Pulmonary hypertension (PHN) in respiratory distress syndrome (RDS) evolving to bronchopulmonarydysplasia (BPD) results acutely from poor lung inflation and increased blood flow through the patent ductusarteriosus, and chronically from altered reactivity, vascular remodeling, and hypoplasia of the pulmonaryvascular bed. The lung develops in relative hypoxia compared to 21% 02 seen at normal term delivery and,especially, to hyperoxia that preterm neonates commonly face. Hypoxia-inducible factors (HIFs) could lowerpulmonary artery pressures by modulating surfactant, ductus arteriosus, and pulmonary vasculardevelopment. Preliminary data show that HIFs can impact lung expansion at birth, expression ofsurfactant proteins and lipids, patency of the ductus arteriosus, and angiogenic factors andprocesses in developing lungs - all of which canmodify pulmonary hypertension. Further data showthat HIFs are highly expressed and stable in third trimester fetal primate lungs, while one of them, HIF-1a,declines dramatically after preterm birth. Using cofactors 02, Fe2+, oxoglutarate, and ascorbate, HIF prolyl-hydroxylases (PHDs) specifically regulate HIFstability. We reported that PHDinhibitors (PHDi)profoundly alter stability of HIFs and downstream gene expression (VEGF and its receptors) in lungendothelial and epithelial cells, and fetal lung explants, even in extreme hyperoxia. We hypothesize thatPHDi can decrease PHNby restoring the fetal VEGF/eNOS axis and improving perinatal surfactanthomeostasis. We propose to examine effects of PHDi delivered antenatally or postnatally, and by differingroutes, in ovine models of RDS and persistent PHN in preterm and term ovine models, respectively.Chronically instrumented fetal/neonatal lambs will have pre- and/or postnatal hemodynamic, blood gas, andrespiratory physiology measurements. In lung tissue from these animals, we will measure HIFs, HIF-dependent gene products, surfactant proteins and lipids, inflammatory cytokines and cells, and lungmorphometry to assess vascular development and remodeling. Results will provide valuable informationabout pathophysiologic roles of HIFs in perinatal PHN and potential therapeutic uses of PHDi in RDS andPHN.
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