Systemic biomarkers of neutrophilic inflammation, tissue injury and repair in COPD patients with differing levels of disease severity.
The identification and validation of biomarkers to support the assessment of novel therapeutics for COPD continues to be an important area of research. The aim of the current study was to identify systemic protein biomarkers correlated with measures of COPD severity, as well as specific protein signatures associated with comorbidities such as metabolic syndrome. 142 protein analytes were measured in serum of 140 patients with stable COPD, 15 smokers without COPD and 30 non-smoking controls. Seven analytes (sRAGE, EN-RAGE, NGAL, Fibrinogen, MPO, TGF-α and HB-EGF) showed significant differences between severe/very severe COPD, mild/moderate COPD, smoking and non-smoking control groups. Within the COPD subjects, univariate and multivariate analyses identified analytes significantly associated with FEV(1), FEV(1)/FVC and DLCO. Most notably, a set of 5 analytes (HB-EGF, Fibrinogen, MCP-4, sRAGE and Sortilin) predicted 21% of the variability in DLCO values. To determine common functions/pathways, analytes were clustered in a correlation network by similarity of expression profile. While analytes related to neutrophil function (EN-RAGE, NGAL, MPO) grouped together to form a cluster associated with FEV(1) related parameters, analytes related to the EGFR pathway (HB-EGF, TGF-α) formed another cluster associated with both DLCO and FEV(1) related parameters. Associations of Fibrinogen with DLCO and MPO with FEV(1)/FVC were stronger in patients without metabolic syndrome (r  =  -0.52, p  =  0.005 and r  =  -0.61, p =  0.023, respectively) compared to patients with coexisting metabolic syndrome (r  =  -0.25, p  =  0.47 and r  =  -0.15, p  =  0.96, respectively), and may be driving overall associations in the general cohort. In summary, our study has identified known and novel serum protein biomarkers and has demonstrated specific associations with COPD disease severity, FEV(1), FEV(1)/FVC and DLCO. These data highlight systemic inflammatory pathways, neutrophil activation and epithelial tissue injury/repair processes as key pathways associated with COPD.
Inflammation Disease Therapy Area, Hoffmann-La Roche, Nutley, New Jersey, United States of America.
Debra A
DA
Cockayne
Donavan T
DT
Cheng
Benjamin
B
Waschki
Sriram
S
Sridhar
Palanikumar
P
Ravindran
Holly
H
Hilton
Galina
G
Kourteva
Hans
H
Bitter
Sreekumar G
SG
Pillai
Sudha
S
Visvanathan
Kai-Christian
KC
Müller
Olaf
O
Holz
Helgo
H
Magnussen
Henrik
H
Watz
Jay S
JS
Fine
D000209:Acute-Phase Proteins; D000368:Aged; D015415:Biomarkers / Q000097:blood*; D015331:Cohort Studies; D015897:Comorbidity; D005260:Female; D005340:Fibrinogen / Q000032:analysis; D005541:Forced Expiratory Volume / Q000502:physiology; D016179:Granulocyte Colony-Stimulating Factor / Q000097:blood; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood; D007377:Interleukin-3 / Q000097:blood; D000071068:Lipocalin-2; D054834:Lipocalins / Q000097:blood; D008297:Male; D024821:Metabolic Syndrome / Q000097:blood / Q000175:diagnosis*; D015999:Multivariate Analysis; D011518:Proto-Oncogene Proteins / Q000097:blood; D011653:Pulmonary Diffusing Capacity / Q000502:physiology; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood / Q000175:diagnosis*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000097:blood; D011993:Recombinant Fusion Proteins / Q000097:blood; D012044:Regression Analysis; D009418:S100 Proteins / Q000097:blood; D000067616:S100A12 Protein; D012907:Smoking; D016211:Transforming Growth Factor alpha / Q000097:blood
D000209:Acute-Phase Proteins; D015415:Biomarkers; C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D007377:Interleukin-3; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D011518:Proto-Oncogene Proteins; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins; D009418:S100 Proteins; D000067616:S100A12 Protein; C090441:S100A12 protein, human; D016211:Transforming Growth Factor alpha; C404145:myelopoietin; D016179:Granulocyte Colony-Stimulating Factor; D005340:Fibrinogen