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Prenatal VEGF Nanodelivery Reverses Congenital Diaphragmatic Hernia–associated Pulmonary Abnormalities
(American Thoracic Society, 2025-06)
Stavros P. Loukogeorgakis
;
Federica Michielin
;
Noura Al-Juffali
;
JIMENEZ GREZ, JULIO ALBERTO
;
Soichi Shibuya
2
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Complementary Effect of Maternal Sildenafil and Fetal Tracheal Occlusion Improves Lung Development in the Rabbit Model of Congenital Diaphragmatic Hernia
(2020)
Francesca Maria Russo
;
Marina Gabriela Monteiro Carvalho Mori Da Cunha
;
Julio Jimenez
;
Flore Lesage
;
Mary Patrice Eastwood
<jats:sec> <jats:title>Objective:</jats:title> <jats:p>To evaluate the effect of combining antenatal sildenafil with fetal tracheal occlusion (TO) in fetal rabbits with surgically induced congenital diaphragmatic hernia (CDH).</jats:p> </jats:sec> <jats:sec> <jats:title>Background:</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods:</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>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, <jats:italic toggle="yes">P</jats:italic>=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%, <jats:italic toggle="yes">P</jats:italic><0.0001). Sildenafil alone induced an improvement in the mean terminal bronchiolar density (2.5 ± 0.8 br/mm<jats:sup>2</jats:sup> vs 3.5 ± 0.9 br/mm<jats:sup>2</jats:sup>, <jats:italic toggle="yes">P</jats:italic>=0.043) and lung mechanics (static elastance 61 ± 36 cmH<jats:sub>2</jats:sub>O /mL vs 113 ± 40 cmH<jats:sub>2</jats:sub>O/mL, <jats:italic toggle="yes">P</jats:italic>=0.008), but both effects were more pronounced in fetuses undergoing additional TO (2.1 ± 0.8 br/mm<jats:sup>2</jats:sup>, <jats:italic toggle="yes">P</jats:italic>=0.001 and 31 ± 9 cmH<jats:sub>2</jats:sub>O/mL, <jats:italic toggle="yes">P</jats:italic><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, <jats:italic toggle="yes">P</jats:italic><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.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion:</jats:title> <jats:p>In the rabbit model for CDH, the combination of maternal sildenafil and TO has a complementary effect on vascular and parenchymal lung development.</jats:p> </jats:sec>
3Scopus© Citations 19
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Complementary Effect of Maternal Sildenafil and Fetal Tracheal Occlusion Improves Lung Development in the Rabbit Model of Congenital Diaphragmatic Hernia
(2020)
Francesca Maria Russo
;
Marina Gabriela Monteiro Carvalho Mori Da Cunha
;
Julio Jimenez
;
Flore Lesage
;
Mary Patrice Eastwood
<jats:sec> <jats:title>Objective:</jats:title> <jats:p>To evaluate the effect of combining antenatal sildenafil with fetal tracheal occlusion (TO) in fetal rabbits with surgically induced congenital diaphragmatic hernia (CDH).</jats:p> </jats:sec> <jats:sec> <jats:title>Background:</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods:</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>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, <jats:italic toggle="yes">P</jats:italic>=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%, <jats:italic toggle="yes">P</jats:italic><0.0001). Sildenafil alone induced an improvement in the mean terminal bronchiolar density (2.5 ± 0.8 br/mm<jats:sup>2</jats:sup> vs 3.5 ± 0.9 br/mm<jats:sup>2</jats:sup>, <jats:italic toggle="yes">P</jats:italic>=0.043) and lung mechanics (static elastance 61 ± 36 cmH<jats:sub>2</jats:sub>O /mL vs 113 ± 40 cmH<jats:sub>2</jats:sub>O/mL, <jats:italic toggle="yes">P</jats:italic>=0.008), but both effects were more pronounced in fetuses undergoing additional TO (2.1 ± 0.8 br/mm<jats:sup>2</jats:sup>, <jats:italic toggle="yes">P</jats:italic>=0.001 and 31 ± 9 cmH<jats:sub>2</jats:sub>O/mL, <jats:italic toggle="yes">P</jats:italic><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, <jats:italic toggle="yes">P</jats:italic><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.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion:</jats:title> <jats:p>In the rabbit model for CDH, the combination of maternal sildenafil and TO has a complementary effect on vascular and parenchymal lung development.</jats:p> </jats:sec>
1Scopus© Citations 19
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The amniotic fluid as a source of mesenchymal stem cells with lung‐specific characteristics
(2017)
Flore Lesage
;
Silvia Zia
;
JIMENEZ GREZ, JULIO ALBERTO
;
Jan Deprest
;
Jaan Toelen
<jats:p>What is already known about this topic? <jats:list list-type="bullet"> <jats:list-item><jats:p>Fetal tissues are interesting sources of stem cells for autologous therapy in a neonatal context.</jats:p></jats:list-item> <jats:list-item><jats:p>AF‐MSC are a heterogeneous stem cell population of which the exact origin remains elusive.</jats:p></jats:list-item> </jats:list></jats:p><jats:p>What does this study add? <jats:list list-type="bullet"> <jats:list-item><jats:p>This study identifies AF‐MSC with lung‐specific characteristics.</jats:p></jats:list-item> <jats:list-item><jats:p>This study provides a reliable culture method that supports the expansion of lung‐specific AF‐MSC.</jats:p></jats:list-item> </jats:list></jats:p>
8Scopus© Citations 6
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Simvastatin attenuates lung functional and vascular effects of hyperoxia in preterm rabbits
