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


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.
Nordic Bioscience, Biomarkers and Research, Herlev, Denmark; Section of Social Medicine, Department of Public Health, University of Copenhagen, Copenhagen, Denmark. Electronic address: jsa@nordicbioscience.com.
Jannie M B
JM
Sand
Section of Respiratory Medicine, Hvidovre Hospital, Hvidovre, Denmark.
Gerd
G
Martinez
Section of Respiratory Medicine, Hvidovre Hospital, Hvidovre, Denmark.
Anne-Kirsten
AK
Midjord
Nordic Bioscience, Biomarkers and Research, Herlev, Denmark.
Morten A
MA
Karsdal
Nordic Bioscience, Biomarkers and Research, Herlev, Denmark.
Diana J
DJ
Leeming
Section of Social Medicine, Department of Public Health, University of Copenhagen, Copenhagen, Denmark; Section of Respiratory Medicine, Hvidovre Hospital, Hvidovre, Denmark.
Peter
P
Lange
D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood*; D003094:Collagen / Q000378:metabolism*; D000939:Epitopes / Q000097:blood*; D005260:Female; D006801:Humans; D008297:Male; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood* / Q000378:metabolism
D015415:Biomarkers; D000939:Epitopes; D003094:Collagen
Biomarker; COPD; Collagen; Extracellular matrix; Neo-epitope; Remodeling