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Pulmonary immune cell transcriptome changes in double-hit model of BPD induced by chorioamnionitis and postnatal
Diksha Shrestha1,2,3, George Xiangyun Ye2,3, Deborah Stabley2
1Department of Pediatrics, Nemours AI duPont Hospital for Children, Wilmington, DE, USA.
Insights
Infants with bronchopulmonary dysplasia (BPD) experience long-term respiratory issues due to altered lung immune cell function. This study reveals lasting T cell receptor signaling pathway dysregulation, offering potential therapeutic targets for improved respiratory health.
Area of Science:
- Immunology
- Pulmonology
- Developmental Biology
Background:
- Bronchopulmonary dysplasia (BPD) in preterm infants leads to lifelong respiratory morbidities.
- Mechanisms linking BPD to increased pathogen susceptibility are poorly understood.
- Perinatal events' impact on lung-specific immune cells in BPD is unclear.
Purpose of the Study:
- Investigate the effects of a double-hit model of BPD on resident pulmonary immune cells.
- Identify transcriptomic changes in lung immune cells following perinatal insults.
- Determine long-term consequences of BPD-associated inflammation on immune cell function.
Main Methods:
- Utilized a double-hit model of BPD (prenatal chorioamnionitis + postnatal hyperoxia).
- Performed global transcriptome analysis on all resident pulmonary immune cells.
- Assessed gene expression and immune cell populations at multiple time points.
Main Results:
- Significant upregulation of genes in chemokine signaling and chemotaxis.
- Downregulation of genes involved in T lymphocyte and T cell receptor signaling.
- Reduced proportion of CD8a+CD3+ pulmonary immune cells, persisting long-term.
Conclusions:
- Perinatal inflammation in BPD causes short- and long-term dysregulation of T cell receptor signaling.
- This dysregulation may contribute to increased respiratory morbidities in BPD patients.
- Identified novel therapeutic targets for modulating pulmonary immune cells in BPD.
Background:
Preterm infants with bronchopulmonary dysplasia (BPD) have lifelong increased risk of respiratory morbidities associated with environmental pathogen exposure and underlying mechanisms are poorly understood. The resident immune cells of the lung play vital roles in host defense. However, the effect of perinatal events associated with BPD on pulmonary-specific immune cells is not well understood.
Methods:
We used a double-hit model of BPD induced by prenatal chorioamnionitis followed by postnatal hyperoxia, and performed a global transcriptome analysis of all resident pulmonary immune cells.
Results:
We show significant up-regulation of genes involved in chemokine-mediated signaling and immune cell chemotaxis, and down-regulation of genes involved in multiple T lymphocyte functions. Multiple genes involved in T cell receptor signaling are downregulated and Cd8a gene expression remains downregulated at 2 months of age in spite of recovery in normoxia for 6 weeks. Furthermore, the proportion of CD8a+CD3+ pulmonary immune cells is decreased.
Conclusions:
Our study has highlighted that perinatal lung inflammation in a double-hit model of BPD results in short- and long-term dysregulation of genes associated with the pulmonary T cell receptor signaling pathway, which may contribute to increased environmental pathogen-associated respiratory morbidities seen in children and adults with BPD.
Impact:
In a translationally relevant double-hit model of BPD induced by chorioamnionitis and postnatal hyperoxia, we identified pulmonary immune cell-specific transcriptomic changes and showed that T cell receptor signaling genes are downregulated in short term and long term. This is the first comprehensive report delineating transcriptomic changes in resident immune cells of the lung in a translationally relevant double-hit model of BPD. Our study identifies novel resident pulmonary immune cell-specific targets for potential therapeutic modulation to improve short- and long-term respiratory health of preterm infants with BPD.
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