title: IL-1 receptor blockade prevents fetal cortical brain injury but not preterm birth in a mouse model of inflammation-induced preterm birth and perinatal brain injury.
abstract: OBJECTIVE
  Exposure to intrauterine inflammation, associated with preterm birth, has been linked to a devastating spectrum of neurobehavioral disorders. Mechanisms of this injury are unknown. Using a mouse model of intrauterine inflammation, we have observed a disruption of fetal neuronal morphology along with a marked elevation of interleukin (IL)-1β in the fetal brain and placenta. In this study, we hypothesized that IL-1 plays a key role in perinatal brain injury.
  
  
  METHODS
  Utilizing a mouse model of inflammation-induced preterm birth, we investigated the role of IL-1 in fetal cortical injury as well as preterm birth. In these studies, dams received systemic treatment with IL-1 receptor antagonist prior to administration of intrauterine inflammation.
  
  
  RESULTS
  Systemic maternal antagonism of IL-1 improved fetal cortical neuronal injury associated with the exposure to intrauterine inflammation, without affecting the phenotype of preterm birth. IL-1 receptor antagonist blocked activation of neuronal nitric oxide synthase in perinatal cortex, a key enzyme implicated in neurotoxicity.
  
  
  CONCLUSIONS
  Our data suggest that fetal cortical brain injury and preterm birth may occur by divergent mechanisms. Furthermore, our studies indicate maternal administration of IL-1 receptor antagonist (IL-1RA) blocked neuronal nitric oxide synthase activation observed in the brain cortex and, we speculate, that this alteration in activation leads to demonstrated decreased neurotoxicity.
authors.affiliation: Department of Obstetrics and Gynecology, Maternal and Child Health Research Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Kirstin
authors.initials: K
authors.lastname: Leitner
authors.forename: Mofeedah
authors.initials: M
authors.lastname: Al Shammary
authors.forename: Michael
authors.initials: M
authors.lastname: McLane
authors.forename: Michael V
authors.initials: MV
authors.lastname: Johnston
authors.forename: Michal A
authors.initials: MA
authors.lastname: Elovitz
authors.forename: Irina
authors.initials: I
authors.lastname: Burd
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005333:Fetus; D005786:Gene Expression Regulation; D006801:Humans; D007231:Infant, Newborn; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides; D051379:Mice; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D047928:Premature Birth / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014599:Uterus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D017472:Receptors, Interleukin-1; C496320:NOS1 protein, human; D052248:Nitric Oxide Synthase Type I
keywords: IL-1 receptor antagonist; intrauterine inflammation; mouse model