Specific elastin degradation products are associated with poor outcome in the ECLIPSE COPD cohort

Abstract

Chronic obstructive pulmonary disease (COPD) is characterized by a slow heterogeneous progression. Therefore, improved biomarkers that can accurately identify patients with the highest likelihood of progression and therefore the ability to benefit from a given treatment, are needed. Elastin is an essential structural protein of the lungs. In this study, we investigated whether elastin degradation products generated by the enzymes proteinase 3, cathepsin G, neutrophil elastase, MMP7 or MMP9/12 were prognostic biomarkers for COPD-related outcomes. The elastin degradome was assessed in a subpopulation (n = 1307) of the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) cohort with 3 years of clinical follow-up. Elastin degraded by proteinase 3 could distinguish between COPD participants and non-smoking controls (p = 0.0006). A total of 30 participants (3%) died over the 3 years of observation. After adjusting for confounders, plasma levels of elastin degraded by proteinase 3 and cathepsin G were independently associated with mortality outcome with a hazard ratio per 1 SD of 1.49 (95%CI 1.24–1.80, p < 0.0001) and 1.31 (95%CI 1.10–1.57, p = 0.0029), respectively. Assessing the elastin degradome demonstrated that specific elastin degradation fragments have potential utility as biomarkers identifying subtypes of COPD patients at risk of poor prognosis and supports further exploration in confirmatory studies.

A specific proteinase 3 activity footprint in α1-antitrypsin deficiency

“…The fibrinogen footprint of PR3 activity is also likely to be an indirect marker of elastin degradation considered central to the pathophysiology of emphysema. Since our results were generated, a recent article using a similar methodology to measure a PR3-specific elastin cleavage product in healthy controls and a COPD cohort indicates similar increased PR3 compared with an NE cleavage product to that seen here [23]. Direct comparison of both assays should, however, be undertaken in a single α 1 -AT-deficient cohort for final confirmation.…”

Endotrophin, an extracellular hormone, in combination with neoepitope markers of von Willebrand factor improves prediction of mortality in the ECLIPSE COPD cohort

“…ECM remodeling, including both formation and degradation of the lung tissue, has been shown to be increased in patients with COPD [22][23][24][25]. Furthermore, an accelerated rate of remodeling was associated with acute exacerbations of COPD and an elevated risk of mortality [18,[22][23][24][25][26]. Abdillahi et al showed that type VI collagen mRNA and protein are increased in the lungs of COPD patients when compared to controls [27].…”

Markers of disease activity in COPD: an 8-year mortality study in the ECLIPSE cohort

“…Another limitation of the data was the lack of adjudication of the cause of death, as performed in several prospective interventional trials [39][40][41]. A limited number of serum and blood biomarkers were evaluated and did not include recently described markers such as collagen and elastin turnover biomarkers [42], which could be of use in assessing different components of COPD disease activity. Finally, the ECLIPSE population was recruited by specialists, often at academic centres with expertise in clinical trials, and does not represents a population-based sample.…”