Simvastatin attenuates lung functional and vascular effects of hyperoxia in preterm rabbits.
Journal
Pediatric research
ISSN: 1530-0447
Titre abrégé: Pediatr Res
Pays: United States
ID NLM: 0100714
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
19
04
2019
accepted:
30
10
2019
revised:
01
10
2019
pubmed:
10
12
2019
medline:
20
7
2021
entrez:
10
12
2019
Statut:
ppublish
Résumé
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. Preterm rabbits were randomized to either normoxia (21% O 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. 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.
Sections du résumé
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% O
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.
Identifiants
pubmed: 31816623
doi: 10.1038/s41390-019-0711-2
pii: 10.1038/s41390-019-0711-2
doi:
Substances chimiques
Simvastatin
AGG2FN16EV
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1193-1200Références
Doyle, L. W. et al. Ventilation in extremely preterm infants and respiratory function at 8 years. N. Engl. J. Med. 377, 329–337 (2017).
doi: 10.1056/NEJMoa1700827
Stoll, B. J. et al. Trends in care practices, morbidity, and mortality of extremely preterm neonates, 1993−2012. Jama 314, 1039–1051 (2015).
doi: 10.1001/jama.2015.10244
Nardiello, C. et al. Standardisation of oxygen exposure in the development of mouse models for bronchopulmonary dysplasia. Dis. Model Mech. 10, 185–196 (2017).
doi: 10.1242/dmm.027086
Salaets, T., Gie, A., Tack, B., Deprest, J. & Toelen, J. Modelling bronchopulmonary dysplasia in animals: arguments for the preterm rabbit model. Curr. Pharm. Des. 23, 5887–5901 (2017).
doi: 10.2174/1381612823666170926123550
Frank, L. & Sosenko, I. R. Failure of premature rabbits to increase antioxidant enzymes during hyperoxic exposure: increased susceptibility to pulmonary oxygen toxicity compared with term rabbits. Pediatr. Res. 29, 292–296 (1991).
doi: 10.1203/00006450-199103000-00014
Richter, J. et al. Functional assessment of hyperoxia-induced lung injury after preterm birth in the rabbit. Am. J. Physiol. Lung Cell Mol. Physiol. 306, L277–L283 (2014).
doi: 10.1152/ajplung.00315.2013
Jimenez, J. et al. Progressive vascular functional and structural damage in a bronchopulmonary dysplasia model in preterm rabbits exposed to hyperoxia. Int. J. Mol. Sci. 17, pii: E1776 (2016).
Salaets, T. et al. Transcriptome analysis of the preterm rabbit lung after seven days of hyperoxic exposure. PLoS ONE 10, e0136569 (2015).
doi: 10.1371/journal.pone.0136569
Kruger, P. et al. A multicenter randomized trial of atorvastatin therapy in intensive care patients with severe sepsis. Am. J. Respir. Crit. Care Med. 187, 743–750 (2013).
doi: 10.1164/rccm.201209-1718OC
Raymakers, A. J. N., Sadatsafavi, M., Sin, D. D., De Vera, M. A. & Lynd, L. D. The impact of statin drug use on all-cause mortality in patients with COPD: a population-based cohort study. Chest 152, 486–493 (2017).
doi: 10.1016/j.chest.2017.02.002
Makanga, M. et al. Prevention of pulmonary hypoplasia and pulmonary vascular remodeling by antenatal simvastatin treatment in nitrofen-induced congenital diaphragmatic hernia. Am. J. Physiol. Lung Cell Mol. Physiol. 308, L672–L682 (2015).
doi: 10.1152/ajplung.00345.2014
Wong, M. J., Kantores, C., Ivanovska, J., Jain, A. & Jankov, R. P. Simvastatin prevents and reverses chronic pulmonary hypertension in newborn rats via pleiotropic inhibition of RhoA signaling. Am. J. Physiol. Lung Cell Mol. Physiol. 311, L985–L1999 (2016).
doi: 10.1152/ajplung.00345.2016
Bao, X. C. et al. Simvastatin decreases hyperbaric oxygen-induced acute lung injury by upregulating eNOS. Am. J. Physiol. Lung Cell Mol. Physiol. 314, L287–L1297 (2018).
pubmed: 29074491
Tschanz, S. A., Burri, P. H. & Weibel, E. R. A simple tool for stereological assessment of digital images: the STEPanizer. J. Microsc. 243, 47–59 (2011).
doi: 10.1111/j.1365-2818.2010.03481.x
Roubliova, X. I. et al. Morphologic changes and methodological issues in the rabbit experimental model for diaphragmatic hernia. Histol. Histopathol. 25, 1105–1116 (2010).
pubmed: 20607652
Matute-Bello, G. et al. An official American Thoracic Society workshop report: features and measurements of experimental acute lung injury in animals. Am. J. Respir. Cell Mol. Biol. 44, 725–738 (2011).
doi: 10.1165/rcmb.2009-0210ST
O'Reilly, M., Harding, R. & Sozo, F. Altered small airways in aged mice following neonatal exposure to hyperoxic gas. Neonatology 105, 39–45 (2014).
doi: 10.1159/000355641
Schittny, J. C. How high resolution 3-dimensional imaging changes our understanding of postnatal lung development. Histochem. Cell Biol. 150, 677–691 (2018).
doi: 10.1007/s00418-018-1749-7
Manitsopoulos, N. et al. Inhibition of HMGCoA reductase by simvastatin protects mice from injurious mechanical ventilation. Respir. Res. 16, 24 (2015).
