Redox regulation of lung development and perinatal lung epithelial function.
Throughout gestation, low oxygen tensions are a dominant feature of the fetal environment and so may be important in sustaining a normal pattern of lung morphogenesis until the moment of birth. As breathing begins, the equilibration of the lung lumen to postnatal PO2 evokes a series of physiologic and morphogenic maturation events that are partially reversible by hypoxia. In this review, we discuss the experimental evidence that fetal and perinatal oxygen tensions differently influence lung morphogenesis through oxygen- and redox-responsive signaling pathways and identify five loci at which this regulation may occur: (I) proliferation of undifferentiated lung mesenchyme as governed by hypoxia-regulated transcription factors (HIF-1alpha, C/EBPbeta); (II) transient production of reactive oxygen species (ROS) and nuclear oxidation of the perinatal lung epithelium; (III) nuclear transport and oxidation of thioredoxin in hand with the acute activation of nuclear factor- kappaB (NF-kappaB); (IV) ROS-evoked chronic rise in intracellular glutathione and thioredoxin redox buffering capacity; and (V) NF-kappaB-dependent increase in transepithelial Na+ transport and lung lumenal fluid clearance. Although not exhaustive, this analysis leads us to the conclusion that redox events that occur in the lung during gestation, parturition, and the early neonatal period may dramatically influence the expression of genes and physiological events that are crucial to the successful transition from fetal to postnatal lung maturation.
Land
Stephen C
SC
Maternal and Child Health Sciences, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, UK. s.c.land@dundee.ac.uk
Wilson
Stuart M
SM
D000818:Animals; D001692:Biological Transport; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000166:cytology*; D005786:Gene Expression Regulation; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D000860:Hypoxia; D007150:Immunohistochemistry; D008070:Lipopolysaccharides / Q000378:metabolism; D008168:Lung / Q000196:embryology / Q000254:growth & development* / Q000378:metabolism / Q000502:physiology*; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D010920:Placenta / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species; D012143:Respiratory Physiological Phenomena; D012964:Sodium / Q000378:metabolism; D013879:Thioredoxins / Q000378:metabolism
D008070:Lipopolysaccharides; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D013879:Thioredoxins; D012964:Sodium; D005978:Glutathione; D010100:Oxygen