Biomarkers of extracellular matrix turnover are associated with emphysema and eosinophilic-bronchitis in COPD

Abstract

BackgroundChronic obstructive pulmonary disease (COPD) is characterized by airflow obstruction and loss of lung tissue mainly consisting of extracellular matrix (ECM). Three of the main ECM components are type I collagen, the main constituent in the interstitial matrix, type VI collagen, and elastin, the signature protein of the lungs. During pathological remodeling driven by inflammatory cells and proteases, fragments of these proteins are released into the bloodstream, where they may serve as biomarkers for disease phenotypes. The aim of this study was to investigate the lung ECM remodeling in healthy controls and COPD patients in the COPDGene study.MethodsThe COPDGene study recruited 10,300 COPD patients in 21 centers. A subset of 89 patients from one site (National Jewish Health), including 52 COPD patients, 12 never-smoker controls and 25 smokers without COPD controls, were studied for serum ECM biomarkers reflecting inflammation-driven type I and VI collagen breakdown (C1M and C6M, respectively), type VI collagen formation (Pro-C6), as well as elastin breakdown mediated by neutrophil elastase (EL-NE). Correlation of biomarkers with lung function, the SF-36 quality of life questionnaire, and other clinical characteristics was also performed.ResultsThe circulating concentrations of biomarkers C6M, Pro-C6, and EL-NE were significantly elevated in COPD patients compared to never-smoking control patients (all p < 0.05). EL-NE was significantly elevated in emphysema patients compared to smoking controls (p < 0.05) and never-smoking controls (p < 0.005), by more than 250%. C1M was inversely associated with forced expiratory volume in 1 s (FEV1) (r = −0.344, p = 0.001), as was EL-NE (r = −0.302, p = 0.004) and Pro-C6 (r = −0.259, p = 0.015). In the patients with COPD, Pro-C6 was correlated with percent predicted Forced Vital Capacity (FVC) (r = 0.281, p = 0.046) and quality of life using SF-36. C6M and Pro-C6, were positively correlated with blood eosinophil numbers in COPD patients (r = 0.382, p = 0.006 and r = 0.351, p = 0.012, respectively).ConclusionsThese data suggest that type VI collagen turnover and elastin degradation by neutrophil elastase are associated with COPD-induced inflammation (eosinophil-bronchitis) and emphysema. Serological assessment of type VI collagen and elastin turnover may assist in identification of phenotypes likely to be associated with progression and amenable to precision medicine for clinical trials.

<p>Increased von Willebrand Factor Processing in COPD, Reflecting Lung Epithelium Damage, Is Associated with Emphysema, Exacerbations and Elevated Mortality Risk</p>

“…Interestingly, we found that only VWF-N reflected the more chronic progressive condition of emphysema, indicating a sustained increase of VWF release into the circulation. Emphysema is a result of chronic inflammatory responses that induce slow progressive epithelial tissue damage 9 which is in agreement with VWF as a proposed marker of endothelial dysfunction. 18 To our knowledge, no previous studies have shown VWF to be associated with emphysema.…”

Correlation between serological biomarkers of extracellular matrix turnover and lung fibrosis and pulmonary artery hypertension in patients with systemic sclerosis

“…In addition to SSc, high turnover of type VI collagen has been observed in chronic obstructive pulmonary disease (COPD), compared with healthy individuals . However, the PRO‐C6 and C6M levels in COPD patients were only about 8 ng/mL (compared with 12.6 ng/mL in SSc patients in the present study) and about 18 ng/mL (compared with 26.0 ng/mL in SSc patients in the present study), respectively . These observations indicate that type VI collagen, which plays various roles in many major tissues, seems to reflect systemic fibrosis in patients with SSc.…”

MicroRNA‑15a‑5p induces pulmonary artery smooth muscle cell apoptosis in a pulmonary arterial hypertension model via the VEGF/p38/MMP‑2 signaling pathway

“…In addition, EcM fragments degraded by MMP-9 exert chemotactic effects on inflammatory cells. Elastic fiber-derived chemokines in the respiratory tract of long-term smokers can induce aggregation of monocytes/macrophages (36), thereby aggravating the pulmonary inflammatory response and leading to destruction of the alveolar wall. In addition to the EcM degradation, MMPs also exhibit pro-and anti-apoptotic , x100), (E) cell apoptosis analysis by flow cytometry, activity of (F) caspase-3 and (G) caspase-9, levels of (H) TNF-α, (I) IL-18, (J) IL-1β and (K) IL-6.…”