Changes in vasoactive pathways in congenital diaphragmatic hernia associated pulmonary hypertension explain unresponsiveness to pharmacotherapy

Abstract

BackgroundPatients with congenital diaphragmatic hernia (CDH) have structural and functional different pulmonary vessels, leading to pulmonary hypertension. They often fail to respond to standard vasodilator therapy targeting the major vasoactive pathways, causing a high morbidity and mortality. We analyzed whether the expression of crucial members of these vasoactive pathways could explain the lack of responsiveness to therapy in CDH patients.MethodsThe expression of direct targets of current vasodilator therapy in the endothelin and prostacyclin pathway was analyzed in human lung specimens of control and CDH patients.ResultsCDH lungs showed increased expression of both ETA and ETB endothelin receptors and the rate-limiting Endothelin Converting Enzyme (ECE-1), and a decreased expression of the prostaglandin-I2 receptor (PTGIR). These data were supported by increased expression of both endothelin receptors and ECE-1, endothelial nitric oxide synthase and PTGIR in the well-established nitrofen-CDH rodent model.ConclusionsTogether, these data demonstrate aberrant expression of targeted receptors in the endothelin and prostacyclin pathway in CDH already early during development. The analysis of this unique patient material may explain why a significant number of patients do not respond to vasodilator therapy. This knowledge could have important implications for the choice of drugs and the design of future clinical trials internationally.

Pulmonary hypertension secondary to congenital diaphragmatic hernia: factors and pathways involved in pulmonary vascular remodeling

“…Lungs of nitrofen-exposed rats with CDH had increased levels of ET-1, ECE, and both receptors as early as E15. 9,51,[73][74][75][76][77][78] The increase in receptors was confirmed in a study showing that arterioles from nitrofen-exposed CDH lungs constricted more than those in controls in response to ET-1. 79 Interestingly, administering an inhibitor of ECE prenatally to dams exposed to nitrofen was reported to increase the survival rate of pups with CDH.…”

“…77 Finally, babies with CDH had increased levels of ECE during fetal life, whereas in the lungs of control fetuses, ECE expression is low during fetal life and increases just before birth. 77 Angiotensin-converting enzyme (ACE) is produced by the pulmonary vascular endothelium and converts angiotensin I into angiotensin II, a potent vasoconstrictor. Along with angiotensin II receptors, AT-R1 and AT-R2, ACE is expressed in the developing lung as early as the pseudoglandular stage.…”

“…80 Human babies with CDH have been reported to have increased plasma levels of ET-1 and pulmonary levels of both ET-1 receptors. 77,[81][82][83][84] Moreover, lungs from babies who died with CDH have been reported to have ET-a receptors in very small capillaries (<25 μm), whereas these receptors are limited to small and large capillaries in control lungs. 77 Finally, babies with CDH had increased levels of ECE during fetal life, whereas in the lungs of control fetuses, ECE expression is low during fetal life and increases just before birth.…”

“…77,[81][82][83][84] Moreover, lungs from babies who died with CDH have been reported to have ET-a receptors in very small capillaries (<25 μm), whereas these receptors are limited to small and large capillaries in control lungs. 77 Finally, babies with CDH had increased levels of ECE during fetal life, whereas in the lungs of control fetuses, ECE expression is low during fetal life and increases just before birth. 77 Angiotensin-converting enzyme (ACE) is produced by the pulmonary vascular endothelium and converts angiotensin I into angiotensin II, a potent vasoconstrictor.…”

iNO Therapy in Patients with Congenital Diaphragmatic Hernia – Discrepancy between Widespread Use and Therapeutic Effects

“…The latter often does not seem to respond as well to medication as other types of PAH. Mous et al have shown that the reason for this, on one hand, are the changes in the vasoactive signaling path ways, which are typically influenced by commonly used drugs [22]. On the other hand, lung hypoplasia and vascular wall thickening might render patients partly unresponsive to exogenously applied NO and sildenafil.…”