Anatomy, Biochemistry and Physiology, John A. Burns School of Medicine, University of Hawai'i at Mānoa, Honolulu, HI 96822, USA.
Wayne State School of Medicine, Detroit, MI 48201, USA.
Int J Mol Sci. 2024 May 9;25(10):5161. doi: 10.3390/ijms25105161.
Danger-associated molecular patterns (DAMPs) are elevated within the amniotic cavity, and their increases correlate with advancing gestational age, chorioamnionitis, and labor. Although the specific triggers for their release in utero remain unclear, it is thought that they may contribute to the initiation of parturition by influencing cellular stress mechanisms that make the fetal membranes (FMs) more susceptible to rupture. DAMPs induce inflammation in many different tissue types. Indeed, they precipitate the subsequent release of several proinflammatory cytokines that are known to be key for the weakening of FMs. Previously, we have shown that in vitro stretch of human amnion epithelial cells (hAECs) induces a cellular stress response that increases high-mobility group box-1 (HMGB1) secretion. We have also shown that cell-free fetal DNA (cffDNA) induces a cytokine response in FM explants that is fetal sex-specific. Therefore, the aim of this work was to further investigate the link between stretch and the DAMPs HMGB1 and cffDNA in the FM. These data show that stretch increases the level of cffDNA released from hAECs. It also confirms the importance of the sex of the fetus by demonstrating that female cffDNA induced more cellular stress than male fetuses. Our data treating hAECs and human amnion mesenchymal cells with HMGB1 show that it has a differential effect on the ability of the cells of the amnion to upregulate the proinflammatory cytokines and propagate a proinflammatory signal through the FM that may weaken it. Finally, our data show that sulforaphane (SFN), a potent activator of Nrf2, is able to mitigate the proinflammatory effects of stretch by decreasing the levels of HMGB1 release and ROS generation after stretch and modulating the increase of key cytokines after cell stress. HMGB1 and cffDNA are two of the few DAMPs that are known to induce cytokine release and matrix metalloproteinase (MMP) activation in the FMs; thus, these data support the general thesis that they can function as potential central players in the normal mechanisms of FM weakening during the normal distension of this tissue at the end of a normal pregnancy.
危险相关分子模式（DAMPs）在羊水中升高，其增加与妊娠进展、绒毛膜羊膜炎和分娩相关。虽然它们在宫内释放的具体触发因素仍不清楚，但人们认为，它们可能通过影响使胎膜（FM）更容易破裂的细胞应激机制，从而有助于分娩的启动。DAMPs 可在多种不同的组织类型中引发炎症。事实上，它们会引发随后释放几种已知对 FM 减弱至关重要的促炎细胞因子。此前，我们已经表明，体外拉伸人羊膜上皮细胞（hAEC）会诱导细胞应激反应，增加高迁移率族框 1（HMGB1）的分泌。我们还表明，无细胞胎儿 DNA（cffDNA）会诱导 FM 外植体中具有胎儿性别特异性的细胞因子反应。因此，本工作的目的是进一步研究 FM 中拉伸与 DAMPs HMGB1 和 cffDNA 之间的联系。这些数据表明，拉伸会增加 hAEC 释放的 cffDNA 水平。它还通过证明雌性 cffDNA 比雄性胎儿引起更多的细胞应激，证实了胎儿性别的重要性。我们用 HMGB1 处理 hAEC 和人羊膜间充质细胞的数据表明，它对羊膜细胞上调促炎细胞因子的能力具有不同的影响，并通过 FM 传播促炎信号，从而可能削弱 FM。最后，我们的数据表明，萝卜硫素（SFN），一种 Nrf2 的有效激活剂，能够通过降低拉伸后 HMGB1 释放和 ROS 生成的水平以及调节细胞应激后关键细胞因子的增加来减轻拉伸的促炎作用。HMGB1 和 cffDNA 是已知能够诱导 FM 中细胞因子释放和基质金属蛋白酶（MMP）激活的少数 DAMPs 之一；因此，这些数据支持这样的一般论点，即它们可以作为 FM 在正常妊娠末期正常扩张过程中 FM 减弱的正常机制中的潜在核心参与者发挥作用。
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