The usefulness of MMP-9, TIMP-1 and MMP-9/TIMP-1 ratio for diagnosis and assessment of COPD severity

Abstract

Background: Inflammation, oxidative stress and an imbalance between proteases and protease inhibitors are recognized pathophysiological features of chronic obstructive pulmonary disease (COPD). The aim of this study was to evaluate serum levels of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in patients with COPD and to assess their relationship with lung function, symptom severity scores and recent acute exacerbations. Methods: In this observational cohort study, serum levels of MMP-9 and TIMP-1 and the MMP-9/TIMP-1 ratio in the peripheral blood of COPD patients with stable disease and healthy controls were determined, and their association with lung function (postbronchodilator spirometry, body plethysmography, single breath diffusion capacity for carbon monoxide), symptom severity scores (mMRC and CAT) and exacerbation history were assessed. Results: COPD patients (n = 98) had significantly higher levels of serum MMP-9 and TIMP-1 and a higher MMP-9/TIMP-1 ratio than healthy controls (n = 47) (p ≤ 0.001). The areas under the receiver operating characteristic curve for MMP-9, TIMP-1 and the MMP-9/TIMP-1 ratio for COPD diagnosis were 0.974, 0.961 and 0.910, respectively (all p < 0.05). MMP-9 and the MMP-9/TIMP-1 ratio were both negatively correlated with FVC, FEV1, FEV1/FVC, VC, and IC (all p < 0.05). For MMP-9, a positive correlation was found with RV/TLC% (p = 0.005), and a positive correlation was found for the MMP-9/TIMP-1 ratio with RV% and RV/TLC% (p = 0.013 and 0.002, respectively). Patients with COPD GOLD 3 and 4 presented greater MMP-9 levels and a greater MMP-9/TIMP-1 ratio compared to GOLD 1 and 2 patients (p ≤ 0.001). No correlation between diffusion capacity for carbon monoxide and number of acute exacerbations in the previous year was found. Conclusions: COPD patients have elevated serum levels of MMP-9 and TIMP-1 and MMP-9/TIMP-1 ratio. COPD patients have an imbalance between MMP-9 and TIMP-1 in favor of a pro-proteolytic environment, which overall indicates the importance of the MMP-9/TIMP-1 ratio as a potential biomarker for COPD diagnosis and severity.