Abstract
BackgroundThere is a need to identify individuals with COPD at risk for disease progression and mortality. Lung tissue remodeling is associated with the release of extracellular matrix (ECM) fragments into the peripheral circulation. We hypothesized that ECM remodeling was associated with mortality in COPD and measured neo-epitopes originating from ECM proteins associated with lung tissue remodeling.MethodsBiomarkers of ECM remodeling were assessed in a subpopulation (n = 1000) of the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) cohort. Validated immunoassays measuring serological neo-epitopes produced by proteolytic cleavage associated with degradation of collagen type I, III, IV, and VI, elastin, and biglycan, and formation of collagen type VI as well as fibrinogen and C-reactive protein were used. Multivariate models were used to assess the prognostic value of these biomarkers.ResultsThirty subjects (3.0 %) died during follow-up. Non-survivors were older, had reduced exercise capacity, increased dyspnea score, and included fewer current smokers. All collagen biomarkers were significantly elevated in non-survivors compared to survivors. Mortality risk was significantly increased for subjects with collagen remodeling biomarkers in the upper quartile, especially for the degradation fragment of collagen type IV C6M (hazard ratio 6.6 [95 % confidence interval 2.9-15.2], P < 0.0001) after adjusting for relevant confounders.ConclusionsSerological biomarkers of collagen remodeling were strongly associated with mortality in subjects with COPD indicating that assessment of tissue turnover in the parenchyma and small airways may be useful in the prognosis of COPD.Trial registration NCT00292552, GSK Study No. SCO104960.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-016-0440-6) contains supplementary material, which is available to authorized users.
Highlights
There is a need to identify individuals with Chronic obstructive pulmonary disease (COPD) at risk for disease progression and mortality
The chronic inflammatory process in the lungs of individuals with COPD induces the remodeling of the extracellular matrix (ECM), which includes both degradation of old proteins and synthesis of new ones and occurs in both small airways and alveolar walls
We found that biomarkers of the structural changes occurring in both the basement membrane and the interstitial matrix of the lungs were related to mortality in individuals with COPD
Summary
There is a need to identify individuals with COPD at risk for disease progression and mortality. Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by progressive airflow limitation and a chronic inflammatory response of the lungs It is a major cause of morbidity and mortality and is estimated to be the third leading cause of. The chronic inflammatory process in the lungs of individuals with COPD induces the remodeling of the ECM, which includes both degradation of old proteins and synthesis of new ones and occurs in both small airways and alveolar walls. This results in the release of protein fragments or neo-epitopes into the systemic circulation where they can be assessed as biomarkers of lung ECM remodeling (Fig. 1). The biomarker CRPM assesses the local inflammation by measuring MMP-mediated degradation of C-reactive protein (CRP) [19]
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