Systemic inflammatory responses to repeated and increasing endotoxin challenges in fetal sheep

TL;DR

Researchers created a sheep model to study fetal inflammation caused by repeated low-dose LPS exposure, showing consistent physiological and genetic responses.

Contribution

A novel ovine model of fetal inflammatory response syndrome (FIRS) that reliably induces systemic inflammation despite tachyphylaxis.

Findings

Repeated LPS doses caused respiratory and metabolic acidosis in fetal sheep.

Transcriptomic analysis showed upregulated inflammatory genes and NFκB signaling.

Pro-inflammatory cytokines were detected in multiple fetal tissues.

Abstract

Repeated low‐dose administration of lipopolysaccharide (LPS) attenuates subsequent fetal responses, which makes it challenging to investigate interventions to prolonged exposure. Our aim was to develop a fetal inflammatory response syndrome (FIRS) model that consistently and effectively elicits a marked physiological response to increasing LPS doses. Four intravenous LPS boluses (0.3, 1.5, 3, and 15 μg) were administered to fetal sheep over 5 days. Physiological responses were measured via blood gases, pH, lactate, and cortisol concentrations. Fetal peripheral blood mononuclear cells (PBMCs) were analyzed for transcriptomic changes and tissue cytokine expression postmortem. All LPS challenges increased lactate, cortisol, and pCO2 concentrations and decreased pH and pO2 levels at 3 and 5 hours. No interaction was found between day (increasing LPS doses) and hour (LPS response to each dose). PBMC numbers increase with LPS challenges. Transcriptional analysis on PBMCs identified several enriched gene clusters indicating upregulation of inflammatory gene signatures along with complement activation and NFκB signaling pathways. Expression of pro‐inflammatory cytokines (TNFα, IL‐6, or IL‐1β) was measured in lung, heart, liver, placenta, and spleen. Physiological indices show both respiratory and metabolic acidosis with successive and increasing LPS challenges that demonstrate a robust systemic response despite tachyphylaxis to LPS in fetal sheep.

Establishment of an ovine fetal inflammatory response syndrome model. We developed a novel ovine model of fetal inflammatory response syndrome (FIRS) using repeated low‐dose administration of lipopolysaccharide (LPS). Our approach reliably induces a robust physiological response, including respiratory and metabolic acidosis, despite the presence of tachyphylaxis with increasing LPS exposure. Transcriptomic analysis of fetal peripheral blood mononuclear cells revealed enriched gene clusters associated with inflammation, complement activation, and NFκB signaling pathways ‐ key features of systemic fetal inflammation. Activation of these inflammatory cascades plays a central role in driving adverse outcomes in fetuses exposed to chorioamnionitis. The ovine model replicates several aspects of human FIRS and provides a consistent and controlled platform for investigating fetal immune responses to chorioamnionitis.

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