Browsing by Author "Lesage, Flore"
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Item Complementary Effect of Maternal Sildenafil and Fetal Tracheal Occlusion Improves Lung Development in the Rabbit Model of Congenital Diaphragmatic Hernia(2020) Russo, Francesca Maria; Cunha, Marina Gabriela Monteiro Carvalho Mori Da; Jimenez, Julio; Lesage, Flore; Eastwood, Mary Patrice; Toelen, Jaan; Deprest, JanObjective: To evaluate the effect of combining antenatal sildenafil with fetal tracheal occlusion (TO) in fetal rabbits with surgically induced congenital diaphragmatic hernia (CDH). Background: Although antenatal sildenafil administration rescues vascular abnormalities in lungs of fetal rabbits with CDH, it only partially improves airway morphometry. We hypothesized that we could additionally stimulate lung growth by combining this medical treatment with fetal TO. Methods: CDH was created on gestational day (GD)23 (n=54). Does were randomized to receive either sildenafil 10 mg/kg/d or placebo by subcutaneous injection from GD24 to GD30. On GD28, fetuses were randomly assigned to TO or sham neck dissection. At term (GD30) fetuses were delivered, ventilated, and finally harvested for histological and molecular analyses. Unoperated littermates served as controls. Results: The lung-to-body-weight ratio was significantly reduced in sham-CDH fetuses either (1.2 ± 0.3% vs 2.3 ± 0.3% in controls, P=0.0003). Sildenafil had no effect on this parameter, while CDH fetuses undergoing TO had a lung-to-body-weight ratio comparable to that of controls (2.5 ± 0.8%, P<0.0001). Sildenafil alone induced an improvement in the mean terminal bronchiolar density (2.5 ± 0.8 br/mm vs 3.5 ± 0.9 br/mm, P=0.043) and lung mechanics (static elastance 61 ± 36 cmH2O /mL vs 113 ± 40 cmH2O/mL, P=0.008), but both effects were more pronounced in fetuses undergoing additional TO (2.1 ± 0.8 br/mm, P=0.001 and 31 ± 9 cmH2O/mL, P<0.0001 respectively). Both CDH-sham and CDH-TO fetuses treated with placebo had an increased medial wall thickness of peripheral pulmonary vessels (41.9 ± 2.9% and 41.8 ± 3.2%, vs 24.0 ± 2.9% in controls, P<0.0001). CDH fetuses treated with sildenafil, either with or without TO, had a medial thickness in the normal range (29.4% ± 2.6%). Finally, TO reduced gene expression of vascular endothelial growth factor and surfactant protein A and B, but this effect was counteracted by sildenafil. Conclusion: In the rabbit model for CDH, the combination of maternal sildenafil and TO has a complementary effect on vascular and parenchymal lung development.Item Preclinical evaluation of cell-based strategies to prevent or treat bronchopulmonary dysplasia in animal models: a systematic review(Taylor & Francis Online, 2017) Lesage, Flore; Jimenez, Julio; Toelen, Jaan; Deprest, JanBronchopulmonary dysplasia (BPD) remains the most common complication of extreme prematurity as no effective treatment is available to date. This calls for the exploration of new therapeutic options like cell therapy, which is already effective for various human (lung) disorders. We systematically searched the MEDLINE, Embase, and Web of Science databases from the earliest date till January 2017 and included original studies on the perinatal use of cell-based therapies (i.e. cells and/or cell-derivatives) to treat BDP in animal models. Fourth publications describing 47 interventions were retrieved. Newborn mice/rats raised in a hyperoxic environment were studied in most interventions. Different cell types - either intact cells or their conditioned medium - were administered, but bone marrow and umbilical cord blood derived mesenchymal stem cells were most prevalent. All studies reported positive effects on outcome parameters including alveolar and vascular morphometry, lung function, and inflammation. Cell homing to the lungs was demonstrated in some studies, but the therapeutic effects seemed to be mostly mediated via paracrine modulation of inflammation, fibrosis and angiogenesis. CONCLUSION: Multiple rat/mouse studies show promise for cell therapy for BPD. Yet careful study of action mechanisms and side effects in large animal models is imperative before clinical translation can be achieved.Item Simvastatin attenuates lung functional and vascular effects of hyperoxia in preterm rabbits(Nature Pub Group, 2020-06) Salaets, Thomas; Tack, Bieke; Jiménez, Julio; Gie, Andrés; Lesage, Flore; Winter, Derek; Berghen, Nathalie; Allegaert, Karel; Deprest, Jan; Toelen, JaanBackground: 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.Item The amniotic fluid as a source of mesenchymal stem cells with lung‐specific characteristics(2017) Lesage, Flore; Zia, Silvia; Jiménez, Julio; Deprest, Jan; Toelen, JaanThe amniotic fluid is a clinically accessible source of mesenchymal stem cells (AF‐MSC) during gestation, which enables autologous cellular therapy for perinatal disorders. The origin of AF‐MSC remains elusive: renal and neuronal progenitors have been isolated from the AF‐MSC pool, yet no cells with pulmonary characteristics. We analyzed gene expression of pulmonary and renal markers of 212 clonal lines of AF‐MSC isolated from amniocentesis samples. AF‐MSC were cultured on dishes coated with extracellular matrix (ECM) proteins from decellularized fetal rabbit lungs. In vivo differentiation potential of AF‐MSC that expressed markers suggestive of lung fate was tested by renal subcapsular injections in immunodeficient mice. Of all the isolated AF‐MSC lines, 26% were positive for lung endodermal markers FOXA2 and NKX2.1 and lacked expression of renal markers (KSP). This AF‐MSC subpopulation expressed other lung‐specific factors, including IRX1, P63, FOXP2, LGR6, SFTC, and PDPN. Pulmonary marker expression decreased over passages when AF‐MSC were cultured under conventional conditions, yet remained more stable when culturing the cells on lung ECM‐coated dishes. Renal subcapsular injection of AF‐MSC expressing lung‐specific markers resulted in engrafted cells that were SPTB positive. These data suggest that FOXA2+/NKX2.1+/KSP‐ AF‐MSC lines have lung characteristics which are supported by culture on lung ECM‐coated dishes.