Matrix metalloproteinases in the cervical mucus plug in relation to gestational age, plug compartment, and preterm labor

Abstract

BackgroundHigh concentrations of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) have been identified in the cervical mucus plug (CMP) at term of pregnancy. Their physiological and pathophysiological implications, however, remain to be elucidated, and CMPs from preterm labor have never been examined. This study was therefore conducted to describe the concentrations of MMP-2, TIMP-1, MMP-8 and MMP-9 in the CMP in relation to gestational age, IL-8 as an indicator of inflammation, compartment of the CMP, and preterm labor.MethodsAn aliquot of the distal plug compartment facing the vaginal microflora (CMP-dist) was collected from non-pregnant (n = 15), early pregnant (n = 15) and term pregnant women (n = 15). Whole CMPs shed during active vaginal term (n = 15) and preterm (n = 4) labor were also included. Protein concentrations were determined by enzyme-linked immunosorbent assay (ELISA).ResultsMMP-2 was not detectable in the non-pregnant CMP-dists whereas high concentrations were found in early pregnancy followed by an 85% decline at term. High concentrations of TIMP-1 were found in both the non-pregnant and early pregnant CMP-dists with a 90% decline at term. Consequently, the molar TIMP/MMP ratio was 40 in the non-pregnant state and 0.2 at term. The MMP-2 and TIMP-1 concentrations were alike in the CMP-dists and the whole CMPs.MMP-8, MMP-9, and IL-8 were mainly found in the distal CMP compartment. MMP-8 and MMP-9 concentrations were several fold increased in this compartment during pregnancy compared to the non-pregnant state. In the preterm whole CMPs, MMP-8, MMP-9 and IL-8 were 2 to 5 fold increased compared to term whole CMPs.ConclusionsThese results suggest that CMP MMP-2 reflects the non-leukocyte dependent cervical remodeling that occurs in early pregnancy, whereas MMP-8 and MMP-9 are involved in the defense against ascending infections primarily located to the distal compartment of the CMP. The upregulation of MMP-8, MMP-9 and IL-8 in whole CMPs from preterm labor may indicate the involvement of an intrauterine infection.

Colonization of the upper genital tract by vaginal bacterial species in nonpregnant women

“…4 Upper genital tract infection has been presumed to be due to pathologic ascent of vaginal bacteria in to the upper genital tract. The physical barrier of cervical mucous, its high concentrations of antimicrobial peptides and inflammatory cytokines, 5–9 and possibly immunoglobulins 10 or matrix degrading enzymes 11 in the mucous plug are thought to provide a defense against bacterial ascent and the uterine cavity of healthy women has long been considered sterile.…”

Human Three-Dimensional Endometrial Epithelial Cell Model To Study Host Interactions with Vaginal Bacteria and Neisseria gonorrhoeae

“…Cervical mucus contains a high concentration of cytokines (10), antimicrobial peptides (11), and immunoglobulins and matrix metalloproteinases (12) that function to protect the uterus against bacterial colonization. However, many studies indicate that bacteria from the lower FRT are nevertheless able to cross these physical and physiological barriers.…”

Loop electrosurgical excision procedure and risk of vaginal infections during pregnancy: an observational study

“…Two meta‐analyses from 2006 to 2011, incorporating mounting observational data, reported an increased risk for PTB and/or preterm rupture of membranes associated with cervical excision procedures . Putative mechanisms for the increased risk for PTB in women with a prior LEEP, reported in some studies, include disruption in collagen strength as a result of tissue removal, underlying demographic and sexual risk factors, associated with the development of severe dysplasia, and disruption of normal cervical immune defences . After LEEP the transition zone of the cervix is excised and the normal antimicrobial barrier of the cervical gland mucus is altered, possibly facilitating the acquisition of ascending infections …”

“…10,11 Putative mechanisms for the increased risk for PTB in women with a prior LEEP, reported in some studies, include disruption in collagen strength as a result of tissue removal, underlying demographic and sexual risk factors, associated with the development of severe dysplasia, and disruption of normal cervical immune defences. 5,7,8,[12][13][14] After LEEP the transition zone of the cervix is excised and the normal antimicrobial barrier of the cervical gland mucus is altered, possibly facilitating the acquisition of ascending infections. 12,13,15 On the other hand other observational studies have shown no increased risk for preterm delivery, 16,17 and another meta-analysis suggested an increased risk for PTB after cervical excision, but not for the LEEP procedure specifically.…”

“…5,7,8,[12][13][14] After LEEP the transition zone of the cervix is excised and the normal antimicrobial barrier of the cervical gland mucus is altered, possibly facilitating the acquisition of ascending infections. 12,13,15 On the other hand other observational studies have shown no increased risk for preterm delivery, 16,17 and another meta-analysis suggested an increased risk for PTB after cervical excision, but not for the LEEP procedure specifically. 18 A recent meta-analysis suggested that LEEP is associated with a higher risk for PTB, although this risk was attenuated if compared with women with cervical dysplasia but not with LEEP.…”