Vaginal Lactoferrin Modulates PGE2, MMP-9, MMP-2, and TIMP-1 Amniotic Fluid Concentrations

Alessandro Trentini, Martina Maritati, Carlo Cervellati, Maria C Manfrinato, Arianna Gonelli, Carlo A Volta, Fortunato Vesce, Pantaleo Greco, Franco Dallocchio, Tiziana Bellini, Carlo Contini, Alessandro Trentini, Martina Maritati, Carlo Cervellati, Maria C Manfrinato, Arianna Gonelli, Carlo A Volta, Fortunato Vesce, Pantaleo Greco, Franco Dallocchio, Tiziana Bellini, Carlo Contini

Abstract

Inflammation plays an important role in pregnancy, and cytokine and matrix metalloproteases (MMPs) imbalance has been associated with premature rupture of membranes and increased risk of preterm delivery. Previous studies have demonstrated that lactoferrin (LF), an iron-binding protein with anti-inflammatory properties, is able to decrease amniotic fluid (AF) levels of IL-6. Therefore, we aimed to evaluate the effect of vaginal LF administration on amniotic fluid PGE2 level and MMP-TIMP system in women undergoing genetic amniocentesis. One hundred and eleven women were randomly divided into controls (n = 57) or treated with LF 4 hours before amniocentesis (n = 54). Amniotic fluid PGE2, active MMP-9 and MMP-2, and TIMP-1 and TIMP-2 concentrations were determined by commercially available assays and the values were normalized by AF creatinine concentration. PGE2, active MMP-9, and its inhibitor TIMP-1 were lower in LF-treated group than in controls (p < 0.01, p < 0.005, and p < 0.001, resp.). Conversely, active MMP-2 (p < 0.0001) and MMP-2/TIMP-2 molar ratio (p < 0.001) were increased, whilst TIMP-2 was unchanged. Our data suggest that LF administration is able to modulate the inflammatory response following amniocentesis, which may counteract cytokine and prostanoid imbalance that leads to abortion. This trial is registered with Clinical Trial number NCT02695563.

Figures

Figure 1
Figure 1
Concentrations of the inflammation markers measured in the amniotic fluids of controls and patients treated with lactoferrin 4 hours before amniocentesis. Values were normalized for the creatinine concentration and are presented as ng/mg creatinine. The Mann-Whitney U test was used for the comparison between the groups. Significant lower levels of PGE2 ((a), median [interquartile range] controls: 5.38 [4.44–8.24]; LF treated: 3.87 [2.97–6.33], p < 0.01), active MMP-9 ((b), controls: 71.02 [34.51–105.02]; LF treated: 42.67 [13.66–81.12], p < 0.005), and TIMP-1 ((d), controls: 84047 [66028–97949]; LF treated: 65952 [44201–82110], p < 0.001) were found in lactoferrin-treated patients compared to controls. Increased levels of active MMP-2 ((c), controls: 105.67 [80.61–137.17]; LF treated: 282.90 [127.40–492.71], p < 0.0001) were found in patients treated with lactoferrin whereas the levels of TIMP-2 were comparable ((e), controls: 5098 [3276–6829]; LF treated: 6266 [4031–9959], p = 0.233). In all the panels, the line between the data represents the median. PGE2: prostaglandin E2; MMP-9: matrix metalloproteinase-9; MMP-2: matrix metalloproteinase-2; TIMP-1: tissue inhibitor of metalloproteinase-1; TIMP-2: tissue inhibitor of metalloproteinase-2.
Figure 2
Figure 2
Evaluation of MMP/TIMP molar ratio in controls and patients treated with lactoferrin. MMP-9/TIMP-1 molar ratio was not different in controls and patients treated with lactoferrin 4 hours before amniocentesis (a), whereas we observed an increase in the MMP-2/TIMP-2 ratio after treatment with lactoferrin ((b), p < 0.0001). It is noteworthy that the ratio was below 1. In all the panels, the line between the data represents the median. MMP-9: matrix metalloproteinase-9; MMP-2: matrix metalloproteinase-2; TIMP-1: tissue inhibitor of metalloproteinase-1; TIMP-2: tissue inhibitor of metalloproteinase-2.

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