Li Yan, Wang Kai, Zou Qing-Yun, Zhou Chi, Magness Ronald R, Zheng Jing
Department of Obstetrics and Gynecology, Perinatal Research Laboratories, University of Wisconsin, Madison, WI 53715, United States.
Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 200040, PR China.
Med Hypotheses. 2015 May;84(5):494-7. doi: 10.1016/j.mehy.2015.02.001. Epub 2015 Feb 10.
Preterm birth (PTB) is defined as birth before 37 weeks of gestation and is a leading cause of neonatal mortality and morbidity. To date, the etiology of spontaneous PTB (sPTB) remains unclear; however, intrauterine bacterial infection-induced inflammation is considered to be one of the major triggers. Aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor. Upon activation, AhR signaling mediates many biological processes. AhR is abundantly expressed in human placentas, primarily in trophoblasts, and several fetal organs and tissues. The activation of AhR signaling can modulate inflammatory responses via promoting production of pro-inflammatory cytokines by the placenta and fetal membranes. These cytokines could enhance expression and/or activity of cyclooxygenase-2 (COX2) in human trophoblasts and amniotic epithelia, which in turn stimulate synthesis and release of prostaglandins (PGs; e.g., PGE2 and PGF2α). Given the discovery of a number of natural and endogenous AhR ligands in human, we hypothesize that in a subset of patients with high AhR expression in placentas and fetal membranes, repeated exposure to these AhR ligands hyperactivates AhR, inducing hyperactivation of the cytokines/COX2/PGs pathway, resulting in myometrial contractions, ultimately leading to sPTB. We further hypothesize that hyperactivation of this AhR pathway can induce sPTB either directly or in synergy with the bacterial infection. Proof of this hypothesis may provide a novel mechanism underlying sPTB.
早产（PTB）被定义为妊娠37周前分娩，是新生儿死亡和发病的主要原因。迄今为止，自发性早产（sPTB）的病因仍不清楚；然而，宫内细菌感染引起的炎症被认为是主要触发因素之一。芳烃受体（AhR）是一种配体依赖性转录因子。激活后，AhR信号传导介导许多生物学过程。AhR在人胎盘中大量表达，主要在滋养层细胞以及几个胎儿器官和组织中表达。AhR信号传导的激活可通过促进胎盘和胎膜产生促炎细胞因子来调节炎症反应。这些细胞因子可增强人滋养层细胞和羊膜上皮细胞中环氧化酶-2（COX2）的表达和/或活性，进而刺激前列腺素（PGs；例如PGE2和PGF2α）的合成和释放。鉴于在人体内发现了多种天然和内源性AhR配体，我们推测，在胎盘和胎膜中AhR表达较高的一部分患者中，反复接触这些AhR配体可使AhR过度激活，导致细胞因子/COX2/PGs途径过度激活，引起子宫肌层收缩，最终导致sPTB。我们进一步推测，这种AhR途径的过度激活可直接或与细菌感染协同作用诱导sPTB。这一假设的证实可能为sPTB提供一种新的机制。
