Preclinical evaluation of drugs to block inflammation-driven preterm birth.
Intrauterine inflammation, the major cause of early preterm birth, can have microbial and sterile aetiologies. We assessed in a Transwell model the anti-inflammatory efficacies of five drugs on human extraplacental membranes delivered after preterm spontaneous labour (30-34 wk). Drugs [TPCA1 (IKKβ inhibitor), 5 z-7-oxozeaenol (OxZ, TAK1 inhibitor), inhibitor of NF-κB essential modulator binding domain (iNBD), SB239063 (p38 MAPK inhibitor) and N-acetyl cysteine (free radical scavenger free radicals)] were added after 12 h equilibration to the amniotic compartment. Concentrations of IL-6, TNF-α, MCP-1, IL-1β and PGE2in the media, and IL6, TNFA and PTGS2 mRNA expression levels in membranes, were determined after 12 h. Data were analysed using mixed models analyses. Thirteen of the 28 membranes had histological chorioamnionitis (HCA+); five were positive for bacterial culture and six for fetal inflammatory reaction. Baseline PGE2and cytokine production was similar between HCA-and HCA+membranes. Anti-inflammatory effects were also similar between HCA-and HCA+membranes. TPCA1 and OxZ were the most effective drugs; each inhibited amniotic secretion of 4/5 pro-inflammatory mediators and mRNA levels of 2/3, regardless of stimulus. We conclude that treatment with TPCA1 or OxZ, in combination with antibiotics, may minimise the adverse effects of intrauterine inflammation in pregnancy.
1 School of Women's and Infants' Health, King Edward Memorial Hospital, The University of Western Australia, Perth, Western Australia, Australia.
Demelza J
DJ
Ireland
1 School of Women's and Infants' Health, King Edward Memorial Hospital, The University of Western Australia, Perth, Western Australia, Australia.|2 Women and Infants Research Foundation of Western Australia, King Edward Memorial Hospital, Perth, Western Australia, Australia.
Elizabeth A
EA
Nathan
1 School of Women's and Infants' Health, King Edward Memorial Hospital, The University of Western Australia, Perth, Western Australia, Australia.|2 Women and Infants Research Foundation of Western Australia, King Edward Memorial Hospital, Perth, Western Australia, Australia.
Shaofu
S
Li
3 Department of Pathology, Sidra Medical and Research Center, Doha, Qatar.
Adrian K
AK
Charles
1 School of Women's and Infants' Health, King Edward Memorial Hospital, The University of Western Australia, Perth, Western Australia, Australia.
Lisa F
LF
Stinson
1 School of Women's and Infants' Health, King Edward Memorial Hospital, The University of Western Australia, Perth, Western Australia, Australia.|2 Women and Infants Research Foundation of Western Australia, King Edward Memorial Hospital, Perth, Western Australia, Australia.
Matthew W
MW
Kemp
1 School of Women's and Infants' Health, King Edward Memorial Hospital, The University of Western Australia, Perth, Western Australia, Australia.|2 Women and Infants Research Foundation of Western Australia, King Edward Memorial Hospital, Perth, Western Australia, Australia.
John P
JP
Newnham
1 School of Women's and Infants' Health, King Edward Memorial Hospital, The University of Western Australia, Perth, Western Australia, Australia.|2 Women and Infants Research Foundation of Western Australia, King Edward Memorial Hospital, Perth, Western Australia, Australia.
Jeffrey A
JA
Keelan
D000293:Adolescent; D000328:Adult; D000577:Amides / Q000494:pharmacology*; D000650:Amnion / Q000187:drug effects* / Q000473:pathology; D001424:Bacterial Infections / Q000188:drug therapy* / Q000276:immunology; D002478:Cells, Cultured; D002821:Chorioamnionitis / Q000188:drug therapy* / Q000276:immunology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors; D018836:Inflammation Mediators / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors; D011247:Pregnancy; D047928:Premature Birth / Q000188:drug therapy* / Q000276:immunology; D013876:Thiophenes / Q000494:pharmacology*; D055815:Young Adult; D015025:Zearalenone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000008:administration & dosage; D000099151:MAP Kinase Kinase Kinase 7; D007783:Lactones; D012118:Resorcinols
D000577:Amides; D051546:Cyclooxygenase 2; D016207:Cytokines; D051550:I-kappa B Kinase; D018836:Inflammation Mediators; D020930:MAP Kinase Kinase Kinases; D013876:Thiophenes; D015025:Zearalenone; D000099151:MAP Kinase Kinase Kinase 7; C505734:7-oxozeanol; D007783:Lactones; D012118:Resorcinols; C499326:2-((aminocarbonyl)amino)-5-(4-fluorophenyl)-3-thiophenecarboxamide
Chorioamnionitis; cytokine suppressive anti-inflammatory drugs; intrauterine infection; preterm birth