(2019)
Thomas Salaets
;
Bieke Tack
;
JIMENEZ GREZ, JULIO ALBERTO
;
Andre Gie
;
Flore Lesage
Scopus© Citations 7 4
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Local pulmonary drug delivery in the preterm rabbit: feasibility and efficacy of daily intratracheal injections
(2019)
Thomas Salaets
;
André Gie
;
JIMENEZ GREZ, JULIO ALBERTO
;
Margo Aertgeerts
;
Olivier Gheysens
<jats:p> Recent clinical trials in newborns have successfully used surfactant as a drug carrier for an active compound, to minimize systemic exposure. To investigate the translational potential of surfactant-compound mixtures and other local therapeutics, a relevant animal model is required in which intratracheal administration for maximal local deposition is technically possible and well tolerated. Preterm rabbit pups (born at 28 days of gestation) were exposed to either hyperoxia or normoxia and randomized to receive daily intratracheal surfactant, daily intratracheal saline, or no injections for 7 days. At day 7, the overall lung function and morphology were assessed. Efficacy in terms of distribution was assessed by micro-PET-CT on both day 0 and day 7. Lung function as well as parenchymal and vascular structure were altered by hyperoxia, thereby reproducing a phenotype reminiscent of bronchopulmonary dysplasia (BPD). Neither intratracheal surfactant nor saline affected the survival or the hyperoxia-induced BPD phenotype of the pups. Using PET-CT, we demonstrate that 82.5% of the injected radioactive tracer goes and remains in the lungs, with a decrease of only 4% after 150 min. Surfactant and saline can safely and effectively be administered in spontaneously breathing preterm rabbits. The described model and method enable researchers to evaluate intratracheal pharmacological interventions for the treatment of BPD. </jats:p>
Scopus© Citations 21 1
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Preclinical evaluation of cell-based strategies to prevent or treat bronchopulmonary dysplasia in animal models: a systematic review
(2018)
Flore Lesage
;
JIMENEZ GREZ, JULIO ALBERTO
;
Jaan Toelen
;
Jan Deprest
Scopus© Citations 12 1
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A semi-automated method for unbiased alveolar morphometry: Validation in a bronchopulmonary dysplasia model
(2020)
Thomas Salaets
;
Bieke Tack
;
André Gie
;
Benjamin Pavie
;
Nikhil Sindhwani
Scopus© Citations 23 1
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Preterm birth impairs postnatal lung development in the neonatal rabbit model
(2020)
Thomas Salaets
;
Margo Aertgeerts
;
André Gie
;
Janne Vignero
;
Derek de Winter
<jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>Bronchopulmonary dysplasia continues to cause important respiratory morbidity throughout life, and new therapies are needed. The common denominator of all BPD cases is preterm birth, however most preclinical research in this area focusses on the effect of hyperoxia or mechanical ventilation. In this study we investigated if and how prematurity affects lung structure and function in neonatal rabbits.</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>Pups were delivered on either day 28 or day 31. For each gestational age a group of pups was harvested immediately after birth for lung morphometry and surfactant protein B and C quantification. All other pups were hand raised and harvested on day 4 for the term pups and day 7 for the preterm pups (same corrected age) for lung morphometry, lung function testing and qPCR. A subset of pups underwent microCT and dark field imaging on day 0, 2 and 4 for terms and on day 0, 3, 5 and 7 for preterms.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>Preterm pups assessed at birth depicted a more rudimentary lung structure (larger alveoli and thicker septations) and a lower expression of surfactant proteins in comparison to term pups. MicroCT and dark field imaging revealed delayed lung aeration in preterm pups, in comparison to term pups. Preterm birth led to smaller pups, with smaller lungs with a lower alveolar surface area on day 7/day 4. Furthermore, preterm birth affected lung function with increased tissue damping, tissue elastance and resistance and decreased dynamic compliance. Expression of vascular endothelial growth factor (VEGFA) was significantly decreased in preterm pups, however in the absence of structural vascular differences.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions</jats:title> <jats:p>Preterm birth affects lung structure and function at birth, but also has persistent effects on the developing lung. This supports the use of a preterm animal model, such as the preterm rabbit, for preclinical research on BPD. Future research that focuses on the identification of pathways that are involved in in-utero lung development and disrupted by pre-term birth, could lead to novel therapeutic strategies for BPD.</jats:p> </jats:sec>
Scopus© Citations 23 1
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Progressive Vascular Functional and Structural Damage in a Bronchopulmonary Dysplasia Model in Preterm Rabbits Exposed to Hyperoxia
(2016)
Julio Jiménez
;
Jute Richter
;
Taro Nagatomo
;
Thomas Salaets
;
Rozenn Quarck
19Scopus© Citations 36

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