STUDY HYPOTHESIS: 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. STUDY FINDING: 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. WHAT IS KNOWN ALREADY: Oxidative stress-associated fetal membrane damage and cell cycle arrest determine adverse pregnancy outcomes, such as spontaneous PTB and PPROM. STUDY DESIGN, SAMPLES/MATERIALS, 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. MAIN RESULTS AND THE ROLE OF CHANCE: 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. LIMITATIONS, REASONS FOR CAUTION: 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. WIDER IMPLICATIONS OF THE FINDINGS: 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. STUDY FUNDING AND COMPETING INTERESTS: 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.
- MeSH
- dospělí MeSH
- extraembryonální obaly zranění metabolismus MeSH
- homeodoménové proteiny genetika metabolismus MeSH
- lamin typ B genetika metabolismus MeSH
- lidé MeSH
- MAP kinasa-kinasa 4 genetika metabolismus MeSH
- mitogenem aktivovaná proteinkinasa 1 genetika metabolismus MeSH
- mitogenem aktivovaná proteinkinasa 3 genetika metabolismus MeSH
- mitogenem aktivované proteinkinasy p38 genetika metabolismus MeSH
- novorozenec nedonošený MeSH
- novorozenec MeSH
- oxidační stres genetika MeSH
- poškození DNA MeSH
- předčasný odtok plodové vody genetika metabolismus patologie MeSH
- předčasný porod MeSH
- regulace genové exprese MeSH
- signální transdukce genetika MeSH
- stanovení celkové genové exprese MeSH
- stárnutí buněk MeSH
- superoxiddismutasa genetika metabolismus MeSH
- těhotenství MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- novorozenec MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
OBJECTIVE: Senescence is an important biological phenomenon involved in both physiologic and pathologic processes. We propose that chorioamniotic membrane senescence is a mechanism associated with human parturition. The present study was conducted to explore the association between senescence and normal term parturition by examining the morphologic and biochemical evidences in chorioamniotic membranes. STUDY DESIGN: Chorioamniotic membranes were collected from normal term deliveries; group 1: term labor and group 2: term, not in labor. Senescence-related morphologic changes were determined by transmission electron microscopy and biochemical changes were studied by senescence-associated (SA) β-galactosidase staining. Amniotic fluid samples collected from both term labor and term not in labor were analyzed for 14 SA secretory phenotype (SASP) markers. RESULTS: Morphologic evidence of cellular senescence (enlarged cells and organelles) and a higher number of SA β-galactosidase-stained amnion and chorion cells were observed in chorioamniotic membranes obtained from women in labor at term, when compared to term not in labor. The concentration of proinflammatory SASP markers (granulocyte macrophage colony-stimulating factor, interleukin-6 and -8) was significantly higher in the amniotic fluid of women in labor at term than women not in labor. In contrast, SASP factors that protect against cell death (eotaxin-1, soluble Fas ligand, osteoprotegerin, and intercellular adhesion molecule-1) were significantly lower in the amniotic fluid samples from term labor. CONCLUSION: Morphologic and biochemical features of senescence were more frequent in chorioamniotic membranes from women who experienced term labor. Senescence of chorioamniotic membranes were also associated with amniotic fluid SASP markers.
- MeSH
- amnion cytologie metabolismus ultrastruktura MeSH
- beta-galaktosidasa metabolismus MeSH
- chemokin CCL11 metabolismus MeSH
- chorion cytologie metabolismus ultrastruktura MeSH
- dospělí MeSH
- faktor stimulující granulocyto-makrofágové kolonie metabolismus MeSH
- interleukin-6 metabolismus MeSH
- interleukin-8 metabolismus MeSH
- lidé MeSH
- ligand Fas metabolismus MeSH
- mezibuněčná adhezivní molekula-1 metabolismus MeSH
- mitochondrie ultrastruktura MeSH
- mladý dospělý MeSH
- osteoprotegerin metabolismus MeSH
- plodová voda cytologie metabolismus MeSH
- porod v termínu metabolismus MeSH
- porodní děj metabolismus MeSH
- průřezové studie MeSH
- stárnutí buněk * MeSH
- studie případů a kontrol MeSH
- těhotenství MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladý dospělý MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
