is partially funded by the SAFEPEDRUG project (supported by the agency for innovation by Science and Technology in Flanders IWT SBO 130033). This research was supported by a C2 grant from KULeuven (C24/18/101) and a research grant from the Research Foundation—Flanders (FWO G0C4419N). A.G. and J.J. are supported by the Erasmus+ Program of the European Commission (2013-0040). N.B. is a holder of a Ph.D. Fellowship grant fundamental research (FWO 11ZP518N). J.D. is partly funded by the Great Ormond Street Hospital Charity Fund.
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All authors fulfill the journal’s author requirements. T.S. and J.J. conceived, designed and performed the main experiments. T.S. and B.T. had a substantial contribution in acquisition, interpretation and analysis of the main data. A.G., F.L., D.d.W. and N.B. had a substantial contribution in the acquisition and analysis of several explorative outcome measures. T.S., A.G., K.A., J.D. and J.T. drafted and revised the article. All authors approved the final version before submission.
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Salaets, T., Tack, B., Jimenez, J. et al. Simvastatin attenuates lung functional and vascular effects of hyperoxia in preterm rabbits. Pediatr Res 87, 1193–1200 (2020). https://doi.org/10.1038/s41390-019-0711-2
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DOI: https://doi.org/10.1038/s41390-019-0711-2
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