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Pretreatment With Toll-like Receptor 4 Antagonist Inhibits Lipopolysaccharide-Induced Preterm Uterine Contractility, Cytokines, and Prostaglandins in Rhesus Monkeys

University of Washington, Seattle, Oregon National Primate Research Center, Beaverton, adamsk{at}u.washington.edu

David Persing, MD, PhD

Cepheid, Inc, Sunnyvale, California

Miles J. Novy, MD

Oregon National Primate Research Center, Beaverton

Drew W. Sadowsky, MD, PhD

Oregon National Primate Research Center, Beaverton

Michael G. Gravett, MD

University of Washington, Seattle

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 µg; n = 4), or (3) TLR4A pretreatment with LPS (10 µg) 1 hour later (n = 4). AF cytokines, prostaglandins, and uterine contractility were compared using 1-way ANOVA with Bonferroniadjusted pairwise comparisons. Compared with saline controls, LPS induced significant elevations in AF interleukin-8 (IL-8), tumor necrosis factor (TNF)— , PGE₂, PGF₂, and uterine contractility (P < .05). In contrast, TLR4A pretreatment inhibited LPS-induced uterine activity and was associated with significantly lower AF IL-8, TNF-, PGE₂, and PGF₂ versus LPS alone (P < .05). Toll-like receptor antagonists, together with antibiotics, may delay or prevent infection-associated preterm birth.

Key Words: toll-like receptor 4 • intrauterine infection/inflammation • preterm labor • rhesus monkey • animal model.

This version was published on February 1, 2008

Reproductive Sciences, Vol. 15, No. 2, 121-127 (2008)
DOI: 10.1177/1933719107310992


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