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BMC Pulmonary Medicine
Published in: BMC Pulmonary Medicine 1/2017

Open Access 01-12-2017 | Research article

Biomarkers of collagen turnover are related to annual change in FEV1 in patients with chronic obstructive pulmonary disease within the ECLIPSE study

Authors: Diana J. Leeming, Inger Byrjalsen, Jannie M. B. Sand, Asger R. Bihlet, Peter Lange, Ruth Thal-Singer, Bruce E. Miller, Morten A. Karsdal, Jørgen Vestbo, The Evaluation of COPD Longitudinally to Identify Surrogate Endpoints (ECLIPSE) study investigators

Published in: BMC Pulmonary Medicine | Issue 1/2017

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Abstract

Background

Change in forced expiratory volume in one second (FEV1) is important for defining severity of chronic obstructive pulmonary disease (COPD). Serological neoepitope markers of collagen turnover may predict rate of change in FEV1.

Methods

One thousand COPD subjects from the observational, multicentre, three-year ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) study (NCT00292552, trial registration in February 2006) were included. Matrix metalloproteinase (MMP)-generated fragments of collagen type I, and type VI (C1M and C6M) were assessed in month six serum samples. A random-coefficient model with both a random intercept and a random slope was used to test the ability of the markers to predict post-dose bronchodilator FEV1 (PD-FEV1) change over two years adjusting for sex, age, BMI, smoking, bronchodilator reversibility, prior exacerbations, emphysema and chronic bronchitis status at baseline.

Results

Annual change of PD-FEV1 was estimated from a linear model for the two-year study period. Serum C1M and C6M were independent predictors of lung function change (p = 0.007/0.005). Smoking, bronchodilator reversibility, plasma hsCRP and emphysema were also significant predictors. The effect estimate between annual change in PD-FEV1 per one standard deviation (1SD) increase of C1M and C6M was +10.4 mL/yr. and +8.6 mL/yr. C1M, and C6M, had a significant association with baseline FEV1.

Conclusion

We demonstrated that markers of tissue turnover were significantly associated with lung function change. These markers may function as prognostic biomarkers and possibly as efficacy biomarkers in clinical trials focusing on lung function change in COPD.

