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.

中文翻译：

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靶向Toll样受体4以解决早产和胎儿炎症性损伤。

每年，有1500万怀孕提前结束，导致超过100万婴儿死亡，并对许多儿童造成长期健康影响。分娩和分娩的生理过程涉及妊娠组织中免疫细胞和促炎细胞因子的重要作用。有令人信服的证据表明，当感染或其他原因触发过早和过度的炎症反应时，就会引发自然早产的机制。暴露于促炎性介质已成为早产通常伴随的“胎儿炎症反应综合征”的主要因素，在胎儿组织中，计划外作用会干扰正常发育，并易患新生儿发病。Toll样受体（TLR）是炎症激活的关键上游关守。TLR4能够感应和整合来自一系列微生物和内源性触发因素的信号，从而引发并永久性地引起炎症，从而显着参与其中。临床前研究已确定TLR4是促进子宫静止并保护胎儿免受炎性损伤的有吸引力的药理靶标。TLR4信号的新型小分子抑制剂，特别是非阿片类受体拮抗剂（+）-纳洛酮和（+）-纳曲酮，在动物模型中被证明非常有效，可预防由细菌模拟LPS，热灭活的大肠杆菌诱导的早产。或TLR4依赖性促炎脂质，血小板活化因子（PAF）。在这里，我们总结了将TLR4定位为胎儿和妊娠组织炎症的主要调节因子的基本原理，