title: BQ-123 prevents LPS-induced preterm birth in mice via the induction of uterine and placental IL-10.
abstract: 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 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.
authors.affiliation: Department of Pharmaceutical Sciences, St. John's University, 8000 Utopia Parkway, Jamaica, NY, 11439, USA; Women and Children's Research Laboratory, Winthrop University Hospital, 259 1st Street, Mineola, NY, 11501, USA. Electronic address: Nicole.olgun02@stjohns.edu.
authors.forename: Nicole S
authors.initials: NS
authors.lastname: Olgun
authors.affiliation: Women and Children's Research Laboratory, Winthrop University Hospital, 259 1st Street, Mineola, NY, 11501, USA; Department of Pediatrics, Winthrop University Hospital, 259 1st Street, Mineola, NY, 11501, USA. Electronic address: Nhanna@winthrop.org.
authors.forename: Nazeeh
authors.initials: N
authors.lastname: Hanna
authors.affiliation: Department of Pharmaceutical Sciences, St. John's University, 8000 Utopia Parkway, Jamaica, NY, 11439, USA; Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Obstetrics and Gynecology and Women's Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address: Rezniks@stjohns.edu.
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Reznik
mesh_terms: D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D065130:Endothelin A Receptor Antagonists / Q000494:pharmacology*; D019332:Endothelin-1 / Q000235:genetics; D005260:Female; D008070:Lipopolysaccharides; D008810:Mice, Inbred C57BL; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010920:Placenta / Q000187:drug effects* / Q000378:metabolism; D011247:Pregnancy; D011248:Pregnancy Complications / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D014599:Uterus / Q000187:drug effects* / Q000378:metabolism
chemical_list: D016207:Cytokines; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D008070:Lipopolysaccharides; D010456:Peptides, Cyclic; C072247:cyclo(Trp-Asp-Pro-Val-Leu)
keywords: Endothelin-1; Inflammation; Interleukin-10; Preterm birth