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

Respiratory Research

Research

Daphne S. Mous¹  Dick Tibboel¹  Rene M. H. Wijnen¹  Marjon J. Buscop-van Kempen¹  Robbert J. Rottier² 

[1] Department of Pediatric Surgery, Erasmus Medical Center, Sophia Children’s Hospital, PO Box 2040, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands;Department of Pediatric Surgery, Erasmus Medical Center, Sophia Children’s Hospital, PO Box 2040, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands;Department of Cell Biology, Erasmus Medical Center, Rotterdam, The Netherlands;

关键词: Nitric oxide;    Endothelin;    Prostacyclin;    Development;    Lung;    Vasculature;    Vasodilation;   

DOI  :  10.1186/s12931-017-0670-2

 received in 2017-07-05, accepted in 2017-10-31,  发布年份 2017

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© The Author(s). 2017