Pulmonary vascular development in congenital diaphragmatic hernia

Abstract

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

Likely damaging de novo variants in congenital diaphragmatic hernia patients are associated with worse clinical outcomes

“…Previous studies indicated that abnormal pulmonary vascular development and function is a significant clinical problem in CDH infants 29 . In our cohort, CDH cases with LD variants had higher PH prevalence at 1 or 3 months compared to cases without LD variants.…”

Effects of tracheal occlusion on the neonatal cardiopulmonary transition in an ovine model of diaphragmatic hernia

“…Alternatively, poor gas exchange may suggest persistently impaired perfusion of fifth and sixth generation pulmonary vessels that are important for gas exchange. In CDH, reduced pulmonary vascular cross-sectional area in combination with extensive hypermuscularisation and neomuscularisation of distal pulmonary vessels is thought to lead to higher resistance within peripheral pulmonary vessels 35. Luks et al suggested that short-term tracheal occlusion (2 weeks) reduces abnormal muscularisation of pulmonary arterioles; however, their histological analysis defined distal vessels by size, rather than branching generation 36.…”

Prenatal regenerative fetoscopic interventions for congenital anomalies

“…Lung development occurs in four stages starting at 4 weeks’ gestation and continuing into the postnatal period 2627. Lung budding is seen from 16 to 24 weeks’ gestation, and alveolar formation and maturation from 24 weeks’ gestation to 3 years of postnatal life 26.…”

“…Lung budding is seen from 16 to 24 weeks’ gestation, and alveolar formation and maturation from 24 weeks’ gestation to 3 years of postnatal life 26. Concurrent with this process is pulmonary vascular development which occurs through neovascularization and branching of pre-existing conduits between weeks 10 and 11 27282930. Initially the pulmonary vessels are thick and muscular with high vascular resistance that decreases with gestation and after birth to promote gas exchange 27.…”

“…Concurrent with this process is pulmonary vascular development which occurs through neovascularization and branching of pre-existing conduits between weeks 10 and 11 27282930. Initially the pulmonary vessels are thick and muscular with high vascular resistance that decreases with gestation and after birth to promote gas exchange 27. In fetuses with CDH, on histologic exam the lungs appear less developed for gestational age, with the ipsilateral more severely affected than the contralateral lung 31.…”