title: 15-epi-lipoxin A4 reduces the mortality of prematurely born pups in a mouse model of infection-induced preterm birth.
abstract: Preterm birth remains the leading cause of neonatal mortality and morbidity worldwide. There are currently few effective therapies and therefore an urgent need for novel treatments. Although there is much focus on trying to alter gestation of delivery, the primary aim of preterm birth prevention therapies should be to reduce prematurity related mortality and morbidity. Given the link between intrauterine infection and inflammation and preterm labour (PTL), we hypothesized that administration of lipoxins, key anti-inflammatory and pro-resolution mediators, could be a useful novel treatment for PTL. Using a mouse model of infection-induced PTL, we investigated whether 15-epi-lipoxin A4 could delay lipopolysaccharide (LPS)-induced PTL and reduce pup mortality. On D17 of gestation mice (n = 9-12) were pretreated with vehicle or 15-epi-lipoxin A4 prior to intrauterine administration of LPS or PBS. Although pretreatment with 15-epi-lipoxin A4 did not delay LPS-induced PTL, there was a significant reduction in the mortality amongst prematurely delivered pups (defined as delivery within 36 h of surgery) in mice treated with 15-epi-lipoxin A4 prior to LPS treatment, compared with those receiving LPS alone (P < 0.05). Quantitative real-time (QRT)-PCR analysis of utero-placental tissues harvested 6 h post-treatment demonstrated that 15-epi-lipoxin A4 treatment increased Ptgs2 expression in the uterus, placenta and fetal membranes (P < 0.05) and decreased 15-Hpgd expression (P < 0.05) in the placenta and uterus, suggesting that 15-epi-lipoxin A4 may regulate the local production and activity of prostaglandins. These data suggest that augmenting lipoxin levels could be a useful novel therapeutic option in the treatment of PTL, protecting the fetus from the adverse effects of infection-induced preterm birth.
authors.affiliation: MRC Centre for Reproductive Health and Tommy's Centre for Maternal and Fetal Health, University of Edinburgh, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK s.rinaldi@ed.ac.uk.
authors.forename: S F
authors.initials: SF
authors.lastname: Rinaldi
authors.affiliation: MRC Centre for Reproductive Health and Tommy's Centre for Maternal and Fetal Health, University of Edinburgh, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: R D
authors.initials: RD
authors.lastname: Catalano
authors.affiliation: MRC Centre for Reproductive Health and Tommy's Centre for Maternal and Fetal Health, University of Edinburgh, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: J
authors.initials: J
authors.lastname: Wade
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, UK.
authors.forename: A G
authors.initials: AG
authors.lastname: Rossi
authors.affiliation: MRC Centre for Reproductive Health and Tommy's Centre for Maternal and Fetal Health, University of Edinburgh, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: J E
authors.initials: JE
authors.lastname: Norman
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005333:Fetus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides; D044045:Lipoxins / Q000494:pharmacology*; D051379:Mice; D007752:Obstetric Labor, Premature / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D010920:Placenta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D014599:Uterus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D015415:Biomarkers; D008070:Lipopolysaccharides; D044045:Lipoxins; C040527:lipoxin A4; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; D051546:Cyclooxygenase 2
keywords: anti-inflammatory; lipoxin; parturition; preterm birth; resolution