内源性硫化氢抑制子宫激活的机制及其意义

早产发病率高达9-11%，但早产的发生率并未得到有效的控制，原因在于人类妊娠末期子宫激活的机理尚未明晰，发现新的抑制子宫激活的内源性因子为研制有效且安全的治疗早产的新药提供新思路。硫化氢（H2S）是一种新型气体信号分子，我们前期在整体动物和离体细胞实验的研究表明，内源性H2S能够抑制子宫激活。人类的分娩是一个炎症过程，分娩前夕炎性因子参与激活子宫，我们前期实验观察到H2S能够抑制子宫肌炎性因子的生成。在此基础上，本项目系统深入地研究妊娠末期H2S抑制子宫激活的机制，明确H2S是否通过抗炎进而抑制子宫激活，并对其分子机制进行深入研究，观察H2S通过激活KATP通道，p38 MAPK，PI3K/AKT,NF-κB等信号通路中的哪些信号通路发挥抗炎作用，并进一步明确H2S作用的靶分子。本研究结果将有助于阐明妊娠末期子宫激活的机制，为研制有效且安全的治疗早产的新药提供新的思路。

。Preterm birth occurs in 8-10% of all pregnancies and current therapeutic approaches are unsuccessful. This failure is largely due to our ignorance of the fundamental mechanisms that control the length of human pregnancy and the process of human labour. Uterus is a dynamic organ that undergoes distinct molecular changes during pregnancy. At the term, uterus activated by increasing expression of uterine activation proteins (UAPs, e.g. the gap junction protein, connexin43, receptors for agonists and ion channels) that control myometrial excitability and increased production of uterine agonists. There are a number of endogenous factors which modulate uterus activation. Hydrogen sulfide (H2S) is endogenously produced from L-cysteins by cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE). We have found that CBS and CSE expressed in human uterus by IHC and western blotting. The results showed that CSE and CBS in uterus in labor were decreased compared with term not in labor, and the expression of CSE and CBS was negatively correlated with the expression of UAPs. Moreover, H2S inhibited the expression of UAPs in cultured myometrial cells. H2S postponed against LPS-induced preterm delivery. It suggested that H2S inhibited uterus activation. As we known, uterus activation for labour would be induced by inflammation. And we found that H2S inhibited the production of inflammatory cytokines in cultured myometrial cells. On the basis of preliminary experiment, we are going to explore the mechanism of inhibition of uterus activation by endogenous H2S. We will investigate whether the effects of H2S on the regulation of UAPs in uterus were through inhibiting cytokine production. We will employ a set of molecular biological techniques to investigate the mechanism of regulation of inflammation by H2S in myometrium. The study will help to furtherly clarity the mechanism of human parturition.