Multi-organ protection from hyperoxia of the severely premature infant

Cleveland Clinic Lerner Com-Cwru, Cleveland OH

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Abstract

Abstract The broad, long-term objective of this proposal is to develop a safe method of protecting retinal blood vessels from oxygen induced toxicity that accompanies premature birth. Oxygen therapy is necessary to prevent mortality in these infants but is harmful to premature retinal tissue. Oxygen toxicity to the premature retina, known as retinopathy of prematurity (ROP), blinds 150,000- 200,000 children worldwide annually. Quantitative analysis of retinal and lung vasculature in mouse and rat models of human ROP demonstrate that preservation of hypoxia inducible factor (HIF) activity through HIF prolyl hydroxylase domain protein (PHD) inhibition (HIF PHi) safely prevents oxygen-induced lung disease, hypomyelination of the central nervous system, and retinopathy (OIR). We have definitively demonstrated that our systemic strategy of PHD inhibition requires liver specific HIF-1α activation. Our studies have demonstrated that the fetal liver uses HIF induced 1C metabolism (1CM) to protect distal capillary beds from oxygen induced growth suppression. These findings make liver specific HIF PHi a unified approach to preventing ROP by biochemically addressing both hyperoxia of prematurity (by stabilizing HIF in hyperoxia) and separation from the maternal circulation (by stimulating the liver to upregulate protective metabolic pathways). The specific goal of this application is to enable the premature infant to benefit from oxygen supplementation (reducing mortality) by creating a liver specific small molecule to stimulate the oxygen sensor in the severely premature infant to protect it from excess oxygen. Results from these studies will create a therapy to protect severely premature infants and eradicate retinopathy of prematurity while developing a strategy that might revascularize ischemic tissues.