doi: 10.1186/s12931-015-0173-y
Davis, B. B. et al. Simvastatin inhibits smoke-induced airway epithelial injury: implications for COPD therapy. Eur. Respir. J. 42, 350–361 (2013).
doi: 10.1183/09031936.00042512
Bagnato, G. et al. Simvastatin attenuates the development of pulmonary and cutaneous fibrosis in a murine model of systemic sclerosis. Rheumatol. (Oxf.) 52, 1377–1386 (2013).
doi: 10.1093/rheumatology/ket144
Schroll, S. et al. Effects of simvastatin on pulmonary fibrosis, pulmonary hypertension and exercise capacity in bleomycin-treated rats. Acta Physiol. (Oxf.) 208, 191–201 (2013).
doi: 10.1111/apha.12085
Kreuter, M. et al. Effect of statins on disease-related outcomes in patients with idiopathic pulmonary fibrosis. Thorax 72, 148–153 (2017).
doi: 10.1136/thoraxjnl-2016-208819
Zeki, A. A., Franzi, L., Last, J. & Kenyon, N. J. Simvastatin inhibits airway hyperreactivity: implications for the mevalonate pathway and beyond. Am. J. Respir. Crit. Care Med. 180, 731–740 (2009).
doi: 10.1164/rccm.200901-0018OC
Al-Ghanem, G. et al. Bronchopulmonary dysplasia and pulmonary hypertension: a meta-analysis. J. Perinatol. 37, 414–419 (2017).
doi: 10.1038/jp.2016.250
Lagatta, J. M. et al. The impact of pulmonary hypertension in preterm infants with severe bronchopulmonary dysplasia through 1 year. J. Pediatr. 203, 218–224.e213 (2018).
doi: 10.1016/j.jpeds.2018.07.035
Thebaud, B. et al. Vascular endothelial growth factor gene therapy increases survival, promotes lung angiogenesis, and prevents alveolar damage in hyperoxia-induced lung injury: evidence that angiogenesis participates in alveolarization. Circulation 112, 2477–2486 (2005).
doi: 10.1161/CIRCULATIONAHA.105.541524
Kramer, A., Green, J., Pollard, J. Jr. & Tugendreich, S. Causal analysis approaches in Ingenuity Pathway Analysis. Bioinformatics 30, 523–530 (2014).
doi: 10.1093/bioinformatics/btt703
Oesterle, A., Laufs, U. & Liao, J. K. Pleiotropic effects of statins on the cardiovascular system. Circ. Res. 120, 229–243 (2017).
doi: 10.1161/CIRCRESAHA.116.308537
Wang, M. & Casey, P. J. Protein prenylation: unique fats make their mark on biology. Nat. Rev. Mol. Cell Biol. 17, 110–122 (2016).
doi: 10.1038/nrm.2015.11
Schaafsma, D. et al. The mevalonate cascade as a target to suppress extracellular matrix synthesis by human airway smooth muscle. Am. J. Respir. Cell Mol. Biol. 44, 394–403 (2011).
doi: 10.1165/rcmb.2010-0052OC
Takeda, N. et al. Role of RhoA inactivation in reduced cell proliferation of human airway smooth muscle by simvastatin. Am. J. Respir. Cell Mol. Biol. 35, 722–729 (2006).
doi: 10.1165/rcmb.2006-0034OC
Kang, S. et al. Dysfunction of vascular smooth muscle and vascular remodeling by simvastatin. Toxicol. Sci. 138, 446–556 (2014).
doi: 10.1093/toxsci/kfu011
Kang, S. et al. Simvastatin induces the apoptosis of normal vascular smooth muscle through the disruption of actin integrity via the impairment of RhoA/Rac-1 activity. Thromb. Haemost. 116, 496–505 (2016).
doi: 10.1160/TH15-11-0858
Blanco-Colio, L. M. et al. 3-Hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors, atorvastatin and simvastatin, induce apoptosis of vascular smooth muscle cells by downregulation of Bcl-2 expression and Rho A prenylation. Atherosclerosis 161, 17–26 (2002).
doi: 10.1016/S0021-9150(01)00613-X
Matsuzawa, Y. et al. Inhibitory effects of clinical reagents having anti-oxidative activity on transforming growth factor-beta1-induced expression of alpha-smooth muscle actin in human fetal lung fibroblasts. J. Toxicol. Sci. 36, 733–740 (2011).
doi: 10.2131/jts.36.733
Watts, K. L., Sampson, E. M., Schultz, G. S. & Spiteri, M. A. Simvastatin inhibits growth factor expression and modulates profibrogenic markers in lung fibroblasts. Am. J. Respir. Cell Mol. Biol. 32, 290–300 (2005).
doi: 10.1165/rcmb.2004-0127OC
Nakahara, K. et al. Myopathy induced by HMG-CoA reductase inhibitors in rabbits: a pathological, electrophysiological, and biochemical study. Toxicol. Appl. Pharm. 152, 99–106 (1998).
doi: 10.1006/taap.1998.8491
Gerson, R. J. et al. Animal safety and toxicology of simvastatin and related hydroxy-methylglutaryl-coenzyme A reductase inhibitors. Am. J. Med. 87, 28s–38s (1989).
doi: 10.1016/S0002-9343(89)80596-0
Bradbury, P., Traini, D., Ammit, A. J., Young, P. M. & Ong, H. X. Repurposing of statins via inhalation to treat lung inflammatory conditions. Adv. Drug Deliv. Rev. 133, 93–106 (2018).
doi: 10.1016/j.addr.2018.06.005