Preterm premature rupture of the membranes (pPROM) occurs in about 3%-4% of all pregnancies and is a direct antecedent to 40% to 50% of all spontaneous preterm births. Improvements in prenatal care have not reduced the rates of pPROM and subsequent preterm births. Our understanding of the pathways leading to pPROM remains limited and a precise understanding of the mechanistic pathways and biomarkers will greatly improve our knowledge of pPROM. Antibacterial interventions for infection or cessation of cigarette smoking during pregnancy have not reduced the risk of pPROM, severity of histologic chorioamnionitis, or fetal inflammatory response syndrome. However, an approach based on the pathway induced by these risks factors may provide better targets for screening and diagnosis to prevent pPROM. Our recent data show increased reactive oxygen species (ROS), lipid peroxidation, DNA damage, and telomere shortening, in vivo in biological samples from pPROM and in vitro in normal fetal cells exposed to ROS-inducing pPROM risk factor (infection and cigarette smoking). We also found increased prosenescence phospho-p38 MAPK (mapkinase) and senescence-associated ?-galectosidase (? -gal), suggesting premature senescence of the fetal cells. This led us to postulate a new mechanistic pathway to pPROM. We propose ROS-induced premature ageing (senescence phenotype [SP]) of the fetal membranes as a major pathologic initiator of a unique senescence- associated secretory protein (SASP) network that includes inflammatory and proteolytic markers. SP and SASP activation leads to fetal membrane weakening resulting in pPROM. Attenuation of this SP promoting pathway will prevent pPROM complicated by ROS. We will further elucidate the mechanism behind SP activation through our hypothesis that ROS activates p38 MAPK-induced SP in fetal amnion cells by disassociation of Apoptosis signal-regulating kinase 1 (ASK1) from its inactive and inhibitory status in complex with thioredoxin (Trx). The ROS-mediated dissociation ASK1 from Trx activates ASK1 promoting phosphorylation of p38 MAPK and downstream SP effecters of p38 MAPK. Using an in vitro model of amnion cells and lipopolysaccharide (LPS) and cigarette smoke extract (CSE) as 2 independent stimuli, we will document SP activation in fetal cells and the unique SASP signature generated by LPS and CSE. LPS and CSE will produce distinct patterns of SP and SASP. This novel mechanism will provide information on the underlying pathology and events that precede inflammation, thus providing upstream targets screening, diagnosis, and intervention.
NIH ExPorter
NIH ExPorter