Transplacental sildenafil rescues lung abnormalities in the rabbit model of diaphragmatic hernia

Russo, Francesca Maria; Toelen, Jaan; Eastwood, Patrice; Jiménez, Julio; Miyague, A. H.; Velde, Greetje Vande; DeKoninck, Philip; Himmelreich, Uwe; Vergani, Patrizia; Allegaert, Karel; Deprest, Jan

doi:10.1136/thoraxjnl-2015-207949

Cited by 57 publications

(95 citation statements)

References 39 publications

(38 reference statements)

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“…We focused primarily on the physiological effects of antenatal sildenafil treatment in DH lambs, so our study is limited by the absence of histological evidence to confirm the morphological and biochemical features underlying the observed physiology. However, the effects of sildenafil on pulmonary vascular development have been well described in other animal models of CDH and correlate well with our current findings. Interestingly, fetal plasma sildenafil concentrations in our lambs immediately prior to delivery (2–5 ng/mL) were similar to those obtained in rats by Mous et al ,.…”

Section: Discussionsupporting

confidence: 92%

“…Furthermore, antenatal treatment with the PDE‐5 inhibitor sildenafil has been shown to attenuate pulmonary vascular abnormalities in both a nitrofen‐induced CDH rodent model and a surgery‐induced CDH rabbit model, which is more clinically relevant in terms of lung development. In these animal studies, antenatal sildenafil treatment increased cGMP and vascular endothelial growth factor expression in lung tissue, increased distal pulmonary vessel density, decreased pulmonary vascular muscularization, reduced right ventricular wall thickness and increased distal airway complexity. However, it is unclear if these improvements in pulmonary vascular structure and biochemistry translate to improved pulmonary hemodynamics after birth.…”

Section: Introductionmentioning

confidence: 99%

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Antenatal sildenafil treatment improves neonatal pulmonary hemodynamics and gas exchange in lambs with diaphragmatic hernia

Kashyap

DeKoninck

Rodgers

et al. 2019

Ultrasound in Obstet & Gyne

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Objectives Infants with congenital diaphragmatic hernia (CDH) are predisposed to pulmonary hypertension after birth, owing to lung hypoplasia that impairs fetal pulmonary vascular development. Antenatal sildenafil treatment attenuates abnormal pulmonary vascular and alveolar development in rabbit and rodent CDH models, but whether this translates to functional improvements after birth remains unknown. We aimed to evaluate the effect of antenatal sildenafil on neonatal pulmonary hemodynamics and lung function in lambs with diaphragmatic hernia (DH). Methods DH was surgically induced at approximately 80 days' gestation in 16 lamb fetuses (term in lambs is approximately 147 days). From 105 days' gestation, ewes received either sildenafil (0.21 mg/kg/h intravenously) or saline infusion until delivery (n = 8 fetuses in each group). At approximately 138 days' gestation, all lambs were instrumented and then delivered via Cesarean section. The lambs were ventilated for 120 min with continuous recording of physiological (pulmonary and carotid artery blood flow and pressure; cerebral oxygenation) and ventilatory parameters, and regular assessment of arterial blood gas tensions. Only lambs that survived until delivery and with a confirmed diaphragmatic defect at postmortem examination were included in the analysis; these comprised six DH‐sildenafil lambs and six DH‐saline control lambs. Results Lung‐to‐body‐weight ratio (0.016 ± 0.001 vs 0.013 ± 0.001; P = 0.06) and dynamic lung compliance (0.8 ± 0.2 vs 0.7 ± 0.2 mL/cmH2O; P = 0.72) were similar in DH‐sildenafil lambs and controls. Pulmonary vascular resistance decreased following lung aeration to a greater degree in DH‐sildenafil lambs, and was 4‐fold lower by 120 min after cord clamping than in controls (0.6 ± 0.1 vs 2.2 ± 0.6 mmHg/(mL/min); P = 0.002). Pulmonary arterial pressure was also lower (46 ± 2 vs 59 ± 2 mmHg; P = 0.048) and pulmonary blood flow higher (25 ± 3 vs 8 ± 2 mL/min/kg; P = 0.02) in DH‐sildenafil than in DH‐saline lambs at 120 min. Throughout the 120‐min ventilation period, the partial pressure of arterial carbon dioxide tended to be lower in DH‐sildenafil lambs than in controls (63 ± 8 vs 87 ± 8 mmHg; P = 0.057), and there was no significant difference in partial pressure of arterial oxygen between the two groups. Conclusions Sustained maternal antenatal sildenafil infusion reduced pulmonary arterial pressure and increased pulmonary blood flow in DH lambs for the first 120 min after birth. These findings of improved pulmonary vascular function are consistent with improved pulmonary vascular structure seen in two previous animal models. The data support the rationale for a clinical trial investigating the effect of antenatal sildenafil in reducing the risk of neonatal pulmonary hypertension in infants with CDH. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Antenatal sildenafil treatment improves neonatal pulmonary hemodynamics and gas exchange in lambs with diaphragmatic hernia

