Systemic Biomarkers of Collagen and Elastin Turnover Are Associated With Clinically Relevant Outcomes in COPD

Daiana Stolz, Diana Julie Leeming, Jacob Hull Edfort Kristensen, Morten A. Karsdal, Wim Boersma, Renaud Louis, Branislava Milenkovic, Konstantinos Kostikas, Francesco Blasi, Joachim Aerts, Jannie M.B. Sand, Emiel F.M. Wouters, Gernot Rohde, Cristina Prat, Antoni Torres, Tobias Welte, Michael Roth, Eleni Papakonstantinou, Michael Tamm

Research output: Contribution to journalArticlepeer-review

Abstract

Background Extracellular matrix (ECM) remodeling of the lung tissue releases protein fragments into the blood, where they may be detected as serologic surrogate markers of disease activity in COPD. Our goal was to assess the association of ECM turnover with severity and outcome of COPD. Methods In a prospective, observational, multicenter study including 506 patients with COPD (Global Initiative for Chronic Obstructive Lung Disease grades II to IV), serum samples were analyzed at stable state, exacerbation, and 4 weeks after exacerbation. The analysis comprised a panel of five novel neoepitopes, including fragments of collagen type III (C3M) and collagen type VI (C6M), pro-forms of collagen type III (Pro-C3) and type VI (Pro-C6), and neutrophil elastase-generated fragments of elastin (EL-NE) according to enzyme-linked immunosorbent assay. These neoepitopes were also measured at stable state in a derivation cohort that included 100 patients with COPD. Results Serum levels of C3M, C6M, Pro-C3, Pro-C6, and EL-NE were associated with lung function. Patients with the lowest levels of Pro-C3 and Pro-C6 had more severe airflow limitation, hyperinflation, air trapping, and emphysema. C3M and C6M were associated with dyspnea. All ECM biomarkers, except Pro-C6, were increased at exacerbation compared with stable state but, except EL-NE, did not differ between stable state and exacerbation follow-up in the crude and adjusted analyses. In Cox regression adjusted analyses, Pro-C3 was associated with a shorter time to exacerbation (hazard ratio, 0.72; CI, 0.59-0.89; P = .002) and Pro-C6 with survival (hazard ratio, 2.09; CI, 1.18-3.71; P = .011). Conclusions Serum biomarkers of ECM turnover were significantly associated with disease severity and clinically relevant outcomes in patients with COPD. Trial Registry No.: ISRCTN99586989; URL: www.controlled-trials.com.

Original languageEnglish
Pages (from-to)47-59
Number of pages13
JournalChest
Volume151
Issue number1
DOIs
Publication statusPublished - Jan 1 2017

Keywords

  • acute exacerbations of COPD
  • collagen
  • COPD
  • elastin
  • extracellular matrix molecules

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine
  • Cardiology and Cardiovascular Medicine

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