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18: Ethyl pyruvate: a novel therapeutic agent to prevent inflammation induced preterm birth

      Objective

      Genetic and environmental interactions through receptor for advanced glycation end-products (RAGE) signaling pathways contribute to poor obstetric outcomes including preterm birth (PTB). Ethyl pyruvate (EP) is an emerging anti-inflammatory therapeutic proven safe to humans. We investigated the effect of EP on pregnancy outcomes in a murine model of endotoxin induced PTB and underlying molecular mechanism.

      Study Design

      Saline or endotoxin (LPS 2.5, 5, 10 μg/dam) were administered i.p. on d15 (d0=sperm plug) in the following groups of mice (n=5-15/group): 1) BL6 RAGE knockout (RAGEKO); 2) BL6 wild-type (BL6 WT); 3) CD1 overexpressing RAGE transgenic mice (RAGETg); 4) CD1 wild-type (CD1 WT). EP (40mg/kg) was administered i.p. 2h later. Latency period (saline/LPS injection to delivery) and pup survival from postnatal d1 to d20 were continuously monitored. Maternal blood levels of cytokines, HMGB1, progesterone and soluble RAGE were measured by ELISA. Myometrial transcriptomes was assessed by mRNAseq, and protein carbonylation (marker of oxidative stress) evaluated by Western blot.

      Results

      1) LPS shortened gestation, an effect consistently reversed by EP (p<0.05) independent of maternal serum progesterone withdrawal, sRAGE, HMGB1 and cytokine profile (Figure). 2) Myometrial protein carbonylation was reduced by EP. 3) In-utero exposure to LPS increased the rate of stillbirth in RAGETg pups, an effect rescued by EP (p<0.001). 4) LPS induced a marked change in myometrial transcriptome with concerted dysregulation of genes involved in inflammation and acute graft rejection. 5) Myometrial transcripts significantly downregulated by EP ≥ 2-fold (p<0.01) in LPS-treated RAGETg mice included antigen presentation (MHC class II antigens, Fc receptors), redox sensors (TXNL2, PRDX6B), and mitochondrial bioenergetics.

      Conclusion

      EP prevents inflammation induced PTB through immunomodulatory and oxidative stress pathways.
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