Profiling serum biomarkers in patients with COPD: associations with clinical parameters

Background: Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease associated with significant systemic consequences. Recognition of the systemic manifestations has stimulated interest in identifying circulating biomarkers in these patients. A systematic analysis was undertaken of multiple protein analytes in the serum of well characterised patients with COPD and matched controls using novel protein microarray platform (PMP) technology. Methods: Forty-eight patients (65% men) with COPD (forced expiratory volume in 1 s <55%) and 48 matched controls were studied. Anthropometric parameters, pulmonary function tests, 6-minute walk distance, the BODE index and the number of exacerbations were measured and the association of these outcomes with the baseline levels of 143 serum biomarkers measured by PMP was explored. Results: Thirty biomarker clusters were identified and ranked by computing the predictive value of each cluster for COPD (partial least squares discriminant analysis). From the 19 best predictive clusters, 2–3 biomarkers were selected based on their pathophysiological profile (chemoattractants, inflammation, tissue destruction and repair) and the statistical significance of their relationship with clinically important end points was tested. The selected panel of 24 biomarkers correlated (p<0.01) with forced expiratory volume in 1 s, carbon monoxide transfer factor, 6-minute walk distance, BODE index and exacerbation frequency. Conclusion: PMP technology can be useful in identifying potential biomarkers in patients with COPD. Panels of selected serum markers are associated with important clinical predictors of outcome in these patients.

[1]  J. Soriano,et al.  C-reactive protein in patients with COPD, control smokers and non-smokers , 2005, Thorax.

[2]  N. Booth,et al.  The Distribution of the Secreted and Intracellular Forms of Plasminogen Activator Inhibitor 2 (PAI-2) in Human Peripheral Blood Monocytes Is Modulated by Serum , 1998, Thrombosis and Haemostasis.

[3]  C. Cross,et al.  Tissue-specific gene expression of prolactin receptor in the acute-phase response induced by lipopolysaccharides. , 2004, American journal of physiology. Endocrinology and metabolism.

[4]  A. Zentella,et al.  16K prolactin induces NF-kappaB activation in pulmonary fibroblasts. , 2002, Journal of Endocrinology.

[5]  T. Ikeuchi,et al.  Brain-derived neurotrophic factor prevents superoxide anion-induced death of PC12h cells stably expressing TrkB receptor via modulation of reactive oxygen species , 1999, Neuroscience Research.

[6]  D. Corry,et al.  An Immune Basis for Lung Parenchymal Destruction in Chronic Obstructive Pulmonary Disease and Emphysema , 2004, PLoS medicine.

[7]  John R Hurst,et al.  Use of plasma biomarkers at exacerbation of chronic obstructive pulmonary disease. , 2006, American journal of respiratory and critical care medicine.

[8]  D. Mannino,et al.  Chronic obstructive pulmonary disease surveillance--United States, 1971-2000. , 2002, Morbidity and mortality weekly report. Surveillance summaries.

[9]  Leo Breiman,et al.  Bagging Predictors , 1996, Machine Learning.

[10]  X. Busquets,et al.  Systemic effects of chronic obstructive pulmonary disease , 2003, European Respiratory Journal.

[11]  K. Kowal,et al.  The plasmin system in airway remodeling. , 2003, Thrombosis research.

[12]  E. Wouters,et al.  Evidence for a relation between metabolic derangements and increased levels of inflammatory mediators in a subgroup of patients with chronic obstructive pulmonary disease. , 1996, Thorax.

[13]  H. Zou,et al.  Regularization and variable selection via the elastic net , 2005 .

[14]  A. M. Houghton,et al.  Neutrophil elastase contributes to cigarette smoke-induced emphysema in mice. , 2003, The American journal of pathology.

[15]  H. Fehrenbach Animal Models of Chronic Obstructive Pulmonary Disease: Some Critical Remarks , 2003, Pathobiology.

[16]  Ciro Casanova,et al.  The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. , 2004, The New England journal of medicine.

[17]  Rémi Quirion,et al.  Comparative signaling pathways of insulin‐like growth factor‐1 and brain‐derived neurotrophic factor in hippocampal neurons and the role of the PI3 kinase pathway in cell survival , 2004, Journal of neurochemistry.

[18]  K. Meyer,et al.  Vascular endothelial growth factor in bronchoalveolar lavage from normal subjects and patients with diffuse parenchymal lung disease. , 2000, The Journal of laboratory and clinical medicine.

[19]  B. Efron Bayesians, Frequentists, and Scientists , 2005 .

[20]  J. Coll,et al.  Inhibition of Apoptosis by Amphiregulin via an Insulin‐like Growth Factor‐1 Receptor—Dependent Pathway in Non‐Small Cell Lung Cancer Cell Lines , 2003, Annals of the New York Academy of Sciences.

[21]  E. Wouters,et al.  Weight loss is a reversible factor in the prognosis of chronic obstructive pulmonary disease. , 1999, American journal of respiratory and critical care medicine.

[22]  X. Busquets,et al.  [Systemic inflammation during exacerbations of chronic obstructive pulmonary disease]. , 2002, Archivos de bronconeumologia.

[23]  J. Elias The relationship between asthma and COPD. Lessons from transgenic mice. , 2004, Chest.

[24]  N. Voelkel,et al.  Pulmonary vascular involvement in chronic obstructive pulmonary disease , 2003, European Respiratory Journal.

