Significant elevation and correlation of plasma neutrophil gelatinase associated lipocalin and its complex with matrix metalloproteinase-9 in patients with pelvic inflammatory disease
Introduction
Neutrophil gelatinase associated lipocalin (NGAL), also referred to as lipocalin 2, is a 25-kDa secretory glycoprotein that was first isolated from the specific granules of human polymorphonuclear neutrophils [1]. It belongs to a large family of lipocalins, which are a group of small extracellular proteins and characteristically bind small lipophilic molecules because of their common three-dimensional β-barrel structure and have great functional diversity [2]. NGAL is regarded as a“stress protein”, which is induced and produced by numerous types of cells after exposure to various stress conditions, probably in order to activate iron-dependent enzymatic defense systems [3]. It is also an acute phase protein of which expression is up-regulated in human epithelial cells under different inflammatory conditions [4], [5]. It was found that NGAL binds small iron-carrying molecules (siderophores) and it is important in a variety of states, such as bacterial infection and kidney injury [3], [6], [7]. NGAL has emerged as a potentially useful diagnostic biomarker in acute kidney injury [8], [9], [10].
NGAL was originally identified as a glycoprotein in complex with matrix metalloproteinase-9 (MMP-9) in human neutrophils [11], [12]. It bound with MMP-9 covalently to form a 135-kDa disulfide-linked heterodimer. NGAL was shown to be able to bind and stabilize MMP-9 [13] and facilitate intracellular iron delivery, thus playing a regulatory role in iron-dependent gene transcription in kidney development [3]. The NGAL/MMP-9 complex was also demonstrated to prevent MMP-9 degradation and increase MMP-9 enzyme activity in breast and gastric cancers [14], [15]. To date, few data are available on the significance of NGAL and NGAL/MMP-9 complex in pelvic inflammatory disease (PID).
PID probably results in scarring and adhesion formation, those accompany healing of damaged tissues, including genital organs or neighboring pelvic organs after the infection itself is eradicated. It may lead to female infertility of tubal factor. Women, who have tubal factor infertility apparently induced by past episodes of PID, often give no history of PID because many patients with PID have subtle or mild symptoms. In order to prevent the delay in diagnosis of PID that contributes to tubal sequelae, early diagnosis and treatment of PID may decrease the incidence of tubal factor infertility. Therefore, it is reasonable to introduce biologic factors to offer early diagnosis of PID. To our knowledge, no study attempts to investigate the levels of plasma NGAL and NGAL/MMP-9 complex during diagnostic work-up of PID. The purposes of this study were to compare the plasma levels of NGAL and NGAL/MMP-9 complex between patients with PID and normal controls as well as correlate the expression of biomarkers, and further determine their cutoff levels in distinguishing patients with PID from healthy women.
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Subjects and samples collection
We designed a hospital-based case-control study to consecutively enroll 64 patients with PID and 70 healthy women, who visited Department of Obstetrics and Gynecology and Department of Family Medicine for health examination, between April 2006 and September 2007. The controls were included as age-group matched to cases by almost 1:1 control-to-case ratio. They were also matched in sociodemographic and clinical data such as ethnic group, occupation, cigarette smoking and alcohol drinking.
PID was
Results
The plasma level of NGAL was significantly increased in patients with PID before they received treatment as compared to that in control subjects (median: 17.69 vs. 8.83 ng/ml, P < 0.001; Table 1). In addition, the level of NGAL/MMP-9 complex of pretreatment plasma in patients with PID was significantly higher than that of plasma in controls (median: 3.86 vs. 2.23; P < 0.001). Furthermore, the plasma level of NGAL in patients with PID before they received treatment was significantly increased as
Discussion
In this study, we found that the level of plasma NGAL in patients with PID was increased, as compared to that in healthy women. After treatment, the level of NGAL was significantly reduced. The principal characteristic of NGAL is to capture iron particles, the siderophores and transport them to the inner cell, thus causing an increase in the cytoplasmic levels of the precious mineral [17]. Bacteria can produce siderophores to shuttle iron from the extracellular space, therefore providing an
Acknowledgment
This study was supported by research grants from National Science Council, Taiwan (NSC 98-2314-B-040-014-MY3 and NSC 99-2314-B-040-011-MY3).
References (27)
- et al.
The lipocalin protein family: structural and sequence overview
Biochim Biophys Acta
(2000) - et al.
An iron delivery pathway mediated by a lipocalin
Mol Cell
(2002) - et al.
The neutrophil lipocalin NGAL is a bacteriostatic agent that interferes with siderophore-mediated iron acquisition
Mol Cell
(2002) - et al.
Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery
Lancet
(2005) - et al.
A 25 kDa alpha 2-microglobulin-related protein is a component of the 125 kDa form of human gelatinase
FEBS Lett
(1992) - et al.
Isolation and primary sequence of NGAL, a novel protein associated with human neutrophil gelatinase
J Biol Chem
(1993) - et al.
The high molecular weight urinary matrix metalloproteinase (MMP) activity is a complex of gelatinase B/MMP-9 and neutrophil gelatinaseassociated lipocalin (NGAL). Modulation of MMP-9 activity by NGAL
J Biol Chem
(2001) - et al.
Clinical evidence for a protective role of lipocalin-2 against MMP-9 autodegradation and the impact for gastric cancer
European J Cancer
(2007) - et al.
Significant elevation of plasma matrix metalloproteinase-9 level and its ratio to matrix metalloproteinase-2 in patients with pelvic inflammatory disease
Fertil Steril
(2009) - et al.
Lipocalins as biochemical markers of disease
Biochim Biophys Acta
(2000)
Laboratory evaluation of acute upper genital tract infection
Obstet Gynecol
Neutrophil gelatinase-associated lipocalin, a siderophore-binding eukaryotic protein
Biometals
Tissue involution and the acute phase response
Ann NY Acad Sci
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