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Serum metalloproteinase-9 is related to COPD severity and symptoms - cross-sectional data from a population based cohort-study
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.ORCID iD: 0000-0003-4266-1782
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
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2015 (English)In: Respiratory Research, ISSN 1465-9921, E-ISSN 1465-993X, Vol. 16, article id 28Article in journal (Refereed) Published
Abstract [en]

Background: Chronic obstructive pulmonary disease, COPD, is an increasing cause of morbidity and mortality worldwide, and an imbalance between proteases and antiproteases has been implicated to play a role in COPD pathogenesis. Matrix metalloproteinases (MMP) are important proteases that along with their inhibitors, tissue inhibitors of metalloproteinases (TIMP), affect homeostasis of elastin and collagen, of importance for the structural integrity of human airways. Small observational studies indicate that these biomarkers are involved in the pathogenesis of COPD. The aim of this study was to investigate serum levels of MMP-9 and TIMP-1 in a large Swedish population- based cohort, and their association with disease severity and important clinical symptoms of COPD such as productive cough.

Methods: Spirometry was performed and peripheral blood samples were collected in a populations-based cohort (median age 67 years) comprising subjects with COPD (n = 594) and without COPD (n = 948), in total 1542 individuals. Serum MMP-9 and TIMP-1 concentrations were measured with enzyme linked immunosorbant assay (ELISA) and related to lung function data and symptoms.

Results: Median serum MMP-9 values were significantly higher in COPD compared with non-COPD 535 vs. 505 ng/ml (P = 0.017), without any significant differences in serum TIMP-1-levels or MMP-9/TIMP-1-ratio. In univariate analysis, productive cough and decreasing FEV1% predicted correlated significantly with increased MMP-9 among subjects with COPD (P = 0.004 and P = 0.001 respectively), and FEV1% predicted remained significantly associated to MMP-9 in a multivariate model adjusting for age, sex, pack years and productive cough (P = 0.033).

Conclusion: Productive cough and decreasing FEV1 were each associated with MMP-9 in COPD, and decreasing FEV1 remained significantly associated with MMP-9 also after adjustment for common confounders in this population-based COPD cohort. The increased serum MMP-9 concentrations in COPD indicate an enhanced proteolytic activity that is related to disease severity, and further longitudinal studies are important for the understanding of MMP-9 in relation to the disease process and the pathogenesis of different COPD phenotypes.

Place, publisher, year, edition, pages
BioMed Central, 2015. Vol. 16, article id 28
Keywords [en]
mmp-9, metalloproteinase, proteases, COPD, TIMP-1, MMP-9/TIMP-1 ratio, OLIN, Lung-function, productive cough
Keywords [sv]
KOL, OLIN, proteaser, lungfunktion, produktiv hosta, MMP-9/TIMP-1 kvot
National Category
Respiratory Medicine and Allergy
Research subject
Epidemiology; Lung Medicine
Identifiers
URN: urn:nbn:se:umu:diva-102666DOI: 10.1186/s12931-015-0188-4ISI: 000349926800001PubMedID: 25849664OAI: oai:DiVA.org:umu-102666DiVA, id: diva2:808861
Projects
OLINAvailable from: 2015-04-29 Created: 2015-04-29 Last updated: 2018-09-12Bibliographically approved
In thesis
1. Proteolytic imbalance in COPD: epidemiological and clinical aspects
Open this publication in new window or tab >>Proteolytic imbalance in COPD: epidemiological and clinical aspects
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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 TIMP-1 concentration in non-participants compared to participants. Among the deceased, MMP-9 levels and MMP-9/TIMP-1 ratios were higher in COPD compared to non-COPD. In the longitudinal study, all-cause mortality was higher in the COPD group (16%), than in the non-COPD (10%) (p = 0.008).

For the clinical study, 15 subjects were recruited to the two normal lung function groups, while this goal was unachieved for the two COPD groups. The most prevalent reasons for exclusion in the COPD groups were comorbidities. BW- and BAL-MMP-12 concentrations were higher in the COPD group comprising current- and ex-smokers, compared to both ever-smokers (BW: p = 0.001, BAL: p = 0.001) and non-smokers with normal lung function (BW: p = 0.001, BAL: p = 0.001). To evaluate the impact of smoking, COPD ex-smokers were compared to COPD current smokers, with no significant difference in BW- and BAL-MMP- 12. In contrast COPD-ex smokers had higher BW- and BAL-MMP-12 compared to ex-smokers with normal lung function, thus suggesting increased BW- and BAL-MMP-12 as markers of COPD rather than of smoking. MMP-12 concentrations in serum were higher for COPD current smokers compared to COPD ex-smokers (p = 0.028), but there was no significant difference between COPD ex-smokers and ex-smokers with normal lung function. BAL-MMP-12 in COPD was associated with annual decline in FEV1 (r = 0.61, p = 0.005).

Conclusion: Extrapolating the data on MMP-9 and MMP-9/TIMP-1 ratio suggests increased proteolytic activity is related to airflow limitation and consequently to COPD severity. Considering the population-based nature of the study, the association of both MMP-9 and MMP-9/TIMP-1-ratio in COPD to mortality risk could be translated to the general population. Identifying COPD subjects with specific phenotypes proved difficult despite the large number of available individuals. Increased airway levels of MMP-12 indicated a state of increased proteolytic activity and were associated with rapid lung function decline in COPD. These findings imply that proteolytic imbalance is related to symptoms, lung function decline and prognosis, suggesting it represents a relevant disease mechanism in COPD.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2018. p. 95
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1971
Keywords
Matrix metalloproteinases, MMP-9, MMP-12, lung function decline, epidemiology, COPD, OLIN, KOLIN
National Category
Respiratory Medicine and Allergy
Research subject
Medicine
Identifiers
urn:nbn:se:umu:diva-151745 (URN)978-91-7601-908-5 (ISBN)
Public defence
2018-10-05, Sal Betula, Norrlands universitetssjukhus, 901 87 Umeå, 09:00 (Swedish)
Opponent
Supervisors
Funder
Swedish Heart Lung FoundationVästerbotten County Council
Available from: 2018-09-14 Created: 2018-09-12 Last updated: 2018-09-13Bibliographically approved

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