Abstract
Preterm premature rupture of membranes (PPROM), defined as rupture of fetal membranes prior to 37 weeks of gestation, complicates approximately 2–4% of pregnancies and is responsible for 40% of all spontaneous preterm births. PPROM arises from complex pathophysiological pathways with a key actor: inflammation. Sterile inflammation is a feature of senescence-associated fetal membrane maturity. During specific steps of sterile inflammation, cells also release highly inflammatory damage-associated molecular pattern markers (DAMPs), such as high-mobility group box 1 (HMGB1) or S100A8/A9, known to link and activate the receptor for advanced glycation end products (RAGE). The objective of this study was to measure longitudinally during pregnancy concentrations of the soluble form of RAGE (sRAGE) and its main ligands (AGE, HMGB1, S100A8/A9) in blood specimens. We studied 246 pregnant women (82 with PPROM and 164 matched control pregnant women without complications) from a cohort of 7,866 pregnant women recruited in the first trimester and followed during pregnancy until delivery. sRAGE, AGE, HMGB1, and S100A8/A9 concentrations were measured in plasma and in serum-extracted extracellular vesicles from first trimester (T1), second trimester (T2), and delivery (D). In plasma, we observed, in both PPROM and control groups, (i) a significant increase of HMGB1 concentrations between T1 vs. T2, T1 vs. D, but not between T2 vs. D; (ii) a significant decrease of sRAGE concentrations between T1 and T2 and a significant increase between T2 and D; (iii) a significant decrease of AGE from T1 to D; (iv) no significant variation of S100A8/A9 between trimesters. In intergroup comparisons (PPROM vs. control group), there were no significant differences in time variation taking into account the matching effects. There was a correlation between plasma and serum-extracted extracellular vesicle concentrations of sRAGE, AGE, HMGB1, and S100A8/A9. Our results suggest that the rupture of fetal membranes (physiological or premature) is accompanied by a variation in plasma concentrations of sRAGE, HMGB1, and AGE. The study of RAGE and its main ligands in extracellular vesicles did not give additional insight into the pathophysiological process conducting to PPROM.
Highlights
Preterm premature rupture of membranes (PPROM), defined as rupture of fetal membranes prior to 37 weeks of gestation, complicates approximately 2–4% of all pregnancies and is responsible for 40–50% of all preterm births (Naeye and Peters, 1980; Mercer et al, 2000)
Combining maternal characteristics and environmental and clinical known risk factors (Bouvier et al, 2019) to candidate biomarkers may in the future result in proposing a clinically predictive model identifying asymptomatic women at higher risk of PPROM. In this context, taking advantage of a large cohort of pregnant women recruited prospectively at the beginning of pregnancy, we investigated the changes in the concentrations of the soluble form of receptor for advanced glycation end products (RAGE) and its main ligands (AGE, High-mobility group box 1 (HMGB1), S100A8/A9) in plasma and in the serum-extracted extracellular vesicles from first trimester to delivery to better understand the potential role of the RAGE system in PPROM
A significant difference (p < 0.001) for the gestational age at delivery was expectedly observed between the PPROM group [36 weeks, interquartile range (IQR): 35.1–36.4] and the control group (38.7 weeks, IQR: 38.1–39.3) (Table 1)
Summary
Preterm premature rupture of membranes (PPROM), defined as rupture of fetal membranes prior to 37 weeks of gestation, complicates approximately 2–4% of all pregnancies and is responsible for 40–50% of all preterm births (Naeye and Peters, 1980; Mercer et al, 2000). Recent reports indicated that PPROM may be associated with sterile inflammation in the fetal membranes (Romero et al, 2015). In support of this hypothesis, it has been shown that histological chorioamnionitis in the presence of a negative amniotic fluid culture increases the risk of preterm birth (Park et al, 2017). It was observed that HMGB1 induces an inflammatory response, partially mediated by the inflammasome, in the fetal membranes (Plazyo et al, 2016) This intra-amniotic inflammasome activation was highlighted in vivo in human (Gomez-Lopez et al, 2019). Calprotectin (or S100A8/A9) is a known ligand of RAGE (Pruenster et al, 2016) implicated in some pregnancy pathologies as preeclampsia (Pergialiotis et al, 2016)
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