Project description:BackgroundPreterm 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.MethodsWe 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.ResultsWe 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.ConclusionsOur 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.ImpactIn 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.

Project description:Bronchopulmonary dysplasia (BPD) is the major cause of chronic lung disease (CLD) and morbidity in preterm infants, which characterized by impaired pulmonary alveolar development in preterm infants. There is increasing evidence that micro RNA (miRNA) has a close association with the development of pulmonary diseasesincluding lung growth, pulmonary fibrosis, pneumonia, etc. The potential role of miRNA in the pathogenesis of BPD is unclear. This study aims to clarify the role of adrenomedullin (ADM) regulated by miRNA-547-3p during the process of BPD and illustrate the protective effect of ADM involved in preterm infants.We indentified the differential expressed miRNA and their potential target genes, microarray analysis using Agilent Human 4x44K Gene Expression Microarrays v2 and miRCURY LNA™ microRNA Array was performed. The results of miRNA chip were scanned by Axon GenePix 4000B and the signal of probes were read by GenePix Pro 6.0 software. Only the target genes which exist in both two databases and having different expression trend were remained. Thus, miRNA-574-3p and it’s target gene ADM were selected to do the further research in our study. And we verified miRNA-574-3p and ADM expression in BPD premature infants by realtime q-PCR. After the microarray expression analysis, there were 516 probes differential expressed between BPD samples and normal samples. Among them, 510 were up-regulated and 213 were down-regulated. Meanwhile, to the miRNA aspect, there were 37 up-regulated and 44 down-regulated. After text mining, we found ADM was already found play a role in BPD. ADM is an endogenous peptide with potent angiogenic, anti-oxidant, and anti-inflammatory properties. Realtime q-PCR assay results showed that, miRNA-574-3p expression level in blood samples from preterm infants with BPD was significantly decreased, ADM expression level in blood samples from preterm infants with BPD was significantly increased. In our study, we found that up-regulation of ADM regulated by miRNA-574-3p could protect preterm infants with BPD. These data provide novel insights into ADM regulated by miRNA-574-3p which may be shed light on BPD prevention and treatment.

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Pulmonary immune cell transcriptome changes in double-hit model of BPD induced by chorioamnionitis and postnatal hyperoxia

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