title: Damage-Associated Molecular Pattern and Fetal Membrane Vascular Injury and Collagen Disorganization in Lipopolysaccharide-Induced Intra-amniotic Inflammation in Fetal Sheep.
abstract: To understand the changes in the structural integrity of fetal membranes during intrauterine inflammation, we evaluated the time course of expression and localization of damage-associated molecular patterns (DAMPs) and injury/remodeling in collagen and vascular smooth muscle. Time-mated ewes received intra-amniotic (IA) saline or IA lipopolysaccharide (LPS) for 5 hours to 15 days prior to a preterm delivery at 125 ± 2 days (n = 5-7 animals/group). The DAMP high mobility group box 1 (HMGB1) protein assessed by Western blot was induced within 24 hours after IA LPS in the fetal membranes, and HMGB1 expression was localized to amnion epithelium, chorion vascular endothelium, and infiltrating inflammatory cells by immunohistology. Markers of vascular injury, intercellular adhesion molecule 1, and tissue plasminogen activator messenger RNA (mRNA) expression increased 5 to 12 hours after IA LPS in the chorioamnion indicating vascular injury. Chorion vascular remodeling with increased chorion arteriolar smooth muscle actin expression by morphometric analyses of immunohistology was noted 15 days after IA LPS. Collagen expression was nonhomogeneous by histochemical staining, and there was a trend toward decreased mRNA expression of collagen subunit COL5A1 after IA LPS.
  
  
  CONCLUSIONS
  Intrauterine inflammation induced early increases in HMGB1 in the chorioamnion with a concomitant vascular injury followed by chorion arteriolar hypertrophy. There was nonhomogeneous collagen expression in the chorioamnion. These results have implications for understanding the pathogenesis of IA inflammation-induced preterm rupture of membranes.
authors.affiliation: Division of Maternal-Fetal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: Jodi K
authors.initials: JK
authors.lastname: Regan
authors.affiliation: Division of Neonatology and Pulmonary Biology, The Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Paranthaman S
authors.initials: PS
authors.lastname: Kannan
authors.affiliation: School of Women's and Infants' Health, The University of Western Australia, Perth, Western Australia, Australia.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Kemp
authors.affiliation: Department of Pediatrics, Maastricht University Medical Center, Maastricht, Netherlands.
authors.forename: Boris W
authors.initials: BW
authors.lastname: Kramer
authors.affiliation: School of Women's and Infants' Health, The University of Western Australia, Perth, Western Australia, Australia.
authors.forename: John P
authors.initials: JP
authors.lastname: Newnham
authors.affiliation: Division of Neonatology and Pulmonary Biology, The Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Alan H
authors.initials: AH
authors.lastname: Jobe
authors.affiliation: Division of Neonatology and Pulmonary Biology, The Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA suhas.kallapur@cchmc.org.
authors.forename: Suhas G
authors.initials: SG
authors.lastname: Kallapur
mesh_terms: D000067531:Alarmins / Q000378:metabolism*; D000650:Amnion / Q000378:metabolism / Q000473:pathology; D000653:Amniotic Fluid / Q000378:metabolism; D000818:Animals; D003094:Collagen / Q000378:metabolism*; D005321:Extraembryonic Membranes / Q000378:metabolism* / Q000473:pathology; D005260:Female; D024243:HMGB1 Protein / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008070:Lipopolysaccharides; D011247:Pregnancy; D012756:Sheep; D010959:Tissue Plasminogen Activator / Q000378:metabolism
chemical_list: D000067531:Alarmins; D024243:HMGB1 Protein; D008070:Lipopolysaccharides; D018799:Intercellular Adhesion Molecule-1; D003094:Collagen; D010959:Tissue Plasminogen Activator
keywords: HMGB1; alarmins; cytokines; intrauterine infection; preterm labor