Hypoxia-inducible factor (HIF) and HIF-stabilizing agents in neonatal care

Oxygen is essential for multicellular existence. Its reduction to water by the mitochondrial electron transport chain forms the cornerstone of aerobic metabolism. Conditions in which oxygen is limiting for electron transport result in bioenergetic collapse in metazoans. However, compared with postnatal existence, all of mammalian development occurs in a hypoxic environment in utero. Not just an epiphenomenon, this ‘physiological hypoxia’ is required for the activation of a transcriptional response mediated by the hypoxia-inducible factor (HIF) family of transcriptional regulators that coordinates the expression of hundreds of genes, many with developmentally critical functions. Oxygen tension, therefore, is a morphogen. Understanding the physiological significance of hypoxia responses during human development and the role of the HIF family of transcriptional regulators will have important consequences for the care of preterm neonates. Defining clinical care guidelines for the proper oxygenation of critically ill neonates that take account of these observations is therefore of paramount importance. The pharmacological stabilization of HIF family members may therefore have clinical utility in premature infants in whom this important morphogen has been inactivated by exposure to supraphysiological oxygen levels.