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Proteolytic imbalance is related to FEV1 decline in COPD
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary 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.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background

It is generally accepted that metalloproteinases contribute to lung tissue destruction. This study intends to examine how proteolytic imbalance impacts COPD in relation to phenotypes of non-rapid and rapid decline in lung function, by clinically assessing subjects recruited from a population-based cohort.

Methods

Subjects were recruited from the longitudinal OLIN COPD study providing spirometry data over time. In total 52 subjects were included: 12 with COPD and a rapid decline in FEV1 (≥60 mL/year), 10 with COPD and a non-rapid decline in FEV1 (≤30 mL/year), 15 current and ex-smokers with normal lung function, and 15 non-smokers with normal lung function. Proteolytic markers MMP-9, MMP-12 and TIMP-1 were assessed in serum and airway lavages.

Results

MMP-12 in BW and BAL was higher in COPD 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). BAL-MMP-12 in COPD displayed a positive association to annual decline in FEV1

(r = 0.61, p = 0.005). The lowest concentration of S-TIMP-1 (477 (295- 717) ng/mL) was found in COPD with a rapid decline in lung function, with a negative association between annual decline in FEV1 and s-TIMP- 1 (r = -0.42, p = 0.05).

Conclusion

Airway protease activity measured as MMP-12 concentration in BAL was increased in COPD, compared to both smokers with normal lung function and healthy. Individuals with the highest levels of airway MMP- 12 experienced the greatest decline in FEV1. Furthermore, a negative association was found between TIMP-1 in serum and FEV1 decline. Increased airway proteolytic activity may play an important role in the progress of COPD.

Keywords [en]
lung function, matrix metalloproteinases, tissue inhibitor of metalloproteinases, BAL-fluid
National Category
Respiratory Medicine and Allergy
Research subject
Lung Medicine
Identifiers
URN: urn:nbn:se:umu:diva-151744OAI: oai:DiVA.org:umu-151744DiVA, id: diva2:1247408
Available from: 2018-09-12 Created: 2018-09-12 Last updated: 2018-09-12
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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Linder, RobertPourazar, JamshidLindberg, AnneBlomberg, AndersBehndig, Annelie F.

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