早产是围产期新生儿死亡首要原因，人类分娩启动机制尚未阐明导致目前缺乏防治早产的有效手段。胎膜无菌性炎症在足月和早产分娩启动中都起重要作用，但发生机制不清楚。胎膜是糖皮质激素再生能力最强的胎儿组织，且与分娩启动相关。胎膜如何在经典抗炎激素糖皮质激素氛围下发生炎症令人费解，我们推测胎膜可能存在受糖皮质激素正向调控的炎症因子。ChIP-seq检测发现，糖皮质激素可能通过STAT3上调胎膜细胞急性期反应蛋白血清淀粉样蛋白A1(SAA1)表达，预实验证实糖皮质激素和SAA1正反馈协同诱导胎膜细胞糖皮质激素再生和SAA1表达，这将导致SAA1在胎膜大量堆积，产生淀粉样变和无菌性炎症反应，包括炎症因子表达、炎性细胞侵润、前列腺素合成和细胞外基质重构，最终导致子宫收缩和胎膜破裂，从而启动分娩。本项目将利用人原代胎膜细胞、胎膜组织块和由临产及胎膜早破获取的胎膜组织对以上假说进行验证，为早产防治提供新思路。

Preterm birth is the leading cause of perinatal death. Due to poor understanding of the mechanisms underlying human parturition, there is a lack of effective strategies for the prevention of preterm birth. It is now recognized that sterile inflammation of fetal membranes are indispensable to both term and preterm parturition. However, the fetal membranes are also recognized possesing the highest capacity of cortisol regeneration among all fetal tissues. It is intriguing how inflammation can develop in the presence of a high concentration of cortisol, a classical anti-inflammatory hormone, in the fetal membranes. We hypothesize that there may be glucocorticoids-inducible pro-inflammatory factors in the fetal membranes. Our recent chromatin immunoprecipitation sequencing (ChIP-seq) data revealed that the acute phase response protein serum amyloid A1 (SAA1) was among the genes that were possibly upregulated by cortisol via STAT3 in human fetal membrane cells. Our preliminary study showed that both SAA1 expression and coritsol regeneration were under the synergistic induction by coritsol and SAA1, thus forming a positive feedback loop in the production of cortisol and SAA1 in the fetal membranes. This feedback loop may lead to excessive accumulation of SAA1 in the membranes and result in amyloid deposition and sterile inflammatory responses including chemokine and other proinflammatory factor production, infiltration of inflammatory cells, prostaglandin production and extracellular matrix remodelling. All these effects may ultimately cause myometrium contraction and rupture of membranes redulting in the initiation of parturition. In this proposed project, we will examine this hypothesis in cultured primary human fetal membrane cells, tissue explants and in fetal membrane tissue collected at term and preterm parturtion, at premature rupture of membranes. The ultimate goal of this project is to seek novel approches to the development of effective strategies for the prevention of preterm birth.