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Prenatal inflammation primes pulmonary immune cells to postnatal hyperoxia induced lung injury

ABSTRACT: Bronchopulmonary dysplasia (BPD) arises from a combination of prenatal and postnatal environmental factors, but the impact of prenatal inflammation on subsequent postnatal lung injury remains unclear. We aimed to investigate how prenatal lipopolysaccharide (LPS)-induced chorioamnionitis alters the composition of resident pulmonary immune cells and modifies the response to hyperoxia-induced lung injury in neonatal rats. Pregnant Sprague-Dawley rats received intra-amniotic injections of LPS or normal saline (NS) at embryonic day 20. Pups were euthanized on postnatal day 1 (P1) or exposed to 85% oxygen (O₂) or room air (RA) for 14 days and euthanized on postnatal day 14 (P14) for analysis. Resident pulmonary immune cells were quantified by flow cytometry. Mann–Whitney and ANOVA tests were used for group comparisons (p<0.05). mRNA from pulmonary immune cells collected on P1 was subjected to RNA sequencing and differential gene expression analysis. On P1, prenatal LPS exposure did not change the overall percentage of CD45⁺ pulmonary immune cells but decreased the percentages of CD3⁺CD4⁺ T cells, CD3⁺CD8⁺ T cells, and CD45R⁺ B cells compared with the NS+RA group. In contrast, CD161⁺ NK cells and CD43⁺ monocytes were significantly increased. Upregulated genes were enriched in inflammatory biological processes. By P14, cell composition in the LPS+RA group normalized. However, a second insult with postnatal hyperoxia resulted in an increased proportion of CD161⁺ NK cells in the LPS+O₂ group only and an increased proportion of CD43⁺ monocytes in the NS+O₂ group only, with a relative reduction in monocytes in the LPS+O₂ group at P14. In this rat model of BPD, LPS-mediated in-utero inflammation primes neonatal lung immune cells for a dysregulated response to postnatal hyperoxia. Dual prenatal and postnatal injuries result in persistent elevation of NK cells and reduction of monocytes, while other immune subsets respond differentially, suggesting that prenatal events condition the neonatal lung immune system in ways that may influence BPD pathogenesis.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE338797 | GEO | 2026/07/21

REPOSITORIES: GEO

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Project description:Background: Nrf2 is an essential cytoprotective transcription factor. However, association of Nrf2 in organ development and neonatal disease is rarely examined. Hyperoxia exposure to newborn rodents generates pulmonary phenotypes which resemble bronchopulmonary dysplasia (BPD) of prematurity. Methods: To investigate the role of Nrf2 in lung maturation and BPD pathogenesis, Nrf2-deficient (Nrf2-/-) and wild-type (Nrf2+/+) neonates were exposed to air or hyperoxia (O2). Transcriptome analysis determined Nrf2-directed mechanisms in premature lung. Lung injury was assessed by bronchoalveolar lavage analysis and histopathology. Results: In Nrf2-/- neonates, basal expression of cell cycle machinery, redox balance, and lipid/carbohydrate metabolism genes were suppressed while immunity genes were overexpressed compared to Nrf2+/+ pups. O2-induced mortality and pulmonary inflammation/injury were significantly higher in Nrf2-/- than in Nrf2+/+. Lung DNA lesion and oxidation were greater in Nrf2-/- than in Nrf2+/+, constitutively and after O2. Nrf2-dependent genes modulated cellular growth/proliferation, defense, immunity, and lipid metabolism against hyperoxia. Bioinformatic elucidation of Nrf2 binding motifs and augmented O2-induced inflammation in genetically deficient neonates validated Gpx2 and Marco as Nrf2 effectors. Conclusion: Overall, Nrf2 in underdeveloped lungs orchestrated cell cycle, morphogenesis, and immunity as well as cellular defense constitutively and under oxidant stress. Results provide putative molecular mechanisms of Nrf2-directed lung alveolarization and BPD of prematurity. PARALLEL study design with 42 samples comparing 14 groups of age (P1 to P4 corresponding to day 0 to day 3 animals), gene, and exposure: (4 groups Nrf+/+ wild type P1-P4 air exposure) (4 groups Nrf -/- knockout P1-P4 air exposure), (3 groups Nrf+/+ wild type P2-P4 with 100 percent O2 (hyperoxia exposure) and 3 groupsNrf -/- knockout P2-P4 with 100 percent O2 (hyperoxia exposure)) Biological replicates: 3 per group

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Prenatal inflammation primes pulmonary immune cells to postnatal hyperoxia induced lung injury

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