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A Murine Model of Fetal Exposure to Maternal Inflammation to Study the Effects of Acute Chorioamnionitis on Newborn Intestinal Development
Published on: June 24, 2020
Sequential exposure to histological chorioamnionitis and postnatal hyperoxia alters gene expression in cord blood
Rochelle Sequeira Gomes1, Suhita Gayen Nee' Betal1, Sankar Addya2
1Division of Neonatology, Nemours Children's Health at Thomas Jefferson University, Philadelphia, PA, United States.
Background:
Sequential exposure to heterologous noxious stimuli such as histological chorioamnionitis (HCA) and hyperoxia may elicit variable immune responses, resulting in distinct disease manifestations in the neonate. However, the molecular mechanisms underlying innate immune dysregulation in these contexts remain poorly characterized.
Methods:
We conducted a pilot prospective observational study evaluating global gene expression in cord blood monocytes obtained from term infants born to mothers with and without HCA. Monocytes were exposed in vitro to hyperoxia (95% FiO2) or normoxia (21% FiO2) for 18-20 h. Transcriptome profiling was performed using Affymetrix Human Transcriptome Clariom-S chips. Differentially expressed genes were identified (fold change ≥1.5 and p value ≤ 0.05) and used for ingenuity pathway analysis to discover the altered canonical pathways, upstream regulators, networks, and disease associations involved.
Results:
We studied monocytes from 14 neonates (HCA n = 7, no HCA n = 7). Compared with no HCA-Normoxia, HCA alone exhibited 1,195 differentially expressed genes, with transcriptional signatures consistent with monocyte activation and differentiation (including CLEC5A, FCGR3A, FCGR2B, CD101, PRAM1, and FN1 upregulation). Hyperoxia alone yielded 533 differentially expressed genes, while sequential exposure to HCA-Hyperoxia led to 1,599 differentially expressed genes. Hyperoxia without HCA demonstrated upregulated genes associated with inflammatory signaling and immune modulation (including CXCL8, TM4SF19, and PLPP3) and downregulated genes involved in pathogen recognition and monocyte survival (TLR6, TLR8, and PECAM1). Sequential HCA-Hyperoxia exposure was associated with a broader transcriptional response, with upregulation of pro-inflammatory and pro-fibrotic genes (CLEC5A, FN1, and CCL24) and downregulation of immune regulatory genes (USP18, TMEM176B, and HLA-DQB1). Pathway analysis revealed alterations in immune and inflammatory signaling, antigen presentation, neutrophil degranulation, protein ubiquitination, and metabolic regulation.
Conclusions:
Sequential exposure to histological chorioamnionitis and postnatal hyperoxia induces alterations in gene expression and molecular pathways in neonatal cord blood monocytes, affecting immune regulation, which could potentially contribute to the pathogenesis of short- and long-term diseases.