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

University of Washington, Seattle, WA 98195, USA.
Reproductive sciences (Thousand Oaks, Calif.) (Impact Factor: 2.23). 02/2008; 15(2):121-7. DOI: 10.1177/1933719107310992
Source: PubMed


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.

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Available from: Kristina Adams Waldorf
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    • "Given the link between inflammation and spontaneous labour onset, and the association between intrauterine infection and PTL, there has been a growing interest in examining whether anti-inflammatory agents could be effective novel therapeutic options for PTL (Rinaldi et al., 2011). Animal studies have been invaluable in demonstrating the potential of a number of anti-inflammatory agents to delay preterm delivery and improve pup survival, including IL-10 (Terrone et al., 2001; Rodts-Palenik et al., 2004; Robertson et al., 2006), TLR-4 signalling blockade (Adams Waldorf et al., 2008; Li et al., 2010), NFkB inhibitors (Nath et al., 2010; Chang et al., 2011) and 15-deoxy-D 12,14 -prostaglandin J 2 (15d-PGJ 2 ) (Pirianov et al., 2009). The understanding that the resolution of inflammation is an active process involving the production of mediators with specific antiinflammatory and pro-resolution actions has provided new pathways to target in the search for novel treatments for inflammation-associated pathologies (Gilroy et al., 2004; Serhan et al., 2008). "
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    ABSTRACT: Preterm birth remains the leading cause of neonatal mortality and morbidity worldwide. There are currently few effective therapies and therefore an urgent need for novel treatments. Although there is much focus on trying to alter gestation of delivery, the primary aim of preterm birth prevention therapies should be to reduce prematurity related mortality and morbidity. Given the link between intrauterine infection and inflammation and preterm labour (PTL), we hypothesised that administration of lipoxins, key anti-inflammatory and pro-resolution mediators, could be a useful novel treatment for PTL. Using a mouse model of infection-induced PTL we investigated whether 15-epi-lipoxin A4 could delay lipopolysaccharide (LPS)-induced PTL and reduce pup mortality. On D17 of gestation mice (n=9-12) were pre-treated with vehicle or 15-epi-lipoxin A4 prior to intrauterine administration of LPS or PBS. Although pre-treatment with 15-epi-lipoxin A4 did not delay LPS-induced PTL, there was a significant reduction in the mortality amongst prematurely delivered pups (defined as delivery within 36 hours of surgery) in mice treated with 15-epi-lipoxin A4 prior to LPS treatment, compared to those receiving LPS alone (p<0.05). Quantitative real time (QRT)-PCR analysis of utero-placental tissues harvested 6 hours post-treatment demonstrated that 15-epi-lipoxin A4 treatment increased Ptgs2 expression in the uterus, placenta and fetal membranes (p<0.05) and decreased 15-Hpgd expression (p<0.05) in the placenta and uterus, suggesting that 15-epi-lipoxin A4 may regulate the local production and activity of prostaglandins. These data suggest that augmenting lipoxin levels could be a useful novel therapeutic option in the treatment of PTL, protecting the fetus from the adverse effects of infection-induced preterm birth. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.
    Full-text · Article · Jan 2015 · Molecular Human Reproduction
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    • "We theorize that microorganisms , specifically gram-negative bacteria which express LPS, can activate TLR4 (Lien et al., 2000; Tapping et al., 2000) in trophoblasts, resulting in production of the pro-inflammatory cytokines, interleukin (IL)-8 and IL-6 and altered trophoblast invasion. While it has been posited that placental dysfunction, resulting from activation of the innate immune response, is involved in the development of many adverse obstetrical outcomes (Kaga et al., 1996; Elovitz et al., 2003; Adams Waldorf et al., 2008), there is a paucity of research focused on the effects of infection and inflammation on first trimester placental EVT function. Therefore, the present studies were performed to help to elucidate the effects of inflammation on placental EVT function, including the production of pro-inflammatory cytokines and trophoblast invasion, and to determine if the MAPK signaling pathway regulates this response. "
