Chorioamnionitis is associated with inflammatory end-organ damage in the fetus. Tissues in direct contact with amniotic fluid drive a pro-inflammatory response and contribute to this injury. However, due to a lack of direct contact with the amniotic fluid, the liver contribution to this response has not been fully characterized. Given its role as an immunologic organ, we hypothesized that the fetal liver would demonstrate an early innate immune response to an in utero inflammatory challenge. Fetal sheep (131 ± 1 d gestation) demonstrated metabolic acidosis and high cortisol and norepinephrine values within 5 h of exposure to intra-amniotic LPS. Likewise, expression of pro-inflammatory cytokines increased significantly at 1 and 5 h of exposure. This was associated with NF-κB activation, by inhibitory protein IκBα degradation, and nuclear translocation of NF-κB subunits (p65/p50). Corroborating these findings, LPS exposure significantly increased pro-inflammatory innate immune gene expression in fetal sheep hepatic macrophages in vitro. Thus, an in utero inflammatory challenge induces an early hepatic innate immune response with systemic metabolic and stress responses. Within the fetal liver, hepatic macrophages respond robustly to LPS exposure. Our results demonstrate that the fetal hepatic innate immune response must be considered when developing therapeutic approaches to attenuate end-organ injury associated with in utero inflammation.

绒毛膜羊膜炎与胎儿的炎症性终末器官损伤有关。与羊水直接接触的组织会引发促炎反应并导致这种损伤。然而，由于缺乏与羊水的直接接触，肝脏对这种反应的贡献尚未得到充分表征。鉴于其作为免疫器官的作用，我们假设胎儿​​肝脏将对子宫内炎症挑战表现出早期先天免疫反应。胎羊（妊娠 131 ± 1 天）在暴露于羊膜内 LPS 的 5 小时内表现出代谢性酸中毒以及高皮质醇和去甲肾上腺素值。同样，促炎细胞因子的表达在暴露 1 小时和 5 小时后显着增加。这与抑制性蛋白 IκBα 降解和 NF-κB 亚基 (p65/p50) 核易位导致的 NF-κB 激活有关。证实了这些发现，体外LPS暴露显着增加了胎羊肝巨噬细胞中促炎先天免疫基因的表达。因此，子宫内炎症挑战诱导早期肝脏先天免疫反应以及全身代谢和应激反应。在胎儿肝脏内，肝巨噬细胞对 LPS 暴露反应强烈。我们的结果表明，在开发减轻与子宫内炎症相关的终末器官损伤的治疗方法时，必须考虑胎儿肝脏的先天免疫反应。