Trial registration

NCT00292552, Retrospectively registered, trial registration in February 2006.
Appendix
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Literature
1.
Hogg JC, McDonough JE, Gosselink JV, Hayashi S. What drives the peripheral lung-remodeling process in chronic obstructive pulmonary disease? Proc Am Thorac Soc. 2009;6:668–72.CrossRefPubMedPubMedCentral
2.
Burney P, Jithoo A, Kato B, Janson C, Mannino D, Nizankowska-Mogilnicka E, et al. Chronic obstructive pulmonary disease mortality and prevalence: the associations with smoking and poverty--a BOLD analysis. Thorax. 2014;69:465–73.CrossRefPubMed
3.
Vestbo J, Hurd SS, Agusti AG, Jones PW, Vogelmeier C, Anzueto A, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2013;187:347–65.CrossRefPubMed
4.
Segreti A, Stirpe E, Rogliani P, Cazzola M. Defining phenotypes in COPD: an aid to personalized healthcare. Mol Diagn Ther. 2014;18:381–8.CrossRefPubMed
5.
6.
Karsdal MA, Krarup H, Sand JM, Christensen PB, Gerstoft J, Leeming DJ, et al. Review article: the efficacy of biomarkers in chronic fibroproliferative diseases - early diagnosis and prognosis, with liver fibrosis as an exemplar. Aliment Pharmacol Ther. 2014;40:233–49.CrossRefPubMed
7.
8.
Karsdal MA, Nielsen MJ, Sand JM, Henriksen K, Genovese F, Bay-Jensen AC, et al. Extracellular matrix remodeling: the common denominator in connective tissue diseases. Possibilities for evaluation and current understanding of the matrix as more than a passive architecture, but a key player in tissue failure. Assay Drug Dev Technol. 2013;11:70–92.CrossRefPubMedPubMedCentral
9.
10.
Kranenburg AR, Willems-Widyastuti A, Moori WJ, Sterk PJ, Alagappan VK, de Boer WI, et al. Enhanced bronchial expression of extracellular matrix proteins in chronic obstructive pulmonary disease. Am J Clin Pathol. 2006;126:725–35.CrossRefPubMed
11.
Finlay GA, O'Driscoll LR, Russell KJ, D'Arcy EM, Masterson JB, Fitzgerald MX, et al. Matrix metalloproteinase expression and production by alveolar macrophages in emphysema. Am J Respir Crit Care Med. 1997;156:240–7.CrossRefPubMed
12.
Hallgren O, Nihlberg K, Dahlback M, Bjermer L, Eriksson LT, Erjefalt JS, et al. Altered fibroblast proteoglycan production in COPD. Respir Res. 2010;11:55.CrossRefPubMedPubMedCentral
13.
14.
Churg A, Zhou S, Wright JL. Series "matrix metalloproteinases in lung health and disease": matrix metalloproteinases in COPD. Eur Respir J. 2012;39:197–209.CrossRefPubMed
15.
Cane JL, Mallia-Millanes B, Forrester DL, Knox AJ, Bolton CE, Johnson SR. Matrix metalloproteinases −8 and −9 in the airways, blood and urine during exacerbations of COPD. COPD. 2016;13:26–34.CrossRefPubMed
16.
van Kuppevelt TH, Veerkamp JH, Timmermans JA. Immunoquantification of type I, III, IV and V collagen in small samples of human lung parenchyma. Int J Biochem Cell Biol. 1995;27:775–82.CrossRefPubMed
17.
Suki B, Ito S, Stamenovic D, Lutchen KR, Ingenito EP. Biomechanics of the lung parenchyma: critical roles of collagen and mechanical forces. J Appl Physiol. 2005;98:1892–9.CrossRefPubMed
18.
19.
Veidal SS, Karsdal MA, Vassiliadis E, Nawrocki A, Larsen MR, Nguyen QH, et al. MMP mediated degradation of type VI collagen is highly associated with liver fibrosis--identification and validation of a novel biochemical marker assay. PLoS One. 2011;6:e24753.CrossRefPubMedPubMedCentral
20.
Abdillahi SM, Bober M, Nordin S, Hallgren O, Baumgarten M, Erjefalt J, et al. Collagen VI is Upregulated in COPD and serves both as an adhesive target and a bactericidal barrier for Moraxella catarrhalis. J Innate Immun. 2015;7:506–17.CrossRefPubMed
