In utero inflammatory challenge induces an early activation of the hepatic innate immune response in late gestation fetal sheep

Abstract

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.