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Chronic lung disease in preterm lambs: effect of daily vitamin A treatment on alveolarization
Kurt H Albertine1, Mar Janna Dahl, Linda W Gonzales
1Department of Pediatrics, University of Utah Health Sciences Center, Salt Lake City, Utah 84158, USA. kurt.albertine@hsc.utah.edu
Insights
Vitamin A supplementation improved lung development in preterm lambs undergoing mechanical ventilation (MV). It enhanced alveolar and capillary growth while modulating key molecular pathways, offering potential benefits for neonatal chronic lung disease.
Area of Science:
- Neonatal physiology
- Pulmonary medicine
- Developmental biology
Background:
- Neonatal chronic lung disease (CLD) involves impaired alveolar and capillary formation, often exacerbated by mechanical ventilation (MV) with oxygen.
- Vitamin A supplementation shows promise for improving respiratory outcomes in premature infants, but its specific lung structural and molecular effects during MV are not well understood.
Purpose of the Study:
- To investigate the effects of vitamin A supplementation on lung structural development and molecular changes in preterm lambs during prolonged MV.
- To test the hypothesis that vitamin A improves alveolarization, capillary growth, and modulates specific protein expressions related to elastin, cell proliferation, and vascular factors.
Main Methods:
- Preterm lambs (125 days gestation) were mechanically ventilated for 3 weeks.
- Four lambs received daily intramuscular vitamin A supplementation, while four received a vehicle control.
- Lung tissue analysis included morphometry, stereology, gene expression (RT-PCR), and protein analysis (immunoblot, immunohistochemistry).
Main Results:
- Vitamin A treatment significantly increased alveolar secondary septation and alveolar capillary growth.
- It decreased the thickness of mesenchymal tissue cores in distal air spaces.
- Molecularly, vitamin A reduced tropoelastin mRNA and matrix elastin deposition, but increased vascular endothelial growth factor (VEGF), VEGF receptor 2 (VEGF-R2), and midkine.
Conclusions:
- Vitamin A supplementation partially ameliorates lung developmental deficits in chronically ventilated preterm neonates.
- The benefits are linked to improved alveolarization, capillary growth, and modulation of elastin and vascular growth factor pathways.
Abstract:
Neonatal chronic lung disease is characterized by failed formation of alveoli and capillaries, and excessive deposition of matrix elastin, which are linked to lengthy mechanical ventilation (MV) with O(2)-rich gas. Vitamin A supplementation has improved respiratory outcome of premature infants, but there is little information about the structural and molecular manifestations in the lung that occur with vitamin A treatment. We hypothesized that vitamin A supplementation during prolonged MV, without confounding by antenatal steroid treatment, would improve alveolar secondary septation, decrease thickness of the mesenchymal tissue cores between distal air space walls, and increase alveolar capillary growth. We further hypothesized that these structural advancements would be associated with modulated expression of tropoelastin and deposition of matrix elastin, phosphorylated Smad2 (pSmad2), cleaved caspase 3, proliferating cell nuclear antigen (PCNA), VEGF, VEGF-R2, and midkine in the parenchyma of the immature lung. Eight preterm lambs (125 days' gestation, term approximately 150 days) were managed by MV for 3 wk: four were treated with daily intramuscular Aquasol A (vitamin A), 5,000 IU/kg, starting at birth; four received vehicle alone. Postmortem lung assays included quantitative RT-PCR and in situ hybridization, immunoblot and immunohistochemistry, and morphometry and stereology. Daily vitamin A supplementation increased alveolar secondary septation, decreased thickness of the mesenchymal tissue cores between the distal air space walls, and increased alveolar capillary growth. Associated molecular changes were less tropoelastin mRNA expression, matrix elastin deposition, pSmad2, and PCNA protein localization in the mesenchymal tissue core of the distal air space walls. On the other hand, mRNA expression and protein abundance of VEGF, VEGF-R2, midkine, and cleaved caspase 3 were increased. We conclude that vitamin A treatment partially improves lung development in chronically ventilated preterm neonates by modulating expression of tropoelastin, deposition of elastin, and expression of vascular growth factors.