Abstract
Chorioamnionitis, inflammation of fetal membranes, is an important cause of preterm birth and a risk factor for the development of adverse neonatal outcomes including sepsis and intestinal pathologies. Intestinal bile acids (BAs) accumulation and hepatic cytokine production are involved in adverse intestinal outcomes. These findings triggered us to study the liver and enterohepatic circulation (EHC) following intra-amniotic (IA) lipopolysaccharide (LPS) exposure. An ovine chorioamnionitis model was used in which circulatory cytokines and outcomes of the liver and EHC of preterm lambs were longitudinally assessed following IA administration of 10 mg LPS at 5, 12 or 24h or 2, 4, 8 or 15d before preterm birth. Hepatic inflammation was observed, characterized by increased hepatic cytokine mRNA levels (5h – 2d post IA LPS exposure) and increased erythropoietic clusters (at 8 and 15 days post IA LPS exposure). Besides, 12h after IA LPS exposure, plasma BA levels were increased, whereas gene expression levels of several hepatic BA transporters were decreased. Initial EHC alterations normalized over time. Concluding, IA LPS exposure induces significant time-dependent changes in the fetal liver and EHC. These chorioamnionitis induced changes have potential postnatal consequences and the duration of IA LPS exposure might be essential herein.
Highlights
Chorioamnionitis, inflammation of fetal membranes, is an important cause of preterm birth and a risk factor for the development of adverse neonatal outcomes including sepsis and intestinal pathologies
We evaluated the time-dependent effects of intra-uterine administration of LPS from 15 days to 5 hours before premature delivery, on the liver and enterohepatic circulation (EHC) of premature sheep
Recent research showed that the fetal liver is an active immune organ with the ability of inducing an early and robust innate immune response activation, and immune activation is already initiated within 1 hour to 5 hours after an in utero inflammatory challenge[21]
Summary
Chorioamnionitis, inflammation of fetal membranes, is an important cause of preterm birth and a risk factor for the development of adverse neonatal outcomes including sepsis and intestinal pathologies. Intestinal bile acids (BAs) accumulation and hepatic cytokine production are involved in adverse intestinal outcomes These findings triggered us to study the liver and enterohepatic circulation (EHC) following intra-amniotic (IA) lipopolysaccharide (LPS) exposure. Sepsis-associated cholestasis is a common complication in infants and is commonly caused by lipopolysaccharide (LPS), derived from Gram negative bacteria[10] This inflammation-induced cholestasis results from a reduced mRNA expression of various hepatic bile acid (BA) transporters, such as the N a+-taurocholate cotransporting polypeptide (NTCP) and the bile salt export pump (BSEP)[10]. Several mechanisms may account for this hepatotoxity; BAs could disrupt cell membranes through their detergent action on lipid components and promote the generation of reactive oxygen species that oxidatively modify lipids, proteins and nucleic acids, which eventually cause hepatocyte necrosis and a poptosis[11]
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