Abstract
Every year, 15 million pregnancies end prematurely, resulting in more than 1 million infant deaths and long‐term health consequences for many children. The physiological processes of labour and birth involve essential roles for immune cells and pro‐inflammatory cytokines in gestational tissues. There is compelling evidence that the mechanisms underlying spontaneous preterm birth are initiated when a premature and excessive inflammatory response is triggered by infection or other causes. Exposure to pro‐inflammatory mediators is emerging as a major factor in the ‘fetal inflammatory response syndrome’ that often accompanies preterm birth, where unscheduled effects in fetal tissues interfere with normal development and predispose to neonatal morbidity. Toll‐like receptors (TLRs) are critical upstream gatekeepers of inflammatory activation. TLR4 is prominently involved through its ability to sense and integrate signals from a range of microbial and endogenous triggers to provoke and perpetuate inflammation. Preclinical studies have identified TLR4 as an attractive pharmacological target to promote uterine quiescence and protect the fetus from inflammatory injury. Novel small‐molecule inhibitors of TLR4 signalling, specifically the non‐opioid receptor antagonists (+)‐naloxone and (+)‐naltrexone, are proving highly effective in animal models for preventing preterm birth induced by bacterial mimetic LPS, heat‐killed Escherichia coli, or the TLR4‐dependent pro‐inflammatory lipid, platelet‐activating factor (PAF). Here, we summarise the rationale for targeting TLR4 as a master regulator of inflammation in fetal and gestational tissues, and the potential utility of TLR4 antagonists as candidates for preventative and therapeutic application in preterm delivery and fetal inflammatory injury.
Highlights
We have explored the utility of novel TLR4 antagonists of the (+)-naloxone family as pharmacological interventions for preterm a 2020 The Authors
Labour.[121,122] (+)-Naloxone has anti-inflammatory activity similar to that originally described for (À)naloxone, but unlike (À)-naloxone, it does not bind opioid receptors and antagonises TLR4 signalling.[121] (+)-Naloxone is a TLR4 antagonist, that is the positive isomer of the opioid receptor antagonist (À)-naloxone,[121] a well-described nonselective antagonist of the μ-opioid receptor that is commonly prescribed for opioid addiction, including in pregnant women and neonates.[123] (+)Naloxone does not have opioid actions, but binds MD-2 to prevent TLR4 engaging with LPS or other ligands[124] (Figure 3), thereby suppressing NF-jB activation and IL-1b, IL-6 and TNF production.[125,126]
In contrast to anti-TLR4-neutralising antibodies,[69] (+)-naloxone is a small molecule with potential to penetrate the placenta[127] and has a pharmacokinetic profile suited to short systemic exposure or longer term delivery if required
Summary
New therapeutic options to tackle spontaneous preterm birth and mitigate its adverse impact in infants born prematurely are urgently needed.[1,2] Innate immune activation leading to inflammation in gestational tissues is a central, early and rate-limiting mechanism driving preterm birth.[3,4] Upstream events in the inflammatory mechanisms that elicit fetal and placental stress and precede active labour are attractive targets for intervention.[5,6,7] To progress pharmacological solutions, the complex signals involved in initiating parturition, and the mechanisms by which different triggers converge onto a common inflammatory cascade, must be defined.[4]Infection is a common cause of preterm birth, but sterile factors and insults, such as exposure to oxidative stress and toxins, immune or endocrine imbalance, multiple births, and placental hypoxia and haemorrhage, are risk factors.[4,8] For both microbial and sterile causes, inflammatory activation occurs early in the pathophysiological pathway.[3,9,10] Pro-inflammatory cytokines and effector molecules are produced in the fetal membranes, myometrium and cervix well before uterine contractions, membrane rupture and cervical dilatation occur.[9,10,11] These tissue changes are accompanied by extensive accumulation of leucocytes from both the innate and adaptive immune compartments.
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