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

Preterm birth (PTB), defined as any delivery occurring prior to the completion of 37 weeks' 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 ET{sub A} receptor. We have previously shown that antagonism of the ET{sub A} 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 12 h. We discovered that BQ-123, when administered 10 h 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 ET{sub A}more » 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 ET{sub A} receptor blockade via the suppression of ET-1, and induction of a Th2 cytokine dominant state. - Highlights: • The pro-inflammatory response to LPS in the uterus and placenta is ET-1 dependent. • ET{sub A} blockade triggers up-regulation of IL-10 in uterus and placenta. • A positive feedback loop drives ET-1 expression in gestational tissue.« less
Authors:
 [1] ;  [2] ;  [3] ;  [2] ;  [1] ;  [2] ;  [2]
  1. Department of Pharmaceutical Sciences, St. John's University, 8000 Utopia Parkway, Jamaica, NY, 11439 (United States)
  2. (United States)
  3. Women and Children's Research Laboratory, Winthrop University Hospital, 259 1st Street, Mineola, NY, 11501 (United States)
Publication Date:
OSTI Identifier:
22465691
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 282; Journal Issue: 3; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANIMAL TISSUES; AUGMENTATION; INFLAMMATION; INHIBITION; LYMPHOKINES; MICE; PARTURITION; PLACENTA; RECEPTORS; TRANSCRIPTION; UTERUS