title: 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: School of Women's and Infants' Health, The University of Western Australia, Perth, Western Australia, Australia demelza.ireland@uwa.edu.au.
authors: D J
authors: DJ
authors: Ireland
authors: School of Women's and Infants' Health, The University of Western Australia, Perth, Western Australia, Australia.
authors: M W
authors: MW
authors: Kemp
authors: School of Women's and Infants' Health, The University of Western Australia, Perth, Western Australia, Australia.
authors: Y
authors: Y
authors: Miura
authors: School of Women's and Infants' Health, The University of Western Australia, Perth, Western Australia, Australia Division of Perinatal Medicine, Tohoku University Hospital, Sendai, Japan.
authors: M
authors: M
authors: Saito
authors: School of Women's and Infants' Health, The University of Western Australia, Perth, Western Australia, Australia.
authors: J P
authors: JP
authors: Newnham
authors: School of Women's and Infants' Health, The University of Western Australia, Perth, Western Australia, Australia.
authors: J A
authors: JA
authors: Keelan
mesh_terms: D000653:Amniotic Fluid / Q000737:chemistry; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D015415:Biomarkers / Q000032:analysis / Q000097:blood; D002408:Catheters, Indwelling; D002821:Chorioamnionitis / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D005260:Female; D005312:Fetal Blood / Q000737:chemistry; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D008070:Lipopolysaccharides; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020930:MAP Kinase Kinase Kinases / Q000008:administration & dosage / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000627:therapeutic use*; D011247:Pregnancy; D047928:Premature Birth / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D034561:Sheep, Domestic; D015398:Signal Transduction / Q000187:drug effects*; D013876:Thiophenes / Q000008:administration & dosage / Q000627:therapeutic use*; D014904:Western Australia; D015025:Zearalenone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000099151:MAP Kinase Kinase Kinase 7; D007783:Lactones; D012118:Resorcinols
chemical_list: D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D051550:I-kappa B Kinase; D008070:Lipopolysaccharides; D020930:MAP Kinase Kinase Kinases; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D013876:Thiophenes; D015025:Zearalenone; D000099151:MAP Kinase Kinase Kinase 7; C586469:(5-(p-fluorophenyl)-2-ureido)thiophene-3-carboxamide; C505734:7-oxozeanol; D007783:Lactones; D012118:Resorcinols; C482199:lipopolysaccharide, E coli O55-B5
keywords: 5z-7-oxozeaenol; TPCA-1; cytokine-suppressive anti-inflammatory drugs; intrauterine infection; preterm birth