Uterine overdistention induces preterm labor mediated by inflammation: observations in pregnant women and nonhuman primates.
Uterine overdistention induces preterm labor mediated by inflammation: observations in pregnant women and nonhuman primates.
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DOI：
10.1016/j.ajog.2015.08.028
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发表时间：
2015-12
影响因子：
9.8
通讯作者：
Johnson MR
中科院分区：
文献类型：
--
作者：
Adams Waldorf KM;Singh N;Mohan AR;Young RC;Ngo L;Das A;Tsai J;Bansal A;Paolella L;Herbert BR;Sooranna SR;Gough GM;Astley C;Vogel K;Baldessari AE;Bammler TK;MacDonald J;Gravett MG;Rajagopal L;Johnson MR
子宫过度扩张被认为是双胎和多胎妊娠妇女早产的诱因，但其病理生理机制尚不清楚。我们第一次在非人灵长类动物妊娠模型中研究了与快速子宫扩张相关的早产发病机制。使用早产长期插管的妊娠猪尾猕猴（Macaca nemestrina）通过羊膜内球囊的膨胀（N = 6）产生子宫过度扩张的非人灵长类动物模型，将其与盐水对照（N = 5）进行比较。由于早产或在实验结束时进行剖腹产。使用微阵列、定量逆转录酶聚合酶链反应、Luminex（Austin，TX）和酶联免疫吸附试验测量猴（羊水、子宫肌层、母体血浆）和人（胎盘细胞、羊膜、子宫肌层）组织的信使RNA（mRNA）和/或蛋白质水平。统计分析采用协方差分析和Wilcoxon秩和。使用拉普拉斯定律计算生物力学力。球囊扩张后，6只动物中有3只发生早产，这与球囊体积和子宫壁应力增大有关。子宫过度扩张后，炎性细胞因子和前列腺素显著升高，出现与早产相关的“炎性脉冲”（白细胞介素[IL]-1β、肿瘤坏死因子[TNF]-α、IL-6、IL-8、CCL 2、前列腺素E2、前列腺素F2α，均P <0.05）。在机械牵张后的体外培养的羊膜细胞（IL 1 β、IL 6和IL 8 mRNA多个时间点，P <0.05）、羊水过多妇女的羊膜（IL 6和TNF mRNA，P <0.05）以及双胎妇女的羊膜（TNF-α）和子宫肌层（IL 6、IL 8、CCL 2，均P <0.05）中观察到类似的炎症反应。球囊扩张后非人灵长类动物、羊水过多妇女和双胞胎中差异表达的基因参与组织重塑和肌肉生长。羊膜腔内球囊扩张引起的子宫过度扩张与早产前的炎性搏动相关。我们的研究结果表明，炎症是一个早期事件后，对子宫的机械应力，并导致早产时，压力足够大。此外，我们发现子宫组织重塑和肌肉生长的证据，作为一种常见的，也许是补偿，子宫扩张的反应。
Uterine overdistention is thought to induce preterm labor in women with twin and multiple pregnancies, but the pathophysiology remains unclear. We investigated for the first time the pathogenesis of preterm birth associated with rapid uterine distention in a pregnant nonhuman primate model. A nonhuman primate model of uterine overdistention was created using preterm chronically catheterized pregnant pigtail macaques (Macaca nemestrina) by inflation of intraamniotic balloons (N = 6), which were compared to saline controls (N = 5). Cesarean delivery was performed due to preterm labor or at experimental end. Microarray, quantitative reverse transcriptase polymerase chain reaction, Luminex (Austin, TX), and enzyme-linked immunosorbent assay were used to measure messenger RNA (mRNA) and/or protein levels from monkey (amniotic fluid, myometrium, maternal plasma) and human (amniocytes, amnion, myometrium) tissues. Statistical analysis employed analysis of covariance and Wilcoxon rank sum. Biomechanical forces were calculated using the law of Laplace. Preterm labor occurred in 3 of 6 animals after balloon inflation and correlated with greater balloon volume and uterine wall stress. Significant elevations of inflammatory cytokines and prostaglandins occurred following uterine overdistention in an “inflammatory pulse” that correlated with preterm labor (interleukin [IL]-1β, tumor necrosis factor [TNF]-α, IL-6, IL-8, CCL2, prostaglandin E2, prostaglandin F2α, all P < .05). A similar inflammatory response was observed in amniocytes in vitro following mechanical stretch (IL1β, IL6, and IL8 mRNA multiple time points, P < .05), in amnion of women with polyhydramnios (IL6 and TNF mRNA, P < .05) and in amnion (TNF-α) and myometrium of women with twins in early labor (IL6, IL8, CCL2, all P < .05). Genes differentially expressed in the nonhuman primate after balloon inflation and in women with polyhydramnios and twins are involved in tissue remodeling and muscle growth. Uterine overdistention by inflation of an intraamniotic balloon is associated with an inflammatory pulse that precedes and correlates with preterm labor. Our results indicate that inflammation is an early event after a mechanical stress on the uterus and leads to preterm labor when the stress is sufficiently great. Further, we find evidence of uterine tissue remodeling and muscle growth as a common, perhaps compensatory, response to uterine distension.