Systemic Biomarkers of Neutrophilic Inflammation, Tissue Injury and Repair in COPD Patients with Differing Levels of Disease Severity

被引:80
作者
Cockayne, Debra A. [1 ]
Cheng, Donavan T. [2 ]
Waschki, Benjamin [3 ,4 ]
Sridhar, Sriram [2 ]
Ravindran, Palanikumar [2 ]
Hilton, Holly [2 ]
Kourteva, Galina [2 ]
Bitter, Hans [2 ]
Pillai, Sreekumar G. [1 ]
Visvanathan, Sudha [1 ]
Mueller, Kai-Christian [4 ]
Holz, Olaf [4 ]
Magnussen, Helgo [3 ]
Watz, Henrik [3 ]
Fine, Jay S. [1 ]
机构
[1] Hoffmann La Roche Inc, Inflammat Dis Therapy Area, Nutley, NJ 07110 USA
[2] Hoffmann La Roche Inc, Translat Res Sci, Nutley, NJ 07110 USA
[3] Hosp Grosshansdorf, Pulm Res Inst, Grosshansdorf, Germany
[4] Hosp Grosshandorf, Ctr Pneumol & Thorac Surg, Grosshansdorf, Germany
关键词
GLYCATION END-PRODUCTS; OBSTRUCTIVE PULMONARY-DISEASE; EPIDERMAL-GROWTH-FACTOR; SOLUBLE RECEPTOR; METABOLIC SYNDROME; EPITHELIAL REPAIR; PLASMA-FIBRINOGEN; PHYSICAL-ACTIVITY; LUNG-FUNCTION; FACTOR-ALPHA;
D O I
10.1371/journal.pone.0038629
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 nonsmoking controls. Seven analytes (sRAGE, EN-RAGE, NGAL, Fibrinogen, MPO, TGF-alpha 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 FEV1, FEV1/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 FEV1 related parameters, analytes related to the EGFR pathway (HB-EGF, TGF-alpha) formed another cluster associated with both DLCO and FEV1 related parameters. Associations of Fibrinogen with DLCO and MPO with FEV1/FVC were stronger in patients without metabolic syndrome (r = 20.52, 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, FEV1, FEV1/FVC and DLCO. These data highlight systemic inflammatory pathways, neutrophil activation and epithelial tissue injury/repair processes as key pathways associated with COPD.
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页数:12
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