Proteomic analysis of human cervicovaginal fluid collected before preterm premature rupture of the fetal membranes

Abstract

A significant obstetric complication facing contemporary materno-fetal medicine is preterm premature rupture of the fetal membranes (preterm PROM), which occurs in 30% of all preterm births. The objective of this study was to identify differentially expressed proteins in the cervicovaginal fluid of asymptomatic women before the clinical manifestation of preterm PROM. The preterm PROM group comprised of women with samples collected 6-23 days before PROM, who subsequently delivered preterm (nZ5). Women who spontaneously delivered at term served as gestation-matched controls (nZ10). Two-dimensional difference in-gel electrophoresis was used to distinguish differential expression between the pooled groups and fold changes were subsequently confirmed by two-dimensional PAGE of individual samples. Spots of interest were identified by mass spectrometry. Proteins that were significantly reduced with impending preterm PROM included the following: thioredoxin (2.7-fold), interleukin 1 receptor antagonist (1.7-fold), fatty acid-binding protein 5 (2.1-fold), cystatin A (dimer; 1.9-fold), monocyte/neutrophil elastase inhibitor (1.6-fold), squamous cell carcinoma antigen-1 (2.1-fold) and g-glutamyl cyclotransferase (3.0-fold). By contrast, annexin A3 (3.7-fold) and vitamin D binding protein (3.9-fold) were significantly increased with impending preterm PROM. Western blot analysis was also performed on an independent cohort of preterm PROM and control samples to validate these candidate biomarkers. These proteins have known biological functions in oxidative balance, anti-inflammatory activity, metabolism or protease inhibition that may facilitate membrane rupture.

Cervicovaginal microbiome dysbiosis is associated with proteome changes related to alterations of the cervicovaginal mucosal barrier

“…A delicate balance between proteases and antiproteases most likely allows for combating infections, whereas at the same time minimizing tissue damage and inflammation. Studies have indeed shown negative associations between the antiprotease CSTA and known BV complications in pregnant women, [17][18][19] and between the antiproteases CSTA and serine protease inhibitor Kazal-type 5 and HIV acquisition in African sex workers. 15 The authors hypothesized that the latter is likely due to reduced cervicovaginal inflammation, and therefore a reduced influx of CD4 þ CCR5 þ target cells for HIV to mucosal surfaces that are exposed to HIV.…”

“…[9][10][11][12][13][14] Furthermore, in vitro studies have shown that lactobacilli do not generally induce human AMPs, whereas BV-associated bacteria (such as Gardnerella vaginalis, A. vaginae and P. bivia) do. 10,12 The cervicovaginal proteome has been characterized by others before, [15][16][17][18][19][20] but never in the context of different VMB compositions. We hypothesized that VMB dysbiosis is associated with cervicovaginal inflammation, and other changes to the mucosal barrier that might cause increased HIV acquisition and other adverse reproductive health outcomes.…”

New biomarkers for the prediction of spontaneous preterm labour in symptomatic pregnant women: a comparison with fetal fibronectin

“…25 For women who spontaneously labour at a preterm gestation, it is speculated that the Concentration threshold values for albumin (≥19 000 ng/ml) and VDBP (≥90 ng/ml) are based on the results presented in Table 2. *LR+ and OR values were determined using a specificity of >98% as specificities of 100% result in undefined LR+ and OR values.…”

The Interplay of the Interleukin 1 System in Pregnancy and Labor

“…8 In addition, we recently found that IL-1ra was significantly decreased by 40% in the CVF of women who subsequently experienced preterm PROM compared with gestation-matched controls. 34 Future studies elucidating the direct role of IL-1ra in fetal membrane physiology could be of interest.…”