Our research focus is to identify and test novel mechanisms that disrupt vascular cGMP signaling in order to develop new therapies that protect pulmonary development in the injured newborn lung. Pediatric pulmonary vascular disease (PVD) causes important disabilities and death in newborns and infants with lung injury. Although available therapies can relieve the pulmonary hypertension observed in patients that have acquired this disease, there is no treatment that prevents PVD. Currently, no effective therapy directly addresses the pulmonary artery smooth muscle cell (PASMC) hyperplasia and lung fibroblast activation that are the root cause of PVD and distinguish it from adult pulmonary hypertension. Molecules that increase cGMP signaling by stimulating soluble guanylate cyclase (sGC), or by decreasing cGMP degradation, inhibit PVD-like changes in cultured PASMC and fibroblasts. However, they exhibit limited efficacy in preventing PVD in newborns with lung injury. It is suspected that the decreased sGC expression observed in most newborn lung injury models greatly limits the therapeutic promise of these agents. Surprisingly, very little is known about the mechanisms that down-regulate sGC expression in the injured newborn lung and it is unknown whether protection of sGC expression will enhance the salutary activities of sGC agonists. Using a mouse pup model of PVD, active TGF--targeting antibodies, and our recently developed method to isolate peripheral lung mouse pup vascular cells, we determined that TGF- down-regulates sGC expression in the injured lung and PASMC, causes PASMC dedifferentiation, and decreases pulmonary microvascular development and alveolarization. Moreover, using sGCa1 knock out mouse pups and our new techniques to quantify peripheral lung fibroblast myogenic activation and alveolarization, we recently determined that decreased sGC activity in itself causes PVD, stimulates lung myofibroblast conversion, and inhibits alveolarization in the setting of very mild lung injury. Based on these results, we speculate that TGF-- and sGC-signaling crosstalk disrupts pulmonary development in the injured newborn lung and therefore presents a new therapeutic target to prevent PVD. The central hypothesis of this project is that inhibiting TGF--regulated sGC down-regulation in the injured newborn lung will promote cGMP-stimulated PASMC and lung fibroblast differentiation, and improve pulmonary development.
In Aim 1, we propose to identify for the first time the intracellular pathways through which TGF- down-regulates sGC expression in mouse pup PASMC to identify new therapeutic targets.
In Aim 2, we will test how down-regulated sGC expression controls TGF--mediated mouse pup PASMC and lung fibroblast phenotype switching indicative of PVD.
In Aim 3, we will determine how rescuing sGC expression through TGF- inhibition potentiates the protective activity of sGC agonists in preventing PVD. Successful completion of this project will identify new mechanisms that down-regulate sGC signaling and promote rapid development of sGC-rescue therapies that improve pulmonary maturation during lung injury and prevent PVD.
Pediatric pulmonary vascular disease is a major complication of newborn lung injury that causes abnormal pulmonary development, heart failure, difficult breathing, syncope, and death. We have new experimental evidence that a negative interaction between two key signaling systems in the injured newborn lung - transforming growth factor and cGMP - might play an important role in the evolution of this disease. Our proposed studies will determine for the first time the functional importance of this negative signaling system interaction and test, in model systems, whether a new therapeutic approach that targets the abnormal signaling will help protect pulmonary development in the injured newborn lung and prevent pediatric pulmonary vascular disease.
| Zhang, Huili; Du, Lili; Zhong, Ying et al. (2017) Transforming growth factor-? stimulates Smad1/5 signaling in pulmonary artery smooth muscle cells and fibroblasts of the newborn mouse through ALK1. Am J Physiol Lung Cell Mol Physiol 313:L615-L627 |
| Funke, Manuela; Knudsen, Lars; Lagares, David et al. (2016) Lysophosphatidic Acid Signaling through the Lysophosphatidic Acid-1 Receptor Is Required for Alveolarization. Am J Respir Cell Mol Biol 55:105-16 |
