Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
From COPD epidemiology to studies of pathophysiological disease mechanisms: challenges with regard to study design and recruitment process
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.ORCID iD: 0000-0003-4266-1782
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.ORCID iD: 0000-0002-0553-8067
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
Show others and affiliations
2017 (English)In: European Clinical Respiratory Journal, ISSN 2001-8525, Vol. 4, article id 1415095Article in journal (Refereed) Published
Abstract [en]

Background: Chronic obstructive pulmonary disease (COPD) is a largely underdiagnosed disease including several phenotypes. In this report, the design of a study intending to evaluate the pathophysiological mechanism in COPD in relation to the specific phenotypes non-rapid and rapid decline in lung function is described together with the recruitment process of the study population derived from a population based study.

Method: The OLIN COPD study includes a population-based COPD cohort and referents without COPD identified in 2002–04 (n = 1986), and thereafter followed annually since 2005. Lung function decline was estimated from baseline in 2002–2004 to 2010 (first recruitment phase) or to 2012/2013 (second recruitment phase). Individuals who met the predefined criteria for the following four groups were identified; group A) COPD grade 2–3 with rapid decline in FEV1 and group B) COPD grade 2–3 without rapid decline in FEV1 (≥60 and ≤30 ml/year, respectively), group C) ever-smokers, and group D) non-smokers with normal lung function. Groups A–C included ever-smokers with >10 pack years. The intention was to recruit 15 subjects in each of the groups A-D.

Results: From the database groups A–D were identified; group A n = 37, group B n = 29, group C n = 41, and group D n = 55. Fifteen subjects were recruited from groups C and D, while this goal was not reached in the groups A (n = 12) and B (n = 10). The most common reasons for excluding individuals identified as A or B were comorbidities contraindicating bronchoscopy, or inflammatory diseases/immune suppressive medication expected to affect the outcome.

Conclusion: The study is expected to generate important results regarding pathophysiological mechanisms associated with rate of decline in lung function among subjects with COPD and the in-detail described recruitment process, including reasons for non-participation, is a strength when interpreting the results in forthcoming studies.

Place, publisher, year, edition, pages
Taylor & Francis, 2017. Vol. 4, article id 1415095
Keywords [en]
Chronic obstructive pulmonary disease, disease mechanisms, lung function decline, smoking habits
National Category
Respiratory Medicine and Allergy
Research subject
Lung Medicine; Epidemiology
Identifiers
URN: urn:nbn:se:umu:diva-143251DOI: 10.1080/20018525.2017.1415095ISI: 000418831000001OAI: oai:DiVA.org:umu-143251DiVA, id: diva2:1167941
Projects
OLIN-studiernaAvailable from: 2017-12-19 Created: 2017-12-19 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

Open Access in DiVA

fulltext(1436 kB)16 downloads
File information
File name FULLTEXT01.pdfFile size 1436 kBChecksum SHA-512
1fcb4fcee0fa407bc876f9b9bd54c1842ad15221acae28b43cff61f4b98b6b391994c3709e3fc0f4c758a77999aba71c74f5bb349ca891dc9b444c0f9037c288
Type fulltextMimetype application/pdf

Other links

Publisher's full text

Search in DiVA

By author/editor
Lindberg, AnneLinder, RobertBackman, HelenaEriksson Ström, JonasFrølich, AndreasNilsson, UlfRönmark, EvaJohansson Strandkvist, ViktorBehndig, Annelie FBlomberg, Anders
By organisation
MedicineOccupational and Environmental Medicine
In the same journal
European Clinical Respiratory Journal
Respiratory Medicine and Allergy

Search outside of DiVA

GoogleGoogle Scholar
Total: 16 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
urn-nbn

Altmetric score

doi
urn-nbn
Total: 57 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf