Increased mRNA expression of kynurenine pathway enzymes in human placentae exposed to bacterial endotoxin.

Intra-amniotic bacterial infection is a major risk factor for cerebral impairment in infants that are born pre-term however, the causal pathways are largely unknown. Whether placental derived, neuroactive kynurenine metabolites play any role in fetal cerebral damage during episodes of intra-amniotic infection is presently unknown. In this preliminary study, we explored if kynurenine metabolites may be involved, examining if mRNAs of enzymes involved in tryptophan catabolism through the kynurenine pathway (KP) were expressed in the placenta and if their expression was co-ordinately altered with exposure to bacterial infection. We found that placentae from healthy women at term and those with clinical signs of amniotic fluid bacterial infection pre-term expressed mRNAs of the KP enzymes, with higher expression overall in the infected group. Significant increases in indoleamine 2,3-dioxygenase (IDO), tryptophan dioxygenase (TDO) and kynureninase (KYNase) expression were detected in association with infection. These findings suggest that tryptophan may be constitutively degraded through the KP in the human placenta. Whether higher concentrations of placental derived kynurenine metabolites enter the fetus during episodes of infection and their physiological roles if any remains to be elucidated.

Cerebrovascular responses in the fetal sheep brain to low-dose endotoxin.

Clinical and experimental evidence indicate that infection in pregnancy is associated with fetal brain damage. However, the inflammatory processes that compromise the fetal brain are not fully understood. In this study, we used a single, low dose of lipopolysaccharide (LPS, 0.1 microg/kg i.v.) to provoke an acute-phase response in unanesthetized fetal sheep in utero. COX-2 mRNA was increased in the cortex and cerebellum at 24 and 48 h after LPS, and immunoreactive COX-2 protein was increased in perivascular cells throughout gray and white matter at 24 h after LPS administration. Plasma albumin was observed in the parenchyma of the brain in cortex, thalamus, hypothalamus, corpus callosum, fornix, hippocampus, midbrain, subcallosal bundle, and cerebellar Purkinje cells. Large, rounded, lectin-positive cells with the appearance of macrophages were observed around blood vessels in subventricular white matter. These results indicate that blood-brain barrier permeability is increased in the fetal brain after exposure to endotoxin and suggests that cytotoxic and pro-inflammatory substances could pass from the circulation into the brain after peripheral inflammatory stimulation.