title: Pretreatment with toll-like receptor 4 antagonist inhibits lipopolysaccharide-induced preterm uterine contractility, cytokines, and prostaglandins in rhesus monkeys.
abstract: Intrauterine infection, which occurs in most early preterm births, triggers an immune response culminating in preterm labor. The authors hypothesize that blockade of lipopolysaccharide (LPS)-induced immune responses by a toll-like receptor 4 antagonist (TLR4A) would prevent elevations in amniotic fluid (AF) cytokines, prostaglandins, and uterine contractility. Chronically catheterized rhesus monkeys at 128 to 147 days' gestation received intra-amniotic infusions of either (1) saline (n = 6), (2) LPS (0.15-10 microg; n = 4), or (3) TLR4A pretreatment with LPS (10 microg) 1 hour later (n = 4). AF cytokines, prostaglandins, and uterine contractility were compared using 1-way ANOVA with Bonferroni-adjusted pairwise comparisons. Compared with saline controls, LPS induced significant elevations in AF interleukin-8 (IL-8), tumor necrosis factor (TNF)- alpha, PGE(2), PGF(2)(alpha), and uterine contractility (P < .05). In contrast, TLR4A pretreatment inhibited LPS-induced uterine activity and was associated with significantly lower AF IL-8, TNF-alpha, PGE(2), and PGF(2)( alpha) versus LPS alone (P < .05). Toll-like receptor antagonists, together with antibiotics, may delay or prevent infection-associated preterm birth.
authors.affiliation: University of Washington, Seattle, WA 98195, USA. adamsk@u.washington.edu
authors.forename: Kristina M
authors.initials: KM
authors.lastname: Adams Waldorf
authors.forename: David
authors.initials: D
authors.lastname: Persing
authors.forename: Miles J
authors.initials: MJ
authors.lastname: Novy
authors.forename: Drew W
authors.initials: DW
authors.lastname: Sadowsky
authors.forename: Michael G
authors.initials: MG
authors.lastname: Gravett
mesh_terms: D000653:Amniotic Fluid / Q000382:microbiology; D000818:Animals; D002821:Chorioamnionitis; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D004926:Escherichia coli; D005260:Female; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000276:immunology*; D008253:Macaca mulatta; D007752:Obstetric Labor, Premature / Q000276:immunology* / Q000517:prevention & control; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000276:immunology*; D011453:Prostaglandins / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors*; D014590:Uterine Contraction / Q000187:drug effects* / Q000276:immunology; D014591:Uterine Diseases / Q000382:microbiology
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D011453:Prostaglandins; D051197:Toll-Like Receptor 4