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The pentose phosphate pathway mediates hyperoxia-induced lung vascular dysgenesis and alveolar simplification in neonates.
- Source :
-
JCI insight [JCI Insight] 2021 Mar 08; Vol. 6 (5). Date of Electronic Publication: 2021 Mar 08. - Publication Year :
- 2021
-
Abstract
- Dysmorphic pulmonary vascular growth and abnormal endothelial cell (EC) proliferation are paradoxically observed in premature infants with bronchopulmonary dysplasia (BPD), despite vascular pruning. The pentose phosphate pathway (PPP), a metabolic pathway parallel to glycolysis, generates NADPH as a reducing equivalent and ribose 5-phosphate for nucleotide synthesis. It is unknown whether hyperoxia, a known mediator of BPD in rodent models, alters glycolysis and the PPP in lung ECs. We hypothesized that hyperoxia increases glycolysis and the PPP, resulting in abnormal EC proliferation and dysmorphic angiogenesis in neonatal mice. To test this hypothesis, lung ECs and newborn mice were exposed to hyperoxia and allowed to recover in air. Hyperoxia increased glycolysis and the PPP. Increased PPP, but not glycolysis, caused hyperoxia-induced abnormal EC proliferation. Blocking the PPP reduced hyperoxia-induced glucose-derived deoxynucleotide synthesis in cultured ECs. In neonatal mice, hyperoxia-induced abnormal EC proliferation, dysmorphic angiogenesis, and alveolar simplification were augmented by nanoparticle-mediated endothelial overexpression of phosphogluconate dehydrogenase, the second enzyme in the PPP. These effects were attenuated by inhibitors of the PPP. Neonatal hyperoxia augments the PPP, causing abnormal lung EC proliferation, dysmorphic vascular development, and alveolar simplification. These observations provide mechanisms and potential metabolic targets to prevent BPD-associated vascular dysgenesis.
- Subjects :
- Animals
Animals, Newborn
Bronchopulmonary Dysplasia complications
Bronchopulmonary Dysplasia pathology
Cell Proliferation
Glycolysis
Humans
Hyperoxia
Infant, Newborn
Mice, Inbred C57BL
Neovascularization, Pathologic etiology
Oxygen administration & dosage
Phosphogluconate Dehydrogenase metabolism
Pulmonary Alveoli blood supply
Pulmonary Alveoli growth & development
Pulmonary Alveoli metabolism
Pulmonary Alveoli pathology
Mice
Bronchopulmonary Dysplasia metabolism
Endothelial Cells pathology
Lung blood supply
Lung growth & development
Lung metabolism
Lung pathology
Neovascularization, Pathologic metabolism
Oxygen adverse effects
Pentose Phosphate Pathway
Subjects
Details
- Language :
- English
- ISSN :
- 2379-3708
- Volume :
- 6
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- JCI insight
- Publication Type :
- Academic Journal
- Accession number :
- 33497360
- Full Text :
- https://doi.org/10.1172/jci.insight.137594