Hyperoxic Exposure Caused Lung Lipid Compositional Changes in Neonatal Mice

Abstract

Treatments with supplemental oxygen in premature infants can impair lung development, leading to bronchopulmonary dysplasia (BPD). Although a stage-specific alteration of lung lipidome occurs during postnatal lung development, whether neonatal hyperoxia, a known mediator of BPD in rodent models, changes lipid profiles in mouse lungs is still to be elucidated. To answer this question, newborn mice were exposed to hyperoxia for 3 days and allowed to recover in normoxia until postnatal day (pnd) 7 and pnd14, time-points spanning the peak stage of alveologenesis. A total of 2263 lung lipid species were detected by liquid chromatography–mass spectrometry, covering 5 lipid categories and 18 lipid subclasses. The most commonly identified lipid species were glycerophospholipids, followed by sphingolipids and glycerolipids. In normoxic conditions, certain glycerophospholipid and glycerolipid species augmented at pnd14 compared to pnd7. At pnd7, hyperoxia generally increased glycerophospholipid, sphingolipid, and glycerolipid species. Hyperoxia increased NADPH, acetyl CoA, and citrate acid but reduced carnitine and acyl carnitine. Hyperoxia increased oxidized glutathione but reduced catalase. These changes were not apparent at pnd14. Hyperoxia reduced docosahexaenoic acid and arachidonic acid at pnd14 but not at pnd7. Altogether, the lung lipidome changes throughout alveolarization. Neonatal hyperoxia alters the lung lipidome, which may contribute to alveolar simplification and dysregulated vascular development.

Metabolic dysregulation in bronchopulmonary dysplasia: Implications for identification of biomarkers and therapeutic approaches

“…This is validated in neonatal animals where hyperoxia for 4 weeks augmented sphingomyelin species (SM16:0, SM18:0, SM24:0 and SM24:1), long-chain and very long-chain ceramides in bronchoalveolar lavage fluid [ 61 ]. This is also in agreement with our findings that sphingolipids were generally increased in early alveolarization in mice exposed to hyperoxia [ 41 ]. In addition, hyperoxia increased the de novo synthesis of ceramides in lung endothelial cells, leading apoptosis [ 49 ].…”

“…In newborn mice, a high content of monounsaturated lipid species was seen in the lungs, myristic and palmitic acids were observed at 2 weeks of age, while adult lungs were enriched with polyunsaturated lipid species [ 56 ]. This is corroborated by our findings that glycerophospholipid and glycerolipid species were augmented at postnatal day 14 compared to postnatal day 7, under normoxic conditions [ 41 ]. Glycerophospholipids may be used for pulmonary surfactant synthesis in proliferating type II cells during the expansion of the lung interstitium [ 57 ].…”

“…Thus, endothelial cell function changes during the air recovery phase after hyperoxic exposure. Hyperoxia followed by air recovery also increased NADPH along with acetyl CoA, and citric acid in mouse lungs [ 41 ]. Increased PPP provides nucleotide synthesis and NADPH for fatty acid synthesis during proliferation in lung endothelial cells.…”

“…Decreased postnatal docosahexaenoic acid and arachidonic acid levels were associated with an increased risk for BPD in premature infants [ 65 ]. Similarly, neonatal hyperoxia also reduced docosahexaenoic acid and arachidonic acid in mouse lungs [ 41 ]. Docosahexaenoic acid is an omega-3 fatty acid, which suppressed apoptosis in the lungs of mice perinatally exposed to lipopolysaccharide/hyperoxia [ 66 ].…”

Single-cell transcriptomics reveals lasting changes in the lung cellular landscape into adulthood after neonatal hyperoxic exposure

“…AT2 cells are progenitors to ATI cells and also produce surfactant proteins and lipids that reduce surface tension in the alveoli, preventing alveolar collapse (atelectasis) [ 13 ]. Although previous studies using genomic, proteomic, and metabolomic analyses from whole lung tissue have furthered our understanding of the mechanisms underlying lung development, these provide limited spatial insights into the complex multicellular environment in development and with injury and repair [ [14] , [15] , [16] , [17] , [18] , [19] ]. Single-cell RNA sequencing (scRNA-seq) allows for quantitative and unbiased characterization of cellular heterogeneity by providing genome-wide molecular profiles at the individual cell level.…”