Pulmonary Vascular Defects in Congenital Diaphragmatic Hernia : the quest for early factors and intervention

Congenital diaphragmatic hernia (CDH) is a severe anomaly characterized by a diaphragmatic defect, lung hypoplasia and pulmonary hypertension. The associated pulmonary abnormalities are responsible for the high morbidity and mortality among patients with this disease. Vasodilator therapy often has no effect and little is known about the possibly aberrant expressions of the targeted factors of current drugs.
In this thesis we analyzed the expression of important factors in the pulmonary vasculature of CDH patients. In human CDH lungs, we found upregulation of the endothelin A and B receptors and of the endothelin converting enzyme. The latter is a key molecule in the endothelin pathway, by converting endothelin-1 (ET-1) into its active form. Expression of the prostacyclin receptor in human control lungs gradually increased over time, but was decreased in CDH lungs in the fetal, preterm and term phases. The aberrant expressions of the above-mentioned factors could explain why treatment of pulmonary hypertension in patients with CDH fails. Furthermore, we initiated antenatal treatment with sildenafil and selexipag in the nitrofen rat model. We found that the decreased saccular airspaces had enlarged after treatment with sildenafil, and that the pulmonary vessel wall was less muscularized. Treatment with NS-304 alone was followed by improvement in the aberrant cardiac and pulmonary vascularity. Combination therapy of sildenafil and NS-304 did not have added value to each of these compounds separately.
In conclusion, our work shows important alterations already early during development in all three major vasoactive pathways in both human CDH and the well-established nitrofen rat model. Furthermore, it shows the feasibility of antenatal treatment of pulmonary vascular defects in this disease with two different vasodilators acting on the NO and PGI2 pathway. These results indicate the importance of a precision medicine approach, potentially even already starting antenatally.