21.
Jenkins RG, Simpson JK, Saini G, Bentley JH, Russell AM, Braybrooke R, et al. Longitudinal change in collagen degradation biomarkers in idiopathic pulmonary fibrosis: an analysis from the prospective, multicentre PROFILE study. Lancet Respir Med. 2015;3:462–72.CrossRefPubMed
22.
Leeming DJ, Delling G, Koizumi M, Henriksen K, Karsdal MA, Li B, et al. Alpha CTX as a biomarker of skeletal invasion of breast cancer: immunolocalization and the load dependency of urinary excretion. Cancer Epidemiol Biomark Prev. 2006;15:1392–5.CrossRef
23.
Leeming DJ, Byrjalsen I, Jimenez W, Christiansen C, Karsdal MA. Protein fingerprinting of the extracellular matrix remodelling in a rat model of liver fibrosis--a serological evaluation. Liver Int. 2013;33:439–47.CrossRefPubMed
24.
Brasso K, Christensen IJ, Johansen JS, Teisner B, Garnero P, Price PA, et al. Prognostic value of PINP, bone alkaline phosphatase, CTX-I, and YKL-40 in patients with metastatic prostate carcinoma. Prostate. 2006;66:503–13.CrossRefPubMed
25.
Peris P, Alvarez L, Vidal S, Kasper D, Leeming DJ, Monegal A, et al. Biochemical response to bisphosphonate therapy in pagetic patients with skull involvement. Calcif Tissue Int. 2006;79:22–6.CrossRefPubMed
26.
Garnero P. Biomarkers for osteoporosis management: utility in diagnosis, fracture risk prediction and therapy monitoring. Mol Diagn Ther. 2008;12:157–70.CrossRefPubMed
27.
Bay-Jensen AC, Liu Q, Byrjalsen I, Li Y, Wang J, Pedersen C, et al. Enzyme-linked immunosorbent assay (ELISAs) for metalloproteinase derived type II collagen neoepitope, CIIM-increased serum CIIM in subjects with severe radiographic osteoarthritis. Clin Biochem. 2011;44:423–9.CrossRefPubMed
28.
Nielsen MJ, Nedergaard AF, Sun S, Veidal SS, Larsen L, Zheng Q, et al. The neo-epitope specific PRO-C3 ELISA measures true formation of type III collagen associated with liver and muscle parameters. Am J Transl Res. 2013;5:303–15.PubMedPubMedCentral
29.
Nielsen MJ, Kazankov K, Leeming DJ, Karsdal MA, Krag A, Barrera F, et al. Markers of collagen remodeling detect clinically significant fibrosis in chronic hepatitis C patients. PLoS One. 2015;10:e0137302.CrossRefPubMedPubMedCentral
30.
Bay-Jensen AC, Liu Q, Byrjalsen I, Li Y, Wang J, Pedersen C, Leeming DJ, Dam EB, Zheng Q, Qvist P, Karsdal MA. Enzyme-linked immunosorbent assay (ELISAs) for metalloproteinase derived type II collagen neoepitope, CIIM--increased serum CIIM in subjects with severe radiographic osteoarthritis. Clin Biochem. 2011;44(5-6):423–9. doi:10.​1016/​j.​clinbiochem.​2011.​01.​001. Epub 2011 Jan 9. PubMed PMID: 21223960.
31.
Bay-Jensen AC, Byrjalsen I, Siebuhr AS, Christiansen C, Platt A, Karsdal MA. Serological biomarkers of joint tissue turnover predict tocilizumab response at baseline. J Clin Rheumatol. 2014;20:332–5.PubMedPubMedCentral
32.
Sand JM, Knox AJ, Lange P, Sun S, Kristensen JH, Leeming DJ, et al. Accelerated extracellular matrix turnover during exacerbations of COPD. Respir Res. 2015;16:69.CrossRefPubMedPubMedCentral
33.
Stolz D, Leeming DJ, Kristensen JH, Karsdal MA, Boersma W, Louis R, Milenkovic B, Kostikas K, Blasi F, Aerts J, Sand JM, Wouters EF, Rohde G, Prat C, Torres A, Welte T, Roth M, Papakonstantinou E, Tamm M. Systemic Biomarkers of Collagen and Elastin Turnover Are Associated With Clinically Relevant Outcomes in COPD. Chest. 2017;151(1):47–59. doi:10.​1016/​j.​chest.​2016.​08.​1440. Epub 2016 Aug 26. PubMed PMID: 27575358.
34.
