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

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.

Vaginal Lactoferrin Administration Decreases Oxidative Stress in the Amniotic Fluid of Pregnant Women: An Open-Label Randomized Pilot Study

“…Therefore, the in vivo finding that women administered with LF 12 h before amniocentesis had levels of TAS and OSI comparable with controls, but still a significant MDA-lowering activity, may be due to the short in vivo half-life of the protein ( 15 ). This is in line with our previous observations indicating that LF seems more effective at 4 h rather than 12 h of administration ( 16 , 17 ). Thus, from a mechanistic point of view, once LF enters the amniotic compartment it can decrease the formation of lipoperoxides by directly scavenging intermediary ROS, or by “removing” Fe 3+ from the Fenton reaction ( 27 , 28 ).…”

“…Lactoferrin easily fulfill these criteria. In fact, our previous studies demonstrated that LF administration is able to modulate inflammatory markers in the amniotic fluid, including the detrimental MMPs connected to pre-labor rupture of membranes (PROM) and PPROM (16,17). In addition, there is overwhelming evidence that LF can normalize insult-induced reactions due to immune modulation properties (21).…”

“…In previous works, we demonstrated that vaginal lactoferrin administration is able to modulate the expression of inflammatory markers and Matrix Metalloproteases (MMPs), strongly involved in preterm labor, PROM and PPROM (15)(16)(17). Lactoferrin (LF) is an 80 kDa glycoprotein normally present in mammals, with a primary role as a defense mechanism against microbial infections (18).…”

Lactoferrin in Aseptic and Septic Inflammation

“…Almost the same results were obtained by Locci et al [102] in a longitudinal study where intravaginal bLf treatment, consisting of 300 mg bLf for 21 days in asymptomatic women at low risk for PTD, was effective in lowering cervico-vaginal IL-6 levels and improving cervical length [102]. Moreover, in other studies, conducted on pregnant women showing high levels of pro-inflammatory mediators in AF, a single intravaginal bLf administration (300 mg), 4 h or 12 h before amniocentesis, was surprisingly efficient in partially decreasing some mediators of pro-inflammatory processes, including IL-6 [110,111,112].…”

From Pregnancy Loss to COVID 19 Cytokine Storm: A Matter of Inflammation and Coagulation

“…We found that vaginal lactoferrin significantly lowers PGE 2, active MMP-9, and its inhibitor TIMP-1. Conversely, active MMP-2 and MMP-2/TIMP-2 molar ratio are increased, whilst TIMP-2 remains unchanged [60].…”