The pentose phosphate pathway mediates hyperoxia-induced lung vascular dysgenesis and alveolar simplification in neonates
Jiannan Gong, Zihang Feng, Abigail L. Peterson, Jennifer F. Carr, Xuexin Lu, Haifeng Zhao, Xiangming Ji, You-Yang Zhao, Monique E. De Paepe, Phyllis A. Dennery, Hongwei Yao
Jiannan Gong, Zihang Feng, Abigail L. Peterson, Jennifer F. Carr, Xuexin Lu, Haifeng Zhao, Xiangming Ji, You-Yang Zhao, Monique E. De Paepe, Phyllis A. Dennery, Hongwei Yao
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Research Article Pulmonology

The pentose phosphate pathway mediates hyperoxia-induced lung vascular dysgenesis and alveolar simplification in neonates

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.

Authors

Jiannan Gong, Zihang Feng, Abigail L. Peterson, Jennifer F. Carr, Xuexin Lu, Haifeng Zhao, Xiangming Ji, You-Yang Zhao, Monique E. De Paepe, Phyllis A. Dennery, Hongwei Yao

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Figure 7

Endothelial pgd overexpression augments, whereas blocking the PPP attenuates, alveolar simplification in neonatal mice exposed to hyperoxia.

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Endothelial pgd overexpression augments, whereas blocking the PPP attenu...
C57BL/6J neonatal mice (<12 hours old) were exposed to air or hyperoxia (95% O2) for 3 days and were then allowed for recover in room air until P14. At P9, mixtures of nanoparticles and plasmid DNA expressing pgd or empty vector under the control of human CDH5 promoter were administered into mice via a retro-orbital injection. 6-AN (5 and 10 mg/kg, i.p.) or DHEA (10 and 20 mg/kg, i.p.) were administered daily in mice from P9 to P13. (A) H&E staining was performed to assess lung morphology in mouse lungs. Pgd OE, pgd overexpression. Scale bar: 100 μm. (B) Mean linear intercept (Lm) and radical alveolar count (RAC) were calculated in mouse lungs. n = 6 per group. (C) Body weight was calculated after 6-AN or DHEA administration in neonatal mice exposed to hyperoxia. n = 6 per group. (D) Schematic showing that hyperoxic exposure increased the PPP and glycolysis in lung ECs. Hyperoxia-induced increase in the PPP results in abnormal EC proliferation and subsequent dysmorphic vascular development and alveolar simplification in neonates. Data are expressed as mean ± SEM. **P < 0.01, ***P < 0.001 versus air/vector or air; †P < 0.05, ††P < 0.01 versus hyperoxia/vector or hyperoxia/vehicle using ANOVA followed by Tukey-Kramer test (A–C).