Congenital Diaphragmatic Hernia

Abstract

Congenital diaphragmatic hernia (CDH) is still an unsolved problem. A disease which was, for a long time, thought to be merely a hole in the diaphragm appears today to be an intriguing malformation with a poorly understood pathogenesis and a complex pathophysiology. CDH results in various degrees of pulmonary hypoplasia and severe persistent pulmonary hypertension of the newborn. Despite antenatal ultrasound diagnosis and continuous improvement in neonatal intensive care, these features could not be overcome, and the overall mortality rate in CDH is still reaching 50%. Experimental works during the past 20 years suggest that CDH is a disease of impaired lung development associated with, but not caused by, a structural defect of the diaphragm. Furthermore, there is increasing evidence that the lung in CDH is not only small but that there are numerous disorders (e.g. surfactant deficiency, decreased anti-oxidant activity, increased vascular reactivity with decreased nitric oxide and increased endothelin 1 activity, and left heart hypoplasia) which may be associated with impaired lung development. Although antenatal diagnosis of CDH is feasible by ultrasound, there is no reliable predictor of pulmonary hypoplasia, the main prognostic factor in CDH. Whilst modern therapeutic strategies such as high-frequency oscillatory ventilation, exogenous surfactant or inhaled nitric oxide may be beneficial in selected subjects, most newborns with hypoplastic lungs will not survive despite these postnatal therapies. Perhaps these newborns would benefit from antenatal treatment directed at altering lung growth early in utero to minimize pulmonary hypoplasia. Therefore, research is needed to elucidate the aetiology and pathogenesis of CDH. Knowledge about the cellular control of proliferation, differentiation and programmed cell death (apoptosis) in the organogenesis should clarify our understanding of these processes and allow us to develop drugs that stimulate lung growth or even correct the anatomical defect. Furthermore, early and reliable assessment of prognosis for fetuses with CDH at risk of death will become increasingly important in the identification of fetuses most likely to benefit from antenatal therapies and may eventually lead to decreased mortality.

Antenatal maternally-administered phosphodiesterase type 5 inhibitors normalize eNOS expression in the fetal lamb model of congenital diaphragmatic hernia

“…14, 15 Even infants with CDH who do not manifest clinically significant pulmonary hypertension have evidence of increased pulmonary vascular resistance on echocardiogram. 14 Pulmonary hypertension in CDH is due to a combination of increased pulmonary vascular hyperreactivity, 3, 9 increased muscularization of the pulmonary arterioles, 5, 6 and decreased size of the pulmonary vascular bed, 4, 6, 11, 13 and the severity of pulmonary hypertension remains a main determinant of survival for neonates with CDH.…”

“…5 Both abnormal muscularization of distal arterioles 6–8 and an innate pulmonary vascular hyperreactivity 3, 9 contribute to pulmonary hypertension, and these effects occur in both lungs, regardless of the laterality of the diaphragmatic hernia. Treatment includes inhaled nitric oxide, extracorporeal membrane oxygenation, endothelin receptor antagonists and phosphodiesterase type 5 (PDE5) inhibitors.…”

Intra-amniotic Sildenafil Treatment Modulates Vascular Smooth Muscle Cell Phenotype in the Nitrofen Model of Congenital Diaphragmatic Hernia

“…Postnatal clinical instability and mortality associated with CDH is mainly due to lung maldevelopment, resulting in pulmonary hypertension and often severe respiratory failure in newborns with CDH 3 . These pulmonary developmental defects include lung hypoplasia and overly muscularized distal pulmonary arterioles, with increased medial and adventitial wall thickness and decreased pulmonary arterial cross-section 4 – 6 . The increased levels of α-SMA per vessel seen in these hypoplastic lungs on fetal studies further demonstrates the hypermuscularization of these intra-acinar vessels 7 , 8 .…”

Rescuing lung development through embryonic inhibition of histone acetylation

“…In the developing lung epithelium, SIN3A was shown to be required for cell cycling and branching morphogenesis ( 76 ). Abnormalities in lung branching have been reported in patients with CDH ( 118 – 120 ); however, the more common phenotypes associated with CDH include pulmonary hypertension and lung hypoplasia ( 119 , 121 – 123 ). SIN3A has been associated with regulation of cell cycling, and loss of SIN3A has been demonstrated to result in activation of p53, making senescence a likely subsequent loss-of-function phenotype ( 59 , 124 ).…”