Exploring the Role of Matrix Metalloproteinases as Biomarkers in Sporadic Lymphangioleiomyomatosis and Tuberous Sclerosis Complex. A Pilot Study.

Silvia Terraneo,Angela Peron,Silvia Ancona,Olga Torre,Elena Lesma,Gianluca Imeri,Silvia Tresoldi,Fabiano Di Marco,Lisa Giuliani,Stefano Centanni,Paola Cetrangolo,Giuseppina Palumbo

doi:10.3389/fmed.2021.605909

Abstract

Background: Lymphangioleiomyomatosis can develop in a sporadic form (S-LAM) or in women with tuberous sclerosis complex (TSC). The matrix metalloproteinases (MMPs) are extracellular matrix-degrading enzymes potentially involved in cystic lung destruction, and in the process of migration of LAM cells. The aim of the study was to explore the role of MMP-2 and MMP-7, such as vascular endothelial growth factor (VEGF) -C and -D in women with LAM, including patients with minor pulmonary disease (i.e., <10 lung cysts), and TSC with or without LAM.Methods: We evaluated 50 patients: 13 individuals affected by S-LAM, 20 with TSC-LAM, of whom six with minor pulmonary disease, and 17 with TSC without pulmonary involvement. Sixteen healthy women were used as controls.Results: MMP-2 resulted higher in LAM compared to healthy volunteers, and TSC patients (p = 0.040). MMP-7 was higher in TSC-LAM patient, with even greater values in patients with TSC-LAM minor pulmonary disease, than in S-LAM patients, and in controls (p = 0.001). VEGF-D level was lower than 800 pg/mL in all healthy controls and resulted higher in S-LAM and TSC-LAM than in TSC patients and controls (p < 0.001). VEGF-C values were not statistically different in the study population (p = 0.354). The area under ROC curves (AUCs) of MMP-2, and MMP-7 for predicting LAM diagnosis were of 0.756 ± 0.079 (p = 0.004), and 0.828 ± 0.060 (p < 0.001), respectively. Considering only patients with TSC, the AUCs for MMP-2, and MMP-7 in predicting LAM were 0.694 ± 0.088 (p = 0.044), and 0.713 ± 0.090 (p = 0.027), respectively.Conclusions: Our data suggest that MMP-2 and MMP-7 could be promising biomarkers for LAM diagnosis.

Highlights

Lymphangioleiomyiomatosis (LAM) is a rare progressive cystic lung disease affecting mostly women in the childbearing age [1]
matrix metalloproteinases (MMPs)-2 resulted higher in LAM compared to healthy volunteers, and tuberous sclerosis complex (TSC) patients (p = 0.040)
The area under receiver operating characteristic (ROC) curves (AUCs) of MMP-2, and MMP-7 for predicting LAM diagnosis were of 0.756 ± 0.079 (p = 0.004), and 0.828 ± 0.060 (p < 0.001), respectively

Summary

Introduction

Lymphangioleiomyiomatosis (LAM) is a rare progressive cystic lung disease affecting mostly women in the childbearing age [1]. VEGF is able to recruit lymphatic endothelial cells, driving the formation of lymphatic vascular channels This abnormal lymphangiogenesis leads to vascular and airways obstruction and consequent development of air cystic lesions in the pulmonary parenchyma [6]. In patients with LAM, VEGF-D serum level correlates with disease severity, namely chylous effusions and/or lymphatic involvement [11, 12], lung function at presentation and rate of disease progression [13] systemic involvement in patients with TSC [14], and pulmonary functional impairment [15, 16]. The aim of the study was to explore the role of MMP-2 and MMP-7, such as vascular endothelial growth factor (VEGF) -C and -D in women with LAM, including patients with minor pulmonary disease (i.e.,

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Conclusion