Wang Wangsheng, Liu Chao, Sun Kang
Center for Reproductive Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, and Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai 200135, People's Republic of China.
Endocrinology. 2016 Nov;157(11):4487-4498. doi: 10.1210/en.2016-1464. Epub 2016 Oct 3.
Rupture of fetal membranes (ROM) can initiate parturition at both term and preterm birth. Apoptosis of the amnion epithelium plays a key role in structural remodeling of the membranes preceding ROM. However, the causative factors for apoptosis remain unidentified. Toward the end of gestation, a feed-forward regeneration of cortisol via 11β-hydroxysteroid dehydrogenase 1 exists in the fetal membranes. Here, we have examined whether cortisol accumulation is a causative factor for amnion cells apoptosis. By using primary human amnion epithelial and fibroblast cells, we demonstrated cortisol induced apoptosis specifically in epithelial cells but not in fibroblasts via reciprocal regulation of tissue-type plasminogen activator (tPA)/plasmin system. Cortisol increased PLAT expression, the gene encoding tPA, via glucocorticoid receptor binding to a glucocorticoid response element in PLAT promoter, thereby increasing plasmin activity in epithelial cells. Further study revealed that a Fas-mediated extrinsic apoptotic pathway was involved in the induction of epithelial cells apoptosis by cortisol, which was blocked by inhibiting either tPA or plasmin. Consistently, cortisol increased cleaved-caspase-3 and tPA abundance in amnion tissue explants. Moreover, the abundance of cortisol, cleaved-caspase-3, and tPA was significantly increased in amnion tissue after labor-initiated spontaneous rupture of membranes. In conclusion, local accumulation of cortisol is a causative factor for amnion epithelial apoptosis via activation of tPA/plasmin system toward the end of gestation. This may contribute to the ROM at both term and preterm birth.
胎膜破裂（ROM）可在足月和早产时启动分娩。羊膜上皮细胞凋亡在胎膜破裂前的结构重塑中起关键作用。然而，凋亡的致病因素仍未明确。在妊娠末期，胎膜中存在通过11β-羟基类固醇脱氢酶1进行的皮质醇前馈再生。在此，我们研究了皮质醇积累是否是羊膜细胞凋亡的致病因素。通过使用原代人羊膜上皮细胞和成纤维细胞，我们证明皮质醇通过组织型纤溶酶原激活物（tPA）/纤溶酶系统的相互调节，特异性地诱导上皮细胞而非成纤维细胞凋亡。皮质醇通过糖皮质激素受体与PLAT启动子中的糖皮质激素反应元件结合，增加PLAT（编码tPA的基因）的表达，从而增加上皮细胞中的纤溶酶活性。进一步研究表明，Fas介导的外源性凋亡途径参与了皮质醇诱导的上皮细胞凋亡，这一过程可通过抑制tPA或纤溶酶来阻断。同样，皮质醇增加了羊膜组织外植体中裂解的半胱天冬酶-3和tPA的丰度。此外，在分娩引发的自发胎膜破裂后，羊膜组织中皮质醇、裂解的半胱天冬酶-3和tPA的丰度显著增加。总之，妊娠末期皮质醇的局部积累是通过激活tPA/纤溶酶系统导致羊膜上皮细胞凋亡的致病因素。这可能导致足月和早产时的胎膜破裂。
