Thomas Salaets1, Bieke Tack1, Julio Jimenez2, Andre Gie1, Flore Lesage3, Derek de Winter1, Nathalie Berghen1, Karel Allegaert4,5, Jan Deprest1,6, Jaan Toelen1. 1. Department of Development and Regeneration, KULeuven, Leuven, Belgium. 2. Facultad de Medicina, Universidad del Desarollo, Clínica Alemana, Santiago de Chile, Chile. 3. Ottawa Hospital Research Institute & CHEO Research Institute, Ottawa, ON, Canada. 4. Department of Development and Regeneration, KULeuven, Leuven, Belgium. karel.allegaert@uzleuven.be. 5. Department of Pediatrics, Division of Neonatology, Erasmus MC Sophia Children's Hospital, Rotterdam, Netherlands. karel.allegaert@uzleuven.be. 6. Institute for Women's Health, University College London Hospital, London, UK.
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.
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.
Authors: Xenia I Roubliova; Jan A Deprest; Jean Marc Biard; Lieve Ophalvens; Denis Gallot; Jacques C Jani; Cornelis P Van de Ven; Dick Tibboel; Erik K Verbeken Journal: Histol Histopathol Date: 2010-09 Impact factor: 2.303
Authors: Federico Bianco; Fabrizio Salomone; Ilaria Milesi; Xabier Murgia; Sauro Bonelli; Elena Pasini; Raffaele Dellacà; Maria Luisa Ventura; Jane Pillow Journal: Respir Res Date: 2021-02-26