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    ABSTRACT: Defects in extravillous trophoblast (EVT) function could contribute to placental dysfunction resulting in adverse obstetrical outcomes. Adverse obstetrical outcomes have been highly correlated with intrauterine infection; however, the mechanisms linking infection to placental dysfunction remain unclear. We investigated the effects of inflammation on EVT cytokine production and invasion early in pregnancy and determined the cell signaling pathways mediating this response. In our model of inflammation, EVT cells, isolated following first trimester pregnancy terminations (n= 6) were stimulated with lipopolysaccharide (LPS). LPS induced a dose-dependent increase in interleukin (IL)-8 and IL-6 protein production (P < 0.01) and decreased EVT invasion (P = 0.01) versus control. The LPS-mediated changes in cytokine production (P < 0.001) and invasion (P < 0.001) were reversed by dexamethasone (DEX). Exposure to LPS resulted in an increase in mitogen-activated protein kinase (MAPK) signaling pathway phosphorylation, including p44/42 MAPK (P < 0.01), p38 MAPK (P < 0.05), MAPK extracellular signal-regulated kinase 1/2 (MEK1/2) (P< 0.01) and stress-activated protein kinase/c-Jun N-terminal kinase (JNK; P < 0.001), which was reversed by DEX (P < 0.05) for all MAPKs except p38. MAPK-specific inhibitors to MEK1/2 (U0126), p38 MAPK (SB 202190) and JNK (SP 600125) significantly reversed the LPS-mediated increase in IL-6 (P < 0.001) and IL-8 (P < 0.001) production. While U0126 reversed the LPS-induced decrease in EVT invasion (P < 0.001), SB 202190 (P < 0.001) and SP 600125 (P< 0.001) decreased EVT invasion, further indicating that MEK1/2 phosphorylation may be inflammation dependent while p38 MAPK and JNK phosphorylation occurs independently of an inflammatory stimulus. LPS increased IL-8 and IL-6 and decreased EVT invasion through activation of MAPK signaling. MEK1/2 activation may contribute to placental dysfunction, in the setting of inflammation-associated adverse obstetrical outcomes.
    Full-text · Article · Nov 2011 · Human Reproduction
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    • "Nodrelated proteins are expressed and functional in human fetal membranes (Keelan, unpublished). Evidence from a non-human primate model suggests that activation of TLR4 by intrauterine LPS administration is sufficient to trigger preterm contractions (Adams Waldorf et al., 2008), while MyD88 has been shown to play an indispensible role in the initiation of PTB in mice exposed to inactivated bacteria (Filipovich et al., 2009). Genetic studies have identified associations between TLR/cytokine genotypes, IUI and risk of PTB (Krediet et al., 2007; Simhan et al., 2008), and it is likely that maternal/fetal genotype plays a significant role in determining the propensity of the uterus to respond to various microorganisms in the form of an inflammatory reaction sufficient to trigger preterm labour (Annells et al., 2005; Plunkett and Muglia, 2008; Romero et al., 2010). "
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    ABSTRACT: The major cause of spontaneous preterm birth (sPTB) at less than 32 weeks of gestation is intrauterine inflammation as a consequence of colonisation of the gestational membranes by pathogenic microorganisms which trigger activation of the local innate immune system. This results in release of inflammatory mediators, leukocytosis (chorioamnionitis), apoptosis, membrane rupture, cervical ripening and onset of uterine contractions. Recent PCR evidence suggests that in the majority of cases of inflammation-driven preterm birth, microorganisms are present in the amniotic fluid, but these are not always cultured by standard techniques. The nature of the organism and its cell wall constituents, residence time in utero, microbial load, route of infection and extent of tissue penetration are all factors which can modulate the timing and magnitude of the inflammatory response and likelihood of progression to sPTB. Administration of anti-inflammatory drugs could be a viable therapeutic option to prevent sPTB and improve fetal outcomes in women at risk of intrauterine inflammation. Preventing fetal inflammation via administration of placenta-permeable drugs could also have significant perinatal benefits in addition to those related to extension of gestational age, as a fetal inflammatory response is associated with a range of significant morbidities. A number of potential drugs are available, effective against different aspects of the inflammatory process, although the pathways actually activated in spontaneous preterm labour have yet to be confirmed. Several pharmacological candidates are discussed, together with clinical and toxicological considerations associated with administration of anti-inflammatory agents in pregnancy.
    Full-text · Article · Mar 2011 · Journal of Reproductive Immunology
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