[25]  A. Agustí,et al.  Inflamación sistémica durante las agudizaciones de la enfermedad pulmonar obstructiva crónica , 2002 .

[26]  LT Perlee,et al.  Development and standardization of multiplexed antibody microarrays for use in quantitative proteomics , 2004, Proteome Science.

[27]  K. Hirata,et al.  Imbalance between vascular endothelial growth factor and endostatin in emphysema , 2003, European Respiratory Journal.

[28]  Y. Higashimoto,et al.  Increased serum concentrations of tissue inhibitor of metalloproteinase-1 in COPD patients , 2005, European Respiratory Journal.

[29]  Christoph Lange,et al.  The SERPINE2 gene is associated with chronic obstructive pulmonary disease. , 2006, American journal of human genetics.

[30]  N. Voelkel,et al.  Oxidative stress and apoptosis interact and cause emphysema due to vascular endothelial growth factor receptor blockade. , 2003, American journal of respiratory cell and molecular biology.

[31]  W. MacNee,et al.  Systemic oxidative stress in asthma, COPD, and smokers. , 1996, American journal of respiratory and critical care medicine.

[32]  A. Churg,et al.  Proteases and emphysema , 2005, Current opinion in pulmonary medicine.

[33]  R. Rodríguez-Roisín,et al.  Toward a consensus definition for COPD exacerbations. , 2000, Chest.

[34]  K. Aoshiba,et al.  Alveolar wall apoptosis causes lung destruction and emphysematous changes. , 2003, American journal of respiratory cell and molecular biology.

[35]  W. Hardie,et al.  Dose-dependent lung remodeling in transgenic mice expressing transforming growth factor-alpha. , 2001, American journal of physiology. Lung cellular and molecular physiology.

[36]  D. Ruppert The Elements of Statistical Learning: Data Mining, Inference, and Prediction , 2004 .

[37]  S. Shapiro,et al.  Chronic obstructive pulmonary disease • 3: Experimental animal models of pulmonary emphysema , 2002, Thorax.

[38]  F. Maltais,et al.  Oxidative capacity of the skeletal muscle and lactic acid kinetics during exercise in normal subjects and in patients with COPD. , 1996, American journal of respiratory and critical care medicine.

[39]  K. Wright,et al.  Granulocyte inflammatory markers and airway infection during acute exacerbation of chronic obstructive pulmonary disease. , 2001, American journal of respiratory and critical care medicine.

[40]  X. Busquets,et al.  Expression of adhesion molecules and G proteins in circulating neutrophils in chronic obstructive pulmonary disease. , 1998, American journal of respiratory and critical care medicine.

[41]  P. Paré,et al.  The nature of small-airway obstruction in chronic obstructive pulmonary disease. , 2004, The New England journal of medicine.

[42]  L. Fabbri,et al.  Exacerbations of Bronchitis: bronchial eosinophilia and gene expression for interleukin-4, interleukin-5, and eosinophil chemoattractants. , 2001, American journal of respiratory and critical care medicine.

[43]  K. Hirata,et al.  Possible effects of vascular endothelial growth factor in the pathogenesis of chronic obstructive pulmonary disease. , 2003, The American journal of medicine.

[44]  P. Barnes,et al.  Sputum matrix metalloproteases: comparison between chronic obstructive pulmonary disease and asthma. , 2005, Respiratory medicine.

[45]  P. Hirth,et al.  Inhibition of VEGF receptors causes lung cell apoptosis and emphysema. , 2000, The Journal of clinical investigation.

[46]  P. Paré,et al.  Computed tomographic measurements of airway dimensions and emphysema in smokers. Correlation with lung function. , 2000, American journal of respiratory and critical care medicine.

[47]  E. Wouters,et al.  Raised CRP levels mark metabolic and functional impairment in advanced COPD , 2005, Thorax.

[48]  A. Miller,et al.  Lung function testing: selection of reference values and interpretative strategies. , 1992, The American review of respiratory disease.

[49]  A Senthilselvan,et al.  Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis , 2004, Thorax.

[50]  K. Glanz,et al.  Guidelines for School Programs to Prevent Skin Cancer , 2002, MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports.

[51]  W. MacNee,et al.  Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper , 2004, European Respiratory Journal.

[52]  Majid Ezzati,et al.  Estimates of global mortality attributable to smoking in 2000 , 2003, The Lancet.

[53]  R. Hamilton,et al.  Eotaxin-2 alters eosinophil integrin function via mitogen-activated protein kinases. , 2002, American journal of respiratory cell and molecular biology.

[54]  P. Sterk,et al.  Enhanced bronchial expression of vascular endothelial growth factor and receptors (Flk-1 and Flt-1) in patients with chronic obstructive pulmonary disease , 2005, Thorax.

[55]  N. Chavannes,et al.  Local and systemic inflammation in patients with chronic obstructive pulmonary disease: soluble tumor necrosis factor receptors are increased in sputum. , 2002, American journal of respiratory and critical care medicine.

[56]  H. Folkesson,et al.  Transforming growth factor-alpha enhances alveolar epithelial cell repair in a new in vitro model. , 1994, The American journal of physiology.

[57]  S. Kingsmore,et al.  Immunoassays with rolling circle DNA amplification: a versatile platform for ultrasensitive antigen detection. , 2000, Proceedings of the National Academy of Sciences of the United States of America.