Oxidative stress damage-associated molecular signaling pathways differentiate spontaneous preterm birth and preterm premature rupture of the membranes
Oxidative stress damage-associated molecular signaling pathways differentiate spontaneous preterm birth and preterm premature rupture of the membranes
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DOI：
10.1093/molehr/gav074
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发表时间：
2016-02-01
影响因子：
4
通讯作者：
Menon, Ramkumar
中科院分区：
文献类型：
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作者：
Dutta, Eryn H.;Behnia, Faranak;Menon, Ramkumar
研究假设：在患有早产胎膜早破 (PPROM) 的女性中，氧化应激增加可能会加速细胞过早衰老、衰老相关炎症和蛋白水解，从而导致胎膜早破。研究发现：我们通过揭示胎膜氧化还原状态、氧化应激诱导的损伤、不同信号通路和衰老激活的差异，证明了早产 (PTB) 和 PPROM 之间的机制差异。已知的信息已经：氧化应激相关的胎膜损伤和细胞周期停滞决定了不良妊娠结局，例如自发性 PTB 和 PPROM。研究设计、样本/材料、方法：从患有 PTB 和 PPROM 的妇女中采集胎膜和羊水样本。使用分子、生化和组织学标记来记录氧化应激和抗氧化酶状态、DNA 损伤、Ras-GTP 酶和丝裂原激活蛋白激酶的二次信号激活以及两组细胞膜之间衰老激活的差异。 主要结果和机会的作用：与 PTB 相比，PPROM 中的氧化应激较高，抗氧化酶较低。 PTB 膜具有最小的 DNA 损伤，并显示 Ras-GTPase 和 ERK/JNK 信号通路的激活，且衰老迹象最小。 PPROM 有更多数量的细胞出现 DNA 损伤、衰老应激激酶 (p38MAPK) 激活和衰老迹象。限制、注意原因：样本是在分娩后回顾性获得的。我们测试的衰老标志物是特异性的，但不足以证实衰老是 PPROM 中的病理学。 研究结果的更广泛意义：与具有完整胎膜的 PTB 相比，氧化应激诱导的 DNA 损伤和衰老是 PPROM 胎膜的特征。 PTB 和 PPROM 源于不同的病理生理途径。氧化应激和氧化应激诱导的细胞损伤可能是机制信号通路和表型结果的决定因素。 研究经费和竞争利益：这项研究得到加尔维斯顿德克萨斯大学医学分部妇产科 R. Menon 博士的发展基金和捷克共和国卫生部 (UHHK, 001799906）。作者报告不存在利益冲突。
STUDY HYPOTHESIS: In women with preterm premature rupture of the membranes (PPROM), increased oxidative stress may accelerate premature cellular senescence, senescence-associated inflammation and proteolysis, which may predispose them to rupture.STUDY FINDING: We demonstrate mechanistic differences between preterm birth (PTB) and PPROM by revealing differences in fetal membrane redox status, oxidative stress-induced damage, distinct signaling pathways and senescence activation.WHAT IS KNOWN ALREADY: Oxidative stress-associated fetal membrane damage and cell cycle arrest determine adverse pregnancy outcomes, such as spontaneous PTB and PPROM. STUDY DESIGN,SAMPLES/MATERIALS, METHODS: Fetal membranes and amniotic fluid samples were collected from women with PTB and PPROM. Molecular, biochemical and histologic markers were used to document differences in oxidative stress and antioxidant enzyme status, DNA damage, secondary signaling activation by Ras-GTPase and mitogen-activated protein kinases, and activation of senescence between membranes from the two groups.MAIN RESULTS AND THE ROLE OF CHANCE: Oxidative stress was higher and antioxidant enzymes were lower in PPROM compared with PTB. PTB membranes had minimal DNA damage and showed activation of Ras-GTPase and ERK/JNK signaling pathway with minimal signs of senescence. PPROMhad higher numbers of cells with DNA damage, prosenescence stress kinase (p38MAPK) activation and signs of senescence.LIMITATIONS, REASONS FOR CAUTION: Samples were obtained retrospectively after delivery. The markers of senescence that we tested are specific but are not sufficient to confirm senescence as the pathology in PPROM.WIDER IMPLICATIONS OF THE FINDINGS: Oxidative stress-induced DNA damage and senescence are characteristics of fetal membranes from PPROM, compared with PTB with intact membranes. PTB and PPROM arise from distinct pathophysiologic pathways. Oxidative stress and oxidative stress-induced cellular damages are likely determinants of the mechanistic signaling pathways and phenotypic outcome.STUDY FUNDING AND COMPETING INTERESTS: This study is supported by developmental funds to Dr R. Menon from the Department of Obstetrics and Gynecology at The University of Texas Medical Branch at Galveston and funds to Dr M. Kacerovsky' from the Ministry of Health Czech Republic (UHHK, 001799906). The authors report no conflict of interest.