Abstract
Background
Lysyl oxidase-like 2 (LOXL2) belongs to a family of the LOX secretory enzyme, which involves the cross-linkage of extracellular matrix (ECM) proteins. Here, we aimed to analyze the correlation between serum LOXL2 and pelvic adhesion in chronic pelvic inflammatory disease (PID).
Methods
A total of 143 patients with PID and 130 healthy controls were included in this study. The serum levels of LOXL2 were measured using enzyme-linked immunosorbent assay (ELISA) kits. The patients were divided into non-adhesion group (102 cases) and adhesion group (41 cases).
Results
It was found that the serum level of LOXL2 expression was elevated in PID patients compared with healthy controls, and was elevated in PID patients with pelvic adhesion compared to patients without adhesion. In all PID patients, serum LOXL2 level was positively correlated with matrix metalloproteinases-9 (MMP-9), transforming growth factor-β (TGF-β1), whole blood viscosity (WBV) at low shear rate (LSR), WBV at high shear rate (HSR), and hematocrit (HcT). Multivariate logistic regression analysis showed that serum LOXL2 level was an independent risk factor for pelvic adhesion in PID patients (OR = 1.058; 95% CI = 1.030–1.086, P < 0.001).
Conclusions
Serum LOXL2 level not only predicts the presence of PID, but serum LOXL2 concentration is also associated with the presence of pelvic adhesions.
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Background
Pelvic inflammatory disease (PID) is an inflammatory disease caused by infection of microorganisms in the upper genital tract, such as endocervix, endometrium, fallopian tubes and ovaries. PID is characterized by infiltration of neutrophils and T-lymphocytes in the inflammatory lesions and a high neutrophil cell count in blood. PID can be divided into different types based on manifestations, such as endometritis, sal**itis and peritonitis [1]. Chronic infection and inflammation in PID can lead to several sequelae, such as chronic pelvic pain, endometriosis, and ectopic pregnancy [2]. Furthermore, genital tract infections lead to oviduct damage and its healing process involves scarring and adhesion formation, and this pelvic adhesion consequently increases the risk of tubal factor infertility and ectopic pregnancy [3, 26], and endometriosis is also associated with pelvic adhesion and fibrosis [27, 28]. Therefore, we speculate that LOXL2 may also play an important role in the formation of pelvic adhesion and fibrosis in PID, and more studies are needed to validate this hypothesis in PID tissue and animal model.
A large quantity of serum fibrotic markers has been found as possible biomarkers for PID, and our study showed that serum MMP-9, TGF-β1 and ICAM-1 levels were markedly higher in PID patients with pelvic adhesion. MMP-9 is a member of matrix metalloproteinases (MMPs), and is a key proteinase involved in normal matrix remodeling. MMPs can be produced by inflammatory cells to repair damaged ECM, while excessive MMPs can also promote the ECM degradation [29]. The level of plasma MMP-9 was elevated in PID patients compared with healthy controls [30]. TGF‑β1 signaling pathway is implicated in the fibrosis process, and serum TGF‑β1 level was increased in rats with chronic pelvic inflammatory disease (CPID) [31]. Our study supports this report in PID patients and further found its association with pelvic adhesion. TGF-β has potent fibrotic activity as TGF-β can induce endometrial fibrosis in human endometrial carcinoma cells [32]. ICAM-1 is a adhesion molecule that stimulates leukocyte adhesion. Serum ICAM-1 levels were higher in endometriosis patients compared to healthy women [33]. ICAM-1 can also promote human endometriotic stromal cells proliferation and adhesion [34]. Our previous study showed that ICAM-1 expression in uterus or fallopian tube were markedly increased in PID mice [35]. This study added MMP-9, TGF-β1 and ICAM-1 as new serum biomarkers of PID patients, and further showed their positive correlations with LOXL2. MMP-9 and TGF-β1 are both downstream molecules of LOXL2 in matrix remodeling and fibrogenesis of fibrosis associated diseases [8, 36]. Whether and how LOXL2 modulates MMP-9 and TGF-β1 remain totally unknown in PID and deserves further investigation.
There were some limitations to the study. Firstly, the sample size is small and our findings should be validated in study with larger sample. Secondly, the source of serum LOXL2 in PID patients is still unclear, and should be confirmed in biopsy tissue of PID patients. Thirdly, as an indicator for pelvic adhesion, prospective studies should be conducted to observe the predictive effect of LOXL2 on progression and recurrence of pelvic adhesion. Fourthly, an animal model of PID is needed to elucidate the possible mechanisms of LOXL2 in process of pelvic adhesion and fibrosis.
Conclusions
Serum LOXL2 levels are increased in PID patients, and also strongly correlated with pelvic adhesion, and fibrosis-related markers. Although these relationship are correlative and not causative, LOXL2 may be a disease-driver in pathogenesis of fibrotic process in PID in animal models. Our study provides LOXL2 as a biomarker for prediction of pelvic adhesion in PID patients.
Availability of data and materials
Data and materials are available upon request to the corresponding author.
Abbreviations
- ECM:
-
Extracellular matrix
- ELISA:
-
Enzyme-linked immunosorbent assay
- HcT:
-
Hematocrit
- HSR:
-
High shear rate
- LOX:
-
Lysyl oxidase
- LOXL2:
-
Lysyl oxidase like 2
- LSR:
-
Low shear rate
- MMP-9:
-
Matrix metalloproteinases-9
- PID:
-
Pelvic inflammatory disease
- TCM:
-
Traditional Chinese medicine
- TGF-β1:
-
Transforming growth factor-β
- WBV:
-
Whole blood viscosity
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Funding
This study was supported by Leading talents of health system in Pudong New Area (No. PWR12019-04) and Key subjects of TCM gynecology in Pudong New District (No. PWZxk2017-03). The funders provided financial support for the data collection and analysis of this study.
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Chan **e performed the experiment, collected data and wrote the manuscript; Bixin Tang designed the study and revised the manuscript; Kunlun Wu and Qingyi Meng performed the experiment and analyzed the data. Fang Wang performed the statistical analysis and revised the manuscript. All authors have read and approved the manuscript.
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The medical ethics committee of Shanghai Pudong New Area Gongli hospital approved this study protocol, and informed consent was obtained from all patients. All the experimental protocol for involving humans was by the guidelines of the Declaration of Helsinki.
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**e, C., Tang, B., Wu, K. et al. Increased serum LOXL2 concentration in pelvic inflammatory disease with pelvic adhesion. BMC Women's Health 22, 59 (2022). https://doi.org/10.1186/s12905-022-01640-1
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DOI: https://doi.org/10.1186/s12905-022-01640-1