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Proteolytic biomarkers are related to prognosis in COPD: report from a population-based cohort
Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Yrkes- och miljömedicin. The OLIN unit.
Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
Vise andre og tillknytning
2018 (engelsk)Inngår i: Respiratory Research, ISSN 1465-9921, E-ISSN 1465-993X, Vol. 19, artikkel-id 64Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

BACKGROUND: The imbalance between proteases and anti-proteases is considered to contribute to the development of COPD. Our aim was to evaluate the protease MMP-9, the antiprotease TIMP-1 and the MMP-9/TIMP-1-ratio as biomarkers in relation to prognosis. Prognosis was assessed as lung function decline and mortality. This was done among subjects with COPD in a population-based cohort.

METHODS: In 2005, clinical examinations including spirometry and peripheral blood sampling, were made in a longitudinal population-based cohort. In total, 1542 individuals participated, whereof 594 with COPD. In 2010, 1031 subjects participated in clinical examinations, and 952 subjects underwent spirometry in both 2005 and 2010. Serum MMP-9 and TIMP-1 concentrations were measured with enzyme linked immunosorbent assay (ELISA). Mortality data were collected from the Swedish national mortality register from the date of examination in 2005 until 31st December 2010.

RESULTS: The correlation between biomarkers and lung function decline was similar in non-COPD and COPD, but only significant for MMP-9 and MMP-9/TIMP-1-ratio in non-COPD. Mortality was higher in COPD than non-COPD (16% vs. 10%, p = 0.008). MMP-9 concentrations and MMP-9/TIMP-1 ratios in 2005 were higher among those who died during follow up, as well as among those alive but not participating in 2010, when compared to those participating in the 2010-examination. In non-COPD, male sex, age, burden of smoking, heart disease and MMP-9/TIMP-1 ratio were associated with increased risk for death, while increased TIMP-1 was protective. Among those with COPD, age, current smoking, increased MMP-9 and MMP-9/TIMP-1 ratio were associated with an increased risk for death.

CONCLUSIONS: The expected association between these biomarkers and lung function decline in COPD was not confirmed in this population-based study, probably due to a healthy survivor effect. Still, it is suggested that increased proteolytic imbalance may be of greater prognostic importance in COPD than in non-COPD.

sted, utgiver, år, opplag, sider
London: BioMed Central, 2018. Vol. 19, artikkel-id 64
Emneord [en]
Chronic obstructive pulmonary disease (COPD), Matrix metalloproteinases, Mortality, Spirometry, Tissue inhibitor of metalloproteinases
HSV kategori
Identifikatorer
URN: urn:nbn:se:umu:diva-146657DOI: 10.1186/s12931-018-0772-5ISI: 000429829100001PubMedID: 29650051OAI: oai:DiVA.org:umu-146657DiVA, id: diva2:1197991
Tilgjengelig fra: 2018-04-16 Laget: 2018-04-16 Sist oppdatert: 2019-08-08bibliografisk kontrollert
Inngår i avhandling
1. Proteolytic imbalance in COPD: epidemiological and clinical aspects
Åpne denne publikasjonen i ny fane eller vindu >>Proteolytic imbalance in COPD: epidemiological and clinical aspects
2018 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Umeå: Umeå Universitet, 2018. s. 95
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1971The Obstructive Lung Disease in Northern Sweden (OLIN) Studies ; XX
Emneord
Matrix metalloproteinases, MMP-9, MMP-12, lung function decline, epidemiology, COPD, OLIN, KOLIN
HSV kategori
Forskningsprogram
medicin
Identifikatorer
urn:nbn:se:umu:diva-151745 (URN)978-91-7601-908-5 (ISBN)
Disputas
2018-10-05, Sal Betula, Norrlands universitetssjukhus, 901 87 Umeå, 09:00 (svensk)
Opponent
Veileder
Forskningsfinansiär
Swedish Heart Lung FoundationVästerbotten County Council
Tilgjengelig fra: 2018-09-14 Laget: 2018-09-12 Sist oppdatert: 2020-02-25bibliografisk kontrollert

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