Characterization of serological neo-epitope biomarkers reflecting collagen remodeling in clinically stable chronic obstructive pulmonary disease

Objectives: Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation that leads to excessive remodeling of the lung extracellular matrix (ECM), resulting in release of protein fragments (neo-epitopes) to the blood. Serological markers assessing this have previously been associated with exacerbations of COPD. However, characterization of these in individuals with clinically stable COPD is lacking. The aim of this study was to characterize the collagen remodeling in stable COPD by the serological assessment of neo-epitopes.

Design and methods: Sixty-eight subjects with clinically stable COPD were included into the study at baseline, and 27 came back for a four weeks follow-up visit. Serum and plasma levels of neo-epitopes were assessed for the evaluation of collagen type III (C3M), IV (C4M, C4Ma3, P4NP 7S), and VI (C6M, Pro-C6) remodeling.

Results: C3M, C4M, C4Ma3, P4NP 7S, and C6M levels were significantly elevated in COPD subjects compared with healthy controls (p<0.0001 to p=0.044). Each neo-epitope biomarker was significantly correlated between serum and plasma (p<0.0001) and most biomarkers were stable in the majority of patients from baseline to week four. Serum C6M levels were weakly correlated with FEV₁% predicted (r=-0.274, p=0.025) and serum Pro-C6 levels were elevated in subjects with previous exacerbations (p=0.014). C3M, C4Ma3, C6M, and P4NP 7S were weakly correlated with MRC dyspnea scores (p<0.01). No associations were seen with BMI, smoking, duration of COPD, blood oxygen saturation, shuttle walk test distance, GOLD grades, or CAT scores.

Conclusions: Serological biomarkers of collagen remodeling were elevated in subjects with COPD as compared with healthy individuals. Biomarker levels were significantly correlated with measures of dyspnea, indicating a relationship with degree of symptoms, while only C6M showed a weak but significant association with lung function. Biomarker levels were not related to GOLD grades, which was in line with previous studies indicating that ECM remodeling may be related to disease activity rather than severity.