Accelerated extracellular matrix turnover during exacerbations of COPD

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.

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

“…However, recent published report with the same biomarkers in other well-known COPD cohorts support the findings that C6M and EL-NE are significantly associated with lung function in COPD [73, 74], and have been found to be elevated during exacerbations in a smaller study [56]. …”

“…Elastin is a structural protein abundant in lung tissue where it provides resilience and elasticity to the lungs [54], and is of particular interest to the emphysema phenotype, as this is the main protein with predominant expression in the lung, a so-called signature protein, which is degraded during lung inflammation and destruction [35, 50, 55, 56]. Neutrophils have received increased attention for their role in chronic inflammation and wound healing, in addition to their role in the primary inflammatory response [50].…”

“…These biological processes deep within the matrix of the lung, may be associated with COPD phenotypes, disease progression, and events such as exacerbations. In direct alignment, the balance between type VI collagen formation and degradation, was shown to be significantly changed as measured by the same protein biomarkers in serum, in COPD patients with exacerbations [56, 73, 74]. Furthermore, type VI collagen remodeling as measured by these biomarkers has been associated with disease progression, defined by change in FEV 1 , and mortality in COPD patients from the ECLIPSE cohort [65].…”

The emerging role of dipeptidyl-peptidase-4 as a therapeutic target in lung disease

“…The authors also note a relationship between mesothelial cell hypertrophy and increased DPP-4 staining [39]. Remodeling responses in COPD have also revealed a rapid turnover in extracellular matrix protein that is heightened during disease exacerbation [40]. Proteases such as MMP-1, 2, 3, 9, and 14; elastin and cathepsins are pivotal to the activation state of chemokines.…”

Untangling the protease web in COPD: metalloproteinases in the silent zone

“…Measurement of ECM protein fragments produced by specific proteases reflect changes in ECM degradation and deposition. Interestingly, these markers can predict disease progression in lung fibrosis and in COPD exacerbations, show both increases in collagen and elastin turnover and simultaneous de novo synthesis of other ECM proteins 18 19…”