Static state of epithelial mesenchymal transition in fetal membrane cells: a novel inflammatory pathway to parturition

摘要 胎膜(羊膜)提供结构框架，起到机械和保护作用 在怀孕期间的功能。P38丝裂原活化蛋白激酶(MAPK)介导的进展性p38 衰老(衰老的机制)发生在胎膜中。它与胎儿的生长发育有关，而且是 由于宫腔内氧化应激(OS)增加，足月加速。胎儿衰老 组织引起炎症，从而促进分娩；因此，膜在怀孕和 分娩。在整个怀孕期间，膜通过修复细胞自身来维持动态平衡 脱落，基质被降解。这种重塑过程会产生缝隙和微裂缝。在手机上 目前尚不清楚膜上的多能羊膜上皮细胞和间充质细胞如何修复 被破坏的地点。因为重塑对于维持膜的动态平衡和防止不良反应是必不可少的 妊娠结局，了解这个过程是至关重要的。我们已经确定羊膜的损伤 上皮细胞(AEC)迫使AEC增殖和细胞迁移以重建损伤部位，这是正常的 生理反应。初步数据表明，OS-和p38 MAPK介导的衰老导致上皮细胞衰老 通过增加转化生长因子β的产生，促进间质转化，防止组织重塑。我们也 确定转化生长因子β具有双重功能：1)通过p38MAPK的自动磷酸化诱导衰老 2)诱导EMT转录因子促进细胞膜和机械膜的破坏。这些 作用被黄体酮逆转(P4)。我们假设平衡的组织重塑维持胎儿 妊娠期细胞膜动态平衡，但转化生长因子β在足月或应答期由于压倒性OS而升高 早产儿TO感染和炎症(肿瘤坏死因子α)导致p38MAPK介导的不可逆状态 衰老和EMT可促进膜的损伤。此外，我们假设在 妊娠，转化生长因子β介导的转变被孕酮平衡(P4)。我们将使用以下工具来测试我们的假设 2个具体目标： 目的1-确定内毒素(感染)和肿瘤坏死因子α(炎症)是否可引起转化生长因子β-TAB1-p38MAPK 信号通路，导致AEC中的EMT。 目的2-确定P4对内毒素和肿瘤坏死因子α介导的转化生长因子β产生的调节作用及其能力 以减少急诊抢救。转化生长因子β-P4在正常条件下维持膜动态平衡及其机制 感染/炎症促进EMT的干扰可能为早产提供一种新的途径 通过膜破裂来调节。

ABSTRACT Fetal membranes (amniochorion) provide the structural framework and perform mechanical and protective functions during pregnancy. A progressive p38 mitogen-activated protein kinase (MAPK)-mediated senescence (mechanism of aging) occurs in fetal membranes. It is correlated with fetal growth and is accelerated at term due to increased oxidative stress (OS) in the intrauterine cavity. Senescence of fetal tissues causes inflammation that can promote labor; thus, membranes play a critical role in pregnancy and parturition. Throughout gestation, membranes maintain homeostasis by repairing themselves when cells are shed and the matrix is degraded. This remodeling process creates gaps and microfractures. At the cellular level, it remains unclear how the membranes' pluripotent amnion epithelial and mesenchymal cells repair the damaged sites. Since remodeling is essential for maintaining membrane homeostasis and preventing adverse pregnancy outcomes, understanding this process is critical. We have determined that injury to amnion epithelial cells (AEC) forces AEC proliferation and cell migration to rebuild injured sites, which is a normal physiologic response. Pilot data suggest that OS- and p38 MAPK-mediated senescence cause epithelial mesenchymal transition (EMT) and prevent tissue remodeling through increased production of TGFβ. We also determined that TGFβ plays dual functions: 1) induction of senescence by autophosphorylation of p38MAPK and 2) induction of EMT transcription factors to facilitate cellular and mechanical membrane disruption. These effects were reversed by progesterone (P4). We hypothesize that balanced tissue remodeling maintains fetal membrane homeostasis during pregnancy, but TGFβ increase due to overwhelming OS at term or in response to infection and inflammation (TNFα) at preterm causes an irreversible state of p38MAPK-mediated senescence and EMT that can promote membrane damage. Additionally, we hypothesize that during pregnancy, TGFβ-mediated transitions are balanced by progesterone (P4). We will test our hypotheses using 2 specific aims: Aim 1—To determine if LPS (infection) and TNFα (inflammation) can cause TGFβ -TAB1-p38MAPK signaling pathways, leading to EMT in AEC. Aim 2—To determine the regulatory role of P4 in LPS and TNFα-mediated TGFβ production and its ability to reduce EMT. Maintenance of membrane homeostasis by TGFβ-P4 during normal conditions and its disruption by infection/inflammation promoting EMT may provide a novel pathway to preterm parturition mediated by membrane disruption.