Accelerated extracellular matrix turnover during exacerbations of COPD.

Diana J. Leeming,Jacob H. Kristensen,Charlotte E. Bolton,Shu Sun,Alan J. Knox,Morten A. Karsdal,Simon R. Johnson,Peter Lange,Jannie M. B. Sand

doi:10.1186/s12931-015-0225-3

Abstract

BackgroundExacerbations of chronic obstructive pulmonary disease (COPD) contribute significantly to disease progression. However, the effect on tissue structure and turnover is not well described. There is an urgent clinical need for biomarkers of disease activity associated with disease progression. Extracellular matrix (ECM) turnover reflects activity in tissues and consequently assessment of ECM turnover may serve as biomarkers of disease activity. We hypothesized that the turnover of lung ECM proteins were altered during exacerbations of COPD.Methods69 patients with COPD hospitalised for an exacerbation were recruited at admission and returned for a 4 weeks follow-up. Competitive ELISAs measuring circulating protein fragments in serum or plasma assessed the formation and degradation of collagen types III (Pro-C3 and C3M, respectively), IV (P4NP 7S and C4M, respectively), and VI (Pro-C6 and C6M, respectively), and degradation of elastin (ELM7 and EL-NE) and versican (VCANM).ResultsCirculating levels of C3M, C4M, C6M, ELM7, and EL-NE were elevated during an exacerbation of COPD as compared to follow-up (all P <0.0001), while VCANM levels were decreased (P <0.0001). Pro-C6 levels were decreased and P4NP 7S levels were elevated during exacerbation (P <0.0001). Pro-C3 levels were unchanged. At time of exacerbation, degradation/formation ratios were increased for collagen types III and VI and decreased for collagen type IV.ConclusionsExacerbations of COPD resulted in elevated levels of circulating fragments of structural proteins, which may serve as markers of disease activity. This suggests that patients with COPD have accelerated ECM turnover during exacerbations which may be related to disease progression.

Highlights

Exacerbations of chronic obstructive pulmonary disease (COPD) contribute significantly to disease progression
Matrix metalloproteinase 9 (MMP-9) levels are known to be elevated while tissue inhibitor of metalloproteinase 1 (TIMP-1) levels are decreased in sputum of COPD patients at time of exacerbation compared to stable COPD [11], suggesting a destructive environment
Degradation fragments of collagen type III (C3M), collagen type IV (C4M), collagen type VI (C6M), and elastin (ELM7 and elastin by neutrophil elastase (EL-NE)) were significantly elevated at exacerbation compared to follow-up

Summary

Introduction

Exacerbations of chronic obstructive pulmonary disease (COPD) contribute significantly to disease progression. We hypothesized that the turnover of lung ECM proteins were altered during exacerbations of COPD. ECM turnover is part of healthy tissue maintenance, where old proteins are Exacerbations are periods of increased disease activity that drive COPD progression by accelerating loss of lung function [6], reducing quality of life [7], and causing mortality [8]. Exacerbations are key events in COPD pathogenesis, little is known regarding structural changes in lung tissue during these events. In the present work we tested the hypothesis that ECM turnover, assessed systemically by biomarkers of protein degradation and formation, would be accelerated during an exacerbation of COPD where disease activity is high

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Discussion

Conclusion