The antioxidant N‐acetyl cysteine inhibits cytokine and prostaglandin release in human fetal membranes stimulated ex vivo with lipoteichoic acid or live group B streptococcus

Author:

Park Hae‐Ryung1ORCID,Harris Sean M.2,Boldenow Erica3ORCID,Aronoff David M.4,Rea Meaghan2,Xi Chuanwu2,Loch‐Caruso Rita2

Affiliation:

1. Department of Environmental Medicine School of Medicine and Dentistry, University of Rochester Rochester New York USA

2. Department of Environmental Health Sciences School of Public Health, University of Michigan Ann Arbor Michigan USA

3. Department of Biology Calvin University Grand Rapids Michigan USA

4. Department of Medicine School of Medicine, Indiana University Indianapolis Indiana USA

Abstract

AbstractBackgroundsInfection during pregnancy is a significant public health concern due to the increased risk of adverse birth outcomes. Group B Streptococcus or Streptococcus agalactiae (GBS) stands out as a major bacterial cause of neonatal morbidity and mortality. We aimed to explore the involvement of reactive oxygen species (ROS) and oxidative stress pathways in pro‐inflammatory responses within human fetal membrane tissue, the target tissue of acute bacterial chorioamnionitis.MethodsWe reanalyzed transcriptomic data from fetal membrane explants inoculated with GBS to assess the impact of GBS on oxidative stress and ROS genes/pathways. We conducted pathway enrichment analysis of transcriptomic data using the Database for Annotation, Visualization and Integrated Discovery (DAVID), a web‐based functional annotation/pathway enrichment tool. Subsequently, we conducted ex vivo experiments to test the hypothesis that antioxidant treatment could inhibit pathogen‐stimulated inflammatory responses in fetal membranes.ResultsUsing DAVID analysis, we found significant enrichment of pathways related to oxidative stress or ROS in GBS‐inoculated human fetal membranes, for example, “Response to Oxidative Stress” (FDR = 0.02) and “Positive Regulation of Reactive Oxygen Species Metabolic Process” (FDR = 2.6*10−4). There were 31 significantly changed genes associated with these pathways, most of which were upregulated after GBS inoculation. In ex vivo experiments with choriodecidual membrane explants, our study showed that co‐treatment with N‐acetylcysteine (NAC) effectively suppressed the release of pro‐inflammatory cytokines (IL‐6, IL‐8, TNF‐α) and prostaglandin PGE2, compared to GBS‐treated explants (p < .05 compared to GBS‐treated samples without NAC co‐treatment). Furthermore, NAC treatment inhibited the release of cytokines and PGE2 stimulated by lipoteichoic acid (LTA) and lipopolysaccharide (LPS) in whole membrane explants (p < .05 compared to LTA or LPS‐treated samples without NAC co‐treatment).ConclusionsOur study sheds light on the potential roles of ROS in governing the innate immune response to GBS infection, offering insights for developing strategies to mitigate GBS‐related adverse outcomes.

Funder

Medical Center, University of Rochester

Publisher

Wiley

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