Sand JM, Martinez G, Midjord AK, Karsdal MA, Leeming DJ, Lange P. Characterization of serological neo-epitope biomarkers reflecting collagen remodeling in clinically stable chronic obstructive pulmonary disease. Clin Biochem. 2016;49:1144–51.CrossRefPubMed
35.
Sand JM, Leeming DJ, Byrjalsen I, Bihlet AR, Lange P, Tal-Singer R, et al. High levels of biomarkers of collagen remodeling are associated with increased mortality in C. Respir Res. 2016;17:125.CrossRefPubMedPubMedCentral
36.
Vestbo J, Edwards LD, Scanlon PD, Yates JC, Agusti A, Bakke P, et al. Changes in forced expiratory volume in 1 second over time in COPD. N Engl J Med. 2011;365:1184–92.CrossRefPubMed
37.
Leeming D, He Y, Veidal S, Nguyen Q, Larsen D, Koizumi M, et al. A novel marker for assessment of liver matrix remodeling: an enzyme-linked immunosorbent assay (ELISA) detecting a MMP generated type I collagen neo-epitope (C1M). Biomarkers. 2011;16:616–28.CrossRefPubMed
38.
Vestbo J, Anderson W, Coxson HO, Crim C, Dawber F, Edwards L, et al. Evaluation of COPD longitudinally to identify predictive surrogate end-points (ECLIPSE). Eur Respir J. 2008;31:869–73.CrossRefPubMed
39.
Celli BR, Locantore N, Yates J, Tal-Singer R, Miller BE, Bakke P, et al. Inflammatory biomarkers improve clinical prediction of mortality in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012;185:1065–72.CrossRefPubMed
40.
Decramer M, Celli B, Kesten S, Lystig T, Mehra S, Tashkin DP. Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomised controlled trial. Lancet. 2009;374:1171–8.CrossRefPubMed
41.
Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356:775–89.CrossRefPubMed
42.
Celli BR, Thomas NE, Anderson JA, Ferguson GT, Jenkins CR, Jones PW, et al. Effect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: results from the TORCH study. Am J Respir Crit Care Med. 2008;178:332–8.CrossRefPubMed
43.
Tashkin DP, Celli B, Senn S, Burkhart D, Kesten S, Menjoge S, et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008;359:1543–54.CrossRefPubMed
44.
Lange P, Celli B, Agusti A. Lung-function trajectories and chronic obstructive pulmonary disease. N Engl J Med. 2015;373:1575.CrossRefPubMed
45.
Bihlet AR, Karsdal MA, Bay-Jensen AC, Read S, Kristensen JH, Sand JM, et al. Clinical drug development using dynamic biomarkers to enable personalized health care in COPD. Chest. 2015;148:16–23.CrossRefPubMed
46.
Vestbo J, Rennard S. Chronic obstructive pulmonary disease biomarker(s) for disease activity needed--urgently. Am J Respir Crit Care Med. 2010;182:863–4.CrossRefPubMed
47.
Faner R, Tal-Singer R, Riley JH, Celli B, Vestbo J, MacNee W, et al. Lessons from ECLIPSE: a review of COPD biomarkers. Thorax. 2014;69:666–72.CrossRefPubMed
48.
Luisetti M, Ma S, Iadarola P, Stone PJ, Viglio S, Casado B, et al. Desmosine as a biomarker of elastin degradation in COPD: current status and future directions. Eur Respir J. 2008;32:1146–57.CrossRefPubMed
49.
Yokoyama A, Kohno N, Hamada H, Sakatani M, Ueda E, Kondo K, et al. Circulating KL-6 predicts the outcome of rapidly progressive idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 1998;158:1680–4.CrossRefPubMed
50.
Prasse A, Pechkovsky DV, Toews GB, Schafer M, Eggeling S, Ludwig C, et al. CCL18 as an indicator of pulmonary fibrotic activity in idiopathic interstitial pneumonias and systemic sclerosis. Arthritis Rheum. 2007;56:1685–93.CrossRefPubMed
51.
Greene KE, King TE Jr, Kuroki Y, Bucher-Bartelson B, Hunninghake GW, Newman LS, et al. Serum surfactant proteins-a and -D as biomarkers in idiopathic pulmonary fibrosis. Eur Respir J. 2002;19:439–46.CrossRefPubMed
