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

Abstract

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. Here we investigated 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 = 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 fetal weight); controls received vehicle (dimethylsulphoxide). Amniotic fluid (AF), fetal and maternal blood samples were 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 (non-significant) 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 inflammation was 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.

• Authors: D J Ireland, M W Kemp, Y Miura, M Saito, J P Newnham, J A Keelan
• Journal: Molecular human reproduction (Mol Hum Reprod) Vol. 21 Issue 5 Pg. 479-89 (May 2015) ISSN: 1460-2407 [Electronic] England
• PMID: 25648771 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• (5-(p-fluorophenyl)-2-ureido)thiophene-3-carboxamide
• 7-oxozeanol
• Anti-Inflammatory Agents
• Biomarkers
• Lipopolysaccharides
• Phenylurea Compounds
• Protein Kinase Inhibitors
• Thiophenes
• lipopolysaccharide, E coli O55-B5
• Zearalenone
• I-kappa B Kinase
• MAP Kinase Kinase Kinases
• MAP kinase kinase kinase 7

Topics

• Amniotic Fluid (chemistry)
• Animals
• Anti-Inflammatory Agents (administration & dosage, therapeutic use)
• Biomarkers (analysis, blood)
• Catheters, Indwelling
• Chorioamnionitis (immunology, metabolism, physiopathology, prevention & control)
• Disease Models, Animal
• Female
• Fetal Blood (chemistry)
• I-kappa B Kinase (antagonists & inhibitors, metabolism)
• Lipopolysaccharides
• Lung (drug effects, immunology, metabolism, pathology)
• MAP Kinase Kinase Kinases (administration & dosage, therapeutic use)
• Phenylurea Compounds (administration & dosage, therapeutic use)
• Pregnancy
• Premature Birth (etiology, immunology, pathology, prevention & control)
• Protein Kinase Inhibitors (administration & dosage, therapeutic use)
• Sheep, Domestic
• Signal Transduction (drug effects)
• Thiophenes (administration & dosage, therapeutic use)
• Western Australia
• Zearalenone (administration & dosage, analogs & derivatives, therapeutic use)