Hydrogen Sulfide Delays LPS-Induced Preterm Birth in Mice via Anti-Inflammatory Pathways

A major cause of preterm labor in pregnant women is intra-amniotic infection, which is mediated by an inflammatory process. Hydrogen sulfide (H2S), a gaseous transmitter, has been implicated to be involved in inflammatory responses. We sought to investigate whether H2S affects infectious preterm birth using the mouse model of lipopolysaccharides (LPS)-induced preterm birth. Administration of LPS at 0.4 mg/kg with two injections intraperitoneally (i.p.) on gestational day 14.5 induced preterm labor. LPS significantly increased leukocyte infiltration in uterus, stimulated the expression of pro-inflammatory cytokines interleukin 1β (IL-1β), IL-6, tumor necrosis factor α (TNF-α), CCL2 and CXCL15 in myometrium. Administration of NaHS (i.p.) delayed the onset of labor induced by LPS in a dose-dependent manner. NaHS prevented leukocyte infiltration into intrauterine tissues and inhibited the production of pro-inflammatory cytokines in myometrium and decreased the levels of these cytokines in maternal circulation. H2S also decreased LPS-activated extracellular signal-regulated kinase (ERK) 1/2/ nuclear factor (NF)-κB signaling pathways in myometrium. This study provides new in vivo evidence for the roles of H2S in attenuating inflammation, and a potential novel therapeutic strategy for infection-related preterm labor.

孕妇早产的主要诱因之一为羊膜腔内感染，其病理过程由炎症反应介导。硫化氢（H₂S）作为一种气体递质，已被证实参与炎症应答过程。本研究旨在探究硫化氢是否可通过脂多糖（LPS）诱导的早产小鼠模型，干预感染性早产的发生。在妊娠第14.5天以0.4 mg/kg剂量两次腹腔内（i.p.）注射脂多糖，可成功诱导小鼠早产。脂多糖可显著提升子宫组织的白细胞浸润水平，并刺激子宫肌层中促炎细胞因子白细胞介素1β（IL-1β）、白细胞介素6（IL-6）、肿瘤坏死因子α（TNF-α）、CCL2及CXCL15的表达。腹腔注射硫氢化钠（NaHS）可呈剂量依赖性延缓脂多糖诱导的小鼠临产时间。硫氢化钠可抑制白细胞向子宫内组织浸润，阻遏子宫肌层促炎细胞因子的产生，并降低母体外周循环中此类细胞因子的水平。硫化氢还可抑制脂多糖激活的子宫肌层细胞外调节蛋白激酶1/2（ERK1/2）/核因子κB（NF-κB）信号通路。本研究为硫化氢在减轻炎症反应中的作用提供了全新的体内实验证据，并为感染相关性早产提供了潜在的新型治疗策略。