52.
Rabinovich RA, Miller BE, Wrobel K, Ranjit K, Williams MC, Drost E, et al. Circulating desmosine levels do not predict emphysema progression but are associated with cardiovascular risk and mortality in COPD. Eur Respir J. 2016;47:1365–73.CrossRefPubMed
53.
Mannino DM, Tal-Singer R, Lomas DA, Vestbo J, Graham BR, Tetzlaff K, et al. Plasma fibrinogen as a biomarker for mortality and hospitalized exacerbations in people with COPD. Chronic Obstr Pulm Dis (Miami ). 2015;2:23–34.CrossRef
54.
Leeming DJ, Sand JM, Nielsen MJ, Genovese F, Martinez FJ, Hogaboam CM, et al. Serological investigation of the collagen degradation profile of patients with chronic obstructive pulmonary disease or idiopathic pulmonary fibrosis. Biomark Insights. 2012;7:119–26.CrossRefPubMedPubMedCentral
55.
Sand JM, Leeming DJ, Byrjalsen I, Bihlet AR, Lange P, Tal-Singer R, Miller BE, Karsdal MA, Vestbo J. High levels of biomarkers of collagen remodeling are associated with increased mortality in COPD - results from the ECLIPSE study. Respir Res. 2016;17(1):125. PubMed PMID: 27716343; PubMed Central PMCID: PMC5050854.
56.
Vestbo J, Agusti A, Wouters EF, Bakke P, Calverley PM, Celli B, et al. Should we view chronic obstructive pulmonary disease differently after ECLIPSE? A clinical perspective from the study team. Am J Respir Crit Care Med. 2014;189:1022–30.CrossRefPubMed
57.
Deng ZC, Zhao P, Cao C, Sun SF, Zhao F, Lu CY, et al. C-reactive protein as a prognostic marker in chronic obstructive pulmonary disease. Exp Ther Med. 2014;7:443–6.CrossRefPubMed
58.
Dahl M, Vestbo J, Lange P, Bojesen SE, Tybjaerg-Hansen A, Nordestgaard BG. C-reactive protein as a predictor of prognosis in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007;175:250–5.CrossRefPubMed
59.
Agusti A, Edwards LD, Rennard SI, MacNee W, Tal-Singer R, Miller BE, et al. Persistent systemic inflammation is associated with poor clinical outcomes in COPD: a novel phenotype. PLoS One. 2012;7:e37483.CrossRefPubMedPubMedCentral
60.
Lange P, Celli B, Agusti A, Boje JG, Divo M, Faner R, et al. Lung-function trajectories leading to chronic obstructive pulmonary disease. N Engl J Med. 2015;373:111–22.CrossRefPubMed
61.
Ferrari R, Tanni SE, Caram LM, Correa C, Correa CR, Godoy I. Three-year follow-up of interleukin 6 and C-reactive protein in chronic obstructive pulmonary disease. Respir Res. 2013;14:24.CrossRefPubMedPubMedCentral
62.
Shaaban R, Kony S, Driss F, Leynaert B, Soussan D, Pin I, et al. Change in C-reactive protein levels and FEV1 decline: a longitudinal population-based study. Respir Med. 2006;100:2112–20.CrossRefPubMed
63.
Karsdal MA, Henriksen K, Leeming DJ, Woodworth T, Vassiliadis E, Bay-Jensen AC. Novel combinations of post-translational modification (PTM) neo-epitopes provide tissue-specific biochemical markers--are they the cause or the consequence of the disease? Clin Biochem. 2010;43:793–804.CrossRefPubMed
Metadata
Title
Biomarkers of collagen turnover are related to annual change in FEV1 in patients with chronic obstructive pulmonary disease within the ECLIPSE study
Authors
Diana J. Leeming
Inger Byrjalsen
Jannie M. B. Sand
Asger R. Bihlet
Peter Lange
Ruth Thal-Singer
Bruce E. Miller
Morten A. Karsdal
Jørgen Vestbo
The Evaluation of COPD Longitudinally to Identify Surrogate Endpoints (ECLIPSE) study investigators
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Pulmonary Medicine / Issue 1/2017
Electronic ISSN: 1471-2466
DOI
https://doi.org/10.1186/s12890-017-0505-4

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