BQ-123 prevents LPS-induced preterm birth in mice via the induction of uterine and placental IL-10

Nicole S. Olgun, Nazeeh Hanna, Sandra E. Reznik

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Preterm birth (PTB), defined as any delivery occurring prior to the completion of 37weeks' gestation, currently accounts for 11-12% of all births in the United States. Maternal genito-urinary infections account for up to 40% of all PTBS and induce a pro-inflammatory state in the host. The potent vasoconstrictor Endothelin-1 (ET-1) is known to be upregulated in the setting of infection, and elicits its effect by binding to the ETA receptor. We have previously shown that antagonism of the ETA receptor with BQ-123 is capable of preventing LPS-induced PTB in mice. We hypothesize that the administration of BQ-123 post LPS exposure will dismantle a positive feedback loop observed with pro-inflammatory cytokines upstream of ET-1. On GD 15.5, pregnant C57BL/6 mice were injected with PBS, LPS, BQ-123, or LPS+BQ-123. Changes at both the level of transcription and translation were observed in uterus and placenta in the ET-1 axis and in pro- and anti-inflammatory cytokines over the course of 12h. We discovered that BQ-123, when administered 10h post LPS, is capable of increasing production of uterine and placental Interleukin-10, causing a shift away from the pro-inflammatory state. We also observed that antagonism of the ETA receptor decreased IL-1β and TNFα in the placenta while also decreasing transcription of ET-1 in the uterus. Our results reinforce the role of ET-1 at the maternal fetal interface and highlight the potential benefit of ETA receptor blockade via the suppression of ET-1, and induction of a Th2 cytokine dominant state.

Original languageEnglish (US)
Pages (from-to)275-284
Number of pages10
JournalToxicology and Applied Pharmacology
Volume282
Issue number3
DOIs
StatePublished - Feb 1 2015

Keywords

  • Endothelin-1
  • Inflammation
  • Interleukin-10
  • Preterm birth

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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