Intra-amniotic pharmacological blockade of inflammatory signalling pathways in an ovine chorioamnionitis model

Intrauterine inflammation (IUI) associated with infection is the major cause of preterm birth (PTB) at ,32 weeks' gestation and accounts for ~40% of all spontaneous PTBs. Pharmacological strategies to prevent PTB and improve fetal outcomes will likely require both antimicrobial and anti-inflammatory therapies. Hereweinvestigated the effects of two cytokine-suppressive anti-inflammatory drugs (CSAIDs), compounds that specifically target inflammatory signalling pathways, in an ovine model of lipopolysaccharide (LPS)-induced chorioamnionitis. Chronically catheterized ewes at 116 days gestation (n 1/4 7/group) received an intra-amniotic (IA) bolus of LPS (10 mg) plus vehicle or CSAIDS: TPCA-1 (1.2 mg/kg fetal weight) or 5z-7-oxozeaenol (OxZnl; 0.4 mg/kg fetalweight); controls received vehicle (dimethylsulphoxide). Amniotic fluid (AF), fetal and maternal blood sampleswere taken 0, 2, 6, 12, 24 and 48 h later; tissues were taken at autopsy (48 h). Administration of TPCA-1 or OxZnl abrogated the stimulatory effects of LPS (P , 0.01 versus vehicle control) on production of PGE₂ in AF, with lesser (nonsignificant) effects on IL-6 production. Fetal membrane polymorphonuclear cell infiltration score was significantly higher in LPS versus vehicle control animals (P , 0.01), and this difference was absent with TPCA-1 and OxZnl treatment. LPS-induced systemic fetal inflammation was highly variable, with no significant effects of CSAIDs observed. Lung inflammationwas evident with LPS exposure, but unaffected by CSAID treatment. We have shown in a large animal model that IA administration of a single dose of CSAIDs can suppress LPS-induced IA inflammatory responses, while fetal effects were minimal. Further development and investigation of these compounds in infectious models is warranted.