Abstract
Toll-like receptor 4 (TLR4) activation by bacterial infection, or by sterile inflammatory insult is a primary trigger of spontaneous preterm birth. Here we utilize mouse models to investigate the efficacy of a novel small molecule TLR4 antagonist, (+)-naloxone, the non-opioid isomer of the opioid receptor antagonist (−)-naloxone, in infection-associated preterm birth. Treatment with (+)-naloxone prevented preterm delivery and alleviated fetal demise in utero elicited by i.p. LPS administration in late gestation. A similar effect with protection from preterm birth and perinatal death, and partial correction of reduced birth weight and postnatal mortality, was conferred by (+)-naloxone administration after intrauterine administration of heat-killed E. coli. Local induction by E. coli of inflammatory cytokine genes Il1b, Il6, Tnf and Il10 in fetal membranes was suppressed by (+)-naloxone, and cytokine expression in the placenta, and uterine myometrium and decidua, was also attenuated. These data demonstrate that inhibition of TLR4 signaling with the novel TLR4 antagonist (+)-naloxone can suppress the inflammatory cascade of preterm parturition, to prevent preterm birth and perinatal death. Further studies are warranted to investigate the utility of small molecule inhibition of TLR-driven inflammation as a component of strategies for fetal protection and delaying preterm birth in the clinical setting.
Highlights
Precocious inflammation leading to preterm labor can be triggered by infection or by sterile pro-inflammatory insults, originating either within gestational tissues or systemically, from tissues distal to the placenta and fetus[1,16]
Detection of infection is mediated by sensing molecules known as Toll-like receptors (TLRs) that bind conserved molecular structures carried by microorganisms, known as pathogen-associated molecular patterns (PAMPs)
TLR4 is a key sensor for infection-induced preterm birth, since protection is afforded in mice by spontaneous mutation of Tlr[4] in C3H/HeJ mice[27,29,30], null mutation of Tlr[4] in C57Bl/6 mice[22,30], and genetic deficiency in the MyD88 and TRIF adaptor proteins required for TLR4 signaling[28]
Summary
Normal on-time delivery is an inflammatory process that involves release of endogenous TLR ligands from the maturing fetus to ligate TLRs in fetal membranes and placental tissue[22,23,46]. Suppression of TLR4-induced pro-inflammatory cytokine expression in gestational tissues is inferred to be the key mechanism underlying the failure of bacterial agent-induced inflammation to progress to premature labor in mice given (+)-naloxone, in turn protecting mice from subsequent late gestation or perinatal death of fetuses Our data using both LPS and heat-killed E. coli to induce preterm delivery are consistent with previous studies employing these models[27,28], where elevated IL1B, IL6 and TNF signaling are implicated in progressing both the uterine maturation and injury to fetal tissues that results in preterm birth and fetal death respectively. Clinical progression of this work requires extensive investigation of the benefits and risks of pharmacological delay of preterm birth for offspring, effects on neurodevelopment, to ensure any treatment interventions adequately protect the fetus from inflammatory injury in utero
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