Proteolytic imbalance in COPD: epidemiological and clinical aspects

Background: The complete pathologic mechanism behind the development of chronic obstructive pulmonary disease (COPD) remains unclear, but several risk factors have been identified, of which smoking is the most common. Proteolytic imbalance contributes to lung tissue degradation and is related to both smoking and COPD symptoms. Spirometry and symptomatic assessments are the standard diagnostics, but COPD has varying clinical features, that hamper clinical management and research assessment. Evaluating proteolytic markers' relationship to COPD and its clinical presentation could reveal proteolytic imbalance as an important disease mechanism. Aims: 1) To evaluate proteolytic markers in COPD and non-COPD. 2) To study the relationship between proteolytic markers and both lung function decline and prognosis. 3) To recruit subjects from a longitudinal study to a clinical study of disease mechanisms. 4) To study proteolytic markers in airways and serum and their relation to rate of decline in lung function. Methods: Spirometry, serum matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinase-1 (TIMP-1) were evaluated in a population-based study comprising 993 COPD subjects and 993 age- and sex-matched non-COPD referents. In addition, data from 2005 to 2010 were surveyed comprising longitudinal spirometry data and mortality records. For a clinical study, we described the recruitment process of COPD subjects with a FEV1 decline of ≥60 or ≤30 mL/year, along with ever- and never-smoking controls with normal lung function. MMP-9, MMP-12, and TIMP-1 data from bronchial wash (BW), bronchoalveolar lavage (BAL) and serum (collected from 2012 to 2014) were assessed in the clinical study. Results: COPD subjects presented higher serum concentrations of MMP- 9 compared to non-COPD subjects (p = 0.017). MMP-9 and MMP- 9/TIMP-1 ratio had a negative linear association with the forced expiratory volume in one second (FEV1) percentage predicted in COPD. Associating the 2005 levels of MMP-9 and MMP-9/TIMP-1 ratio to decline in FEV1 and FEV1% predicted, revealed a similar negative association pattern in both non-COPD and COPD, however, this was only significant for non-COPD. A non-response analysis comparing proteolytic marker values from 2005 between participating and non-participating subjects at follow-up in 2010 (excluding deceased individuals) demonstrated significantly higher MMP-9 and MMP-9/TIMP-1 ratios in both non-COPD and COPD, and significantly lower TIM