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Why vessels do matter in pulmonary disease
  1. Jurjan Aman1,2,
  2. Harm Jan Bogaard2,
  3. Anton Vonk Noordegraaf2
  1. 1Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands
  2. 2Department of Pulmonary Diseases, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands
  1. Correspondence to Dr Anton Vonk Noordegraaf, Department of Pulmonary Diseases, VU University Medical Center, De Boelelaan 1117, Amsterdam 1081 HV, The Netherlands; a.vonk{at}

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In addition to structural abnormalities of the diaphragm, congenital diaphragmatic hernia (CDH) presents with severe hypoplasia of lung tissue involving both the pulmonary vasculature and the airways. These developmental defects often yield a severe phenotype of pulmonary hypertension (PH) and lung function impairment. Despite adequate surgical repair of the diaphragm, neonatal mortality of CDH remains high, due to ineffectiveness of inhaled nitric oxide (NO) and absence of alternative therapy for PH in the newborn.

Russo et al1 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. 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 al1 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.

In addition to providing relevant steps towards clinical development of sildenafil as a potential therapy for CDH, Russo et al give valuable insights into the mechanisms of lung development. Stressing the key role of cyclic guanosine monophosphate (cGMP)/NO signalling in …

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