Kashyap

DeKoninck

Rodgers

et al. 2019

Ultrasound in Obstet & Gyne

View full text Add to dashboard Cite

show abstract

“…The improved vascularisation was paralleled by reduced pulmonary artery pressure and by morphological changes in the lung parenchyma and functional improvement. In line with previous rodent studies, Russo et al 1 found that the decreased lung weight due to CDH is not rescued in sildenafil-treated fetuses with CDH, suggesting that the sildenafil-induced improvement of vascular and alveolar development contributes to the lung maturation more than the volume growth. These well-performed studies obtained in an animal model that closely resembles both the pharmacokinetics of human pregnancy and alveolar development in humans provide a next step towards a clinically useful therapy for CDH and its postnatal consequences.…”

supporting

confidence: 83%

“…Russo et al 1 demonstrate that maternally administered sildenafil reaches therapeutic levels in the rabbit fetus, without toxicity for mother or the fetus. CDH fetuses treated with sildenafil demonstrated increased pulmonary vascular branching compared with placebo-treated fetuses.…”

mentioning

confidence: 99%

Why vessels do matter in pulmonary disease

Aman

Bogaard

Vonk‐Noordegraaf

2016

Thorax

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“…We and others have performed some studies on the antenatal use of the phosphodiesterase-5 inhibitor sildenafil in different animal models of CDH, showing improvement in alveolarisation and pulmonary vascular development [57][58][59][60][61]. However, the pulmonary pathology in these treated animals did not show complete reversal to the normal lung histology.…”

Section: Treatment Of Pulmonary Vascular Defects In Cdhmentioning

confidence: 99%

Pulmonary vascular development in congenital diaphragmatic hernia

et al. 2018

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Congenital diaphragmatic hernia (CDH) is a rare congenital anomaly characterised by a diaphragmatic defect, persistent pulmonary hypertension (PH) and lung hypoplasia. The relative contribution of these three elements can vary considerably in individual patients. Most affected children suffer primarily from the associated PH, for which the therapeutic modalities are limited and frequently not evidence based. The vascular defects associated with PH, which is characterised by increased muscularisation of arterioles and capillaries, start to develop early in gestation. Pulmonary vascular development is integrated with the development of the airway epithelium. Although our knowledge is still incomplete, the processes involved in the growth and expansion of the vasculature are beginning to be unravelled. It is clear that early disturbances of this process lead to major pulmonary growth abnormalities, resulting in serious clinical challenges and in many cases death in the newborn. Here we provide an overview of the current molecular pathways involved in pulmonary vascular development. Moreover, we describe the abnormalities associated with CDH and the potential therapeutic approaches for this severe abnormality. Normal pulmonary vascular developmentHuman lung development can be divided into different stages based on histology, starting with the embryonic stage at 4 weeks of gestation, followed by the pseudoglandular stage in which branching of the lung buds continues. During the canalicular stage, starting at ∼16 weeks of gestation, the terminal bronchioli are formed. From 24 weeks of gestation until term, the saccular stage, airspaces widen and alveoli are formed. During the alveolar stage, which persists into the postnatal period up to 3 years of age, maturation of the airways occurs [1]. Concomitant with the expansion of the airways is the adaptation of the microvasculature to optimise the exchange of oxygen and carbon dioxide between the blood and the airways. We and others have shown that very early in lung development pulmonary vessels are present and connected to the systemic circulation. The vasculature develops in close relation with the airways and is a rate-limiting factor in branching morphogenesis [2][3][4]. This implies that the pulmonary vasculature plays an important role in lung development. The formation of new blood vessels primarily occurs through

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Transplacental sildenafil rescues lung abnormalities in the rabbit model of diaphragmatic hernia

Abstract: In the rabbit model for DH, antenatal sildenafil rescues vascular branching and architecture, reduces pulmonary vascular resistances and also improves airway morphometry and respiratory mechanics.

Cited by 57 publications

References 39 publications

Antenatal sildenafil treatment improves neonatal pulmonary hemodynamics and gas exchange in lambs with diaphragmatic hernia

Antenatal sildenafil treatment improves neonatal pulmonary hemodynamics and gas exchange in lambs with diaphragmatic hernia

Why vessels do matter in pulmonary disease

Pulmonary vascular development in congenital diaphragmatic hernia

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