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O(2)-evoked regulation of HIF-1alpha and NF-kappaB in perinatal lung epithelium requires glutathione biosynthesis.
- Source :
-
American journal of physiology. Lung cellular and molecular physiology [Am J Physiol Lung Cell Mol Physiol] 2000 Mar; Vol. 278 (3), pp. L492-503. - Publication Year :
- 2000
-
Abstract
- To test the genetic capacity of the perinatal lung to respond to O(2) shifts that coincide with the first respiratory movements, rat fetal alveolar type II (fATII) epithelial cells were cultured at fetal distal lung PO(2) (23 Torr) and then exposed to postnatal (23 --> 76 Torr; mild hyperoxic shift), moderate (23 --> 152 Torr; moderate hyperoxic shift), or severe (23 --> 722 Torr; severe hyperoxic shift) oxygenation. Nuclear abundance and consensus binding characteristics of hypoxia-inducible factor (HIF)-1alpha and nuclear factor (NF)-kappaB (Rel A/p65) plus glutathione biosynthetic capacity were determined. Maximal HIF-1alpha activation at 23 Torr was sustained over the postnatal shift in (Delta) PO(2) and was elevated in vivo throughout late gestation. NF-kappaB was activated by the acute postnatal DeltaPO(2) in fATII cells, becoming maximal with moderate and severe oxygenation in vitro and within 6 h of birth in vivo, declining thereafter. fATII cell and whole lung glutathione and GSH-to-GSSG ratio increased fourfold with a postnatal DeltaPO(2) and were matched by threefold activity increases in gamma-glutamylcysteine synthetase and glutathione synthase. GSH concentration depletion by L-buthionine-(S, R)-sulfoximine abrogated both HIF-1alpha and NF-kappaB activation, with HIF-1alpha showing a heightened sensitivity to GSH concentration. We conclude that O(2)-linked genetic regulation in perinatal lung epithelium is responsive to developmental changes in glutathione biosynthetic capacity.
- Subjects :
- Animals
Antimetabolites pharmacology
Buthionine Sulfoximine pharmacology
Cells, Cultured
Consensus Sequence
DNA metabolism
DNA-Binding Proteins genetics
Epithelial Cells drug effects
Epithelial Cells metabolism
Glutathione antagonists & inhibitors
Glutathione metabolism
Homeostasis physiology
Hypoxia-Inducible Factor 1
Hypoxia-Inducible Factor 1, alpha Subunit
Lung cytology
Lung drug effects
NF-kappa B genetics
Nuclear Proteins genetics
Oxidation-Reduction
Oxidative Stress
Rats
Rats, Sprague-Dawley
Animals, Newborn metabolism
DNA-Binding Proteins metabolism
Fetus metabolism
Glutathione biosynthesis
Lung metabolism
NF-kappa B metabolism
Nuclear Proteins metabolism
Oxygen pharmacology
Transcription Factors
Subjects
Details
- Language :
- English
- ISSN :
- 1040-0605
- Volume :
- 278
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Lung cellular and molecular physiology
- Publication Type :
- Academic Journal
- Accession number :
- 10710521
- Full Text :
- https://doi.org/10.1152/ajplung.2000.278.3.L492