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

D. J. Ireland, M. W. Kemp, Y. Miura, M. Saito, J. P. Newnham, J. A. Keelan

Research output: Contribution to journalArticle

23 Citations (Scopus)

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. 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.

Original languageEnglish
Article numbergav005
Pages (from-to)479-489
Number of pages11
JournalMolecular Human Reproduction
Volume21
Issue number5
DOIs
Publication statusPublished - 2014 Jul 21

Keywords

  • 5z-7-oxozeaenol
  • Cytokine-suppressive anti-inflammatory drugs
  • Intrauterine infection
  • Preterm birth
  • TPCA-1

ASJC Scopus subject areas

  • Reproductive Medicine
  • Embryology
  • Molecular Biology
  • Genetics
  • Obstetrics and Gynaecology
  • Developmental Biology
  • Cell Biology

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