Elevated Matrix Enzyme Activity Is Associated with the Progression of Pulmonary Vascular Disease In the Nitrofen Model of Congenital Diaphragmatic Hernia

Pulmonary vascular disease (PVD) and lung hypoplasia (LH) are the two main causes of mortality and morbidity in patients with congenital diaphragmatic hernia (CDH). Previous studies have shown that remodeling of the extracellular matrix (ECM) by elastase and matrix metalloproteinase (MMP) enzymes, concomitant with smooth muscle cell (SMC) proliferation and deposition of ECM proteins and growth factors, leads to primary pulmonary hypertension (PH) and that blockade of this pathway results in disease reversal. The aim of our study is to determine whether a similar pathway is induced in the PVD associated with CDH and to verify whether its inhibition will lead to reversal of PVD. Firstly, we confirmed various aspects of PVD in the nitrofen induced CDH rat model. These included: left lung hypoplasia, right ventricular hypertrophy, and increased arterial smooth muscle wall thickness alongside decreases in arterial lumen area and total number of distal pulmonary vessels. We also showed increases in elastase and matrix metalloproteinase (MMP) enzyme activities within distal pulmonary arteries (PAs), which, we were able to inhibit using serine elastase (sivelestat, elafin, and serpina1) and MMP (GM6001) inhibitors. Furthermore, we confirmed increased SMC proliferation and deposition of osteopontin (OPN) and epidermal growth factor (EGF) within the diseased vasculatures. We are now working on using sivelestat and GM6001 pharmaceuticals as well as endothelial progenitor cells (EPCs) and mesenchymal stem cells (MSCs) modified to express elafin and serpina1 to determine their abilities to reverse the PVD associated with CDH. This project is part of our translational research program with the ultimate goal of developing a novel strategy of targeting PVD in infants with CDH to improve patient survival and long-term outcome