MMP-2 and TIMP-1 are not produced by PMNs. The third cascade comprises MMP-2, tissue inhibitor of matrix metalloproteinases-1 (TIMP-1), MMP-8/TIMP-1 molar ratio, and C-reactive protein (CRP) (Cascade 3). Thus, HNE and MMP-9 form another PMN-derived proteolytic cascade (Cascade 2), to which elafin associates. Elafin is produced not only by neutrophils but also by epithelial cells.
#Amniotic fluid infection Activator
HNE is an activator of MMP-9, and elafin is an antiprotease of HNE. MPO is the activator of MMP-8 and MMP-9, while IL-6 can act as their inducer (Cascade 1). The process leads to degradation of extracellular matrix components and modulation of cytokines, which may lead in obstetrics to membrane rupture or ripening and softening of the cervix. Those and other such enzymes can form cascades by activating each other. They are formed in inflammatory conditions after recruitment and activation of neutrophils, which release their subcellular granules, that is, degranulating tissue destructive enzymes (for example, MMP-8, MMP-9, and neutrophil elastase (HNE)). Several AF biomarkers form proteolytic cascades. MMP-8 has been linked to MIAC, inflammation, histological chorioamnionitis (HCA), and adverse neonatal outcome. Infection may induce the degranulation of interleukin- (IL-) 6 and matrix metalloproteinases (MMP), from polymorphonuclear neutrophils (PMNs). Amniocentesis and amniotic fluid (AF) rapid biomarker testing may help in optimal timing of delivery.
However, intra-amniotic inflammation in the absence of MIAC also occurs. Intra-amniotic infection (IAI), defined as microbial invasion of the amniotic cavity (MIAC) with intra-amniotic inflammation, is common in women with preterm labor and exists with or without preterm prelabor rupture of membranes (PPROM). Neutrophil based AF biomarkers were associated with IAI and MIAC. Odd ratios of biomarkers for MIAC were 1.2-38 and 95% confidential intervals 1.0-353.6. All biomarkers except elafin and MMP-2 had the sensitivity of 100% with thresholds based on ROC-curve. MMP-8, MMP-9, MPO, elafin, and TIMP-1 concentrations were higher in IAI suspected cases compared to controls and also in IAI suspected cases with MIAC compared to those without MIAC when adjusted by gestational age at amniocentesis. Standard biochemical methods, molecular microbiology, and culture techniques were used. MMP-8 was measured by an immunoenzymometric assay and the others were measured by ELISA. AF biomarkers were divided into three cascades: Cascade 1: matrix metalloproteinase-8 (MMP-8), MMP-9, myeloperoxidase (MPO), and interleukin-6 Cascade 2: neutrophil elastase (HNE), elafin, and MMP-9 Cascade 3: MMP-2, tissue inhibitor of matrix metalloproteinases-1 (TIMP-1), MMP-8/TIMP-1 molar ratio, and C-reactive protein (CRP). Amniocentesis was made to 73 women with singleton pregnancies 27 with suspected IAI and 46 controls. We evaluated amniotic fluid (AF) proteolytic cascade forming biomarkers in relation to microbial invasion of the amniotic cavity (MIAC) and IAI in preterm pregnancies with intact membranes. Intra-amniotic infection (IAI) is a major cause of preterm labor and adverse neonatal outcome.
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