Lymphocyte-Specific Biomarkers Associated With Preterm Birth and Bronchopulmonary Dysplasia

Abstract

Many premature babies who are born with neonatal respiratory distress syndrome (RDS) go on to develop Bronchopulmonary Dysplasia (BPD) and later Post-Prematurity Respiratory Disease (PRD) at one year corrected age, characterized by persistent or recurrent lower respiratory tract symptoms frequently related to inflammation and viral infection. Transcriptomic profiles were generated from sorted peripheral blood CD8+ T cells of preterm and full-term infants enrolled with consent in the NHLBI Prematurity and Respiratory Outcomes Program (PROP) at the University of Rochester and the University at Buffalo. We identified outcome-related gene expression patterns following standard methods to identify markers for oxygen utilization and BPD as outcomes in extremely premature infants. We further identified predictor gene sets for BPD based on transcriptomic data adjusted for gestational age at birth (GAB). RNA-Seq analysis was completed for CD8+ T cells from 145 subjects. Among the subjects with highest risk for BPD (born at <29 weeks gestational age (GA); n=72), 501 genes were associated with oxygen utilization. In the same set of subjects, 571 genes were differentially expressed in subjects with a diagnosis of BPD and 105 genes were different in BPD subjects as defined by physiologic challenge. A set of 92 genes could predict BPD with a moderately high degree of accuracy. We consistently observed dysregulation of TGFB, NRF2, HIPPO, and CD40-associated pathways in BPD. Using gene expression data from both premature and full-term subjects (n=116), we identified a 28 gene set that predicted the PRD status with a moderately high level of accuracy, which also were involved in TGFB signaling. Transcriptomic data from sort-purified peripheral blood CD8+ T cells from 145 preterm and full-term infants identified sets of molecular markers of inflammation associated with independent development of BPD in extremely premature infants at high risk for the disease and of PRD among the preterm and full-term subjects.

CD8A is a Promising Biomarker Associated with Immunocytes Infiltration in Hyperoxia-Induced Bronchopulmonary Dysplasia

“…10 A recent study has further identified a set of differentially expressed genes and the dysregulated pathways associated with T cell activation in BPD subjects. 11 In recent years, bioinformatics approaches have been attempted to unveil the underlying pathways involved in BPD development. Angiogenesis and inflammation were considered as important biological changes that contributed to the BPD development, and the expression of interleukin 6 mRNA was observed pronouncedly increased in early BPD.…”

Tracheal Aspirate miRNA Signatures in Preterm Infants with Severe Bronchopulmonary Dysplasia

“…Therefore, it is possible that lower expression of this miRNA in severe BPD infants is associated with fibrotic phenotypes in severe BPD. It is worthwhile to mention that the Hippo pathway is a powerful regulator of lung development, cell differentiation, and tissue regeneration and homeostasis, and has been found dysregulated in lymphocytes of patients with BPD [61,62]. Therefore, the role of miR-15a and the Hippo pathway in mechanisms leading to BPD severity warrants further investigation.…”

Meta-analysis of gestational duration and spontaneous preterm birth identifies new maternal risk loci

“…The novel meta-analysis loci associated with gestational duration, such as variants in GNAQ and KCNN2 , comprised further intriguing candidates. GNAQ (protein subunit alpha q) plays a role in survival of immune cells and was identified as part of a transcriptomic signature related to human labor in the choriodecidua 28,29 . KCNN2 (potassium calcium-activated channel subfamily N member 2) has no obvious connection to pregnancy-related regulation, but KCNN3 , another molecule in the KCNN family of potassium channel genes, plays a role in uterine function 30 .…”