title: Oxidative stress damage-associated molecular signaling pathways differentiate spontaneous preterm birth and preterm premature rupture of the membranes.
abstract: OBJECTIVE
  In women with preterm premature rupture of the membranes (PPROM), increased oxidative stress may accelerate premature cellular senescence, senescence-associated inflammation and proteolysis, which may predispose them to rupture.
  
  
  RESULTS
  We demonstrate mechanistic differences between preterm birth (PTB) and PPROM by revealing differences in fetal membrane redox status, oxidative stress-induced damage, distinct signaling pathways and senescence activation.
  
  
  BACKGROUND
  Oxidative stress-associated fetal membrane damage and cell cycle arrest determine adverse pregnancy outcomes, such as spontaneous PTB and PPROM.
  
  
  METHODS
  Fetal membranes and amniotic fluid samples were collected from women with PTB and PPROM. Molecular, biochemical and histologic markers were used to document differences in oxidative stress and antioxidant enzyme status, DNA damage, secondary signaling activation by Ras-GTPase and mitogen-activated protein kinases, and activation of senescence between membranes from the two groups.
  
  
  RESULTS
  Oxidative stress was higher and antioxidant enzymes were lower in PPROM compared with PTB. PTB membranes had minimal DNA damage and showed activation of Ras-GTPase and ERK/JNK signaling pathway with minimal signs of senescence. PPROM had higher numbers of cells with DNA damage, prosenescence stress kinase (p38 MAPK) activation and signs of senescence.
  
  
  CONCLUSIONS
  Samples were obtained retrospectively after delivery. The markers of senescence that we tested are specific but are not sufficient to confirm senescence as the pathology in PPROM.
  
  
  CONCLUSIONS
  Oxidative stress-induced DNA damage and senescence are characteristics of fetal membranes from PPROM, compared with PTB with intact membranes. PTB and PPROM arise from distinct pathophysiologic pathways. Oxidative stress and oxidative stress-induced cellular damages are likely determinants of the mechanistic signaling pathways and phenotypic outcome.
  
  
  BACKGROUND
  This study is supported by developmental funds to Dr R. Menon from the Department of Obstetrics and Gynecology at The University of Texas Medical Branch at Galveston and funds to Dr M. Kacerovský from the Ministry of Health Czech Republic (UHHK, 001799906). The authors report no conflict of interest.
authors.affiliation: Division of Maternal-Fetal Medicine & Perinatal Research, Department of Obstetrics & Gynecology, The University of Texas Medical Branch at Galveston, 301 University Blvd, MRB 11-158, Galveston, TX 77555, USA Medical Corps GME Programs (FTOS/OFI), Navy Medicine Professional Development Center, Bethesda, MD, USA.
authors.forename: Eryn H
authors.initials: EH
authors.lastname: Dutta
authors.affiliation: Division of Maternal-Fetal Medicine & Perinatal Research, Department of Obstetrics & Gynecology, The University of Texas Medical Branch at Galveston, 301 University Blvd, MRB 11-158, Galveston, TX 77555, USA.
authors.forename: Faranak
authors.initials: F
authors.lastname: Behnia
authors.affiliation: Department of Microbiology, The University of Texas Medical Branch at Galveston, Galveston, TX, USA.
authors.forename: Istvan
authors.initials: I
authors.lastname: Boldogh
authors.affiliation: Division of Maternal-Fetal Medicine & Perinatal Research, Department of Obstetrics & Gynecology, The University of Texas Medical Branch at Galveston, 301 University Blvd, MRB 11-158, Galveston, TX 77555, USA.
authors.forename: George R
authors.initials: GR
authors.lastname: Saade
authors.affiliation: Department of Epidemiology & Biostatistics, Texas A&M University System Health Science Center, College Station, TX, USA.
authors.forename: Brandie D
authors.initials: BD
authors.lastname: Taylor
authors.affiliation: Department of Obstetrics & Gynecology, Charles University of Prague, Faculty of Medicine, University Hospital in Hradec Kralove, Hradec Kralove, Czech Republic.
authors.forename: Marian
authors.initials: M
authors.lastname: Kacerovský
authors.affiliation: Division of Maternal-Fetal Medicine & Perinatal Research, Department of Obstetrics & Gynecology, The University of Texas Medical Branch at Galveston, 301 University Blvd, MRB 11-158, Galveston, TX 77555, USA ram.menon@utmb.edu.
authors.forename: Ramkumar
authors.initials: R
authors.lastname: Menon
mesh_terms: D000328:Adult; D016922:Cellular Senescence; D004249:DNA Damage; D005321:Extraembryonic Membranes / Q000293:injuries / Q000378:metabolism*; D005260:Female; D005322:Premature Rupture of Fetal Membranes / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D034921:Lamin Type B / Q000235:genetics / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics*; D011247:Pregnancy; D047928:Premature Birth; D015398:Signal Transduction / Q000235:genetics*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000099156:Superoxide Dismutase 2
chemical_list: D018398:Homeodomain Proteins; D034921:Lamin Type B; D048670:MAP Kinase Kinase 4; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D048051:p38 Mitogen-Activated Protein Kinases; D000099156:Superoxide Dismutase 2; C512693:PRRX2 protein, human; C000606290:SOD1 protein, human; C535150:MAPK1 protein, human
keywords: MAPK signaling; aging; biomarkers; oxidative stress; prematurity