The association of plasma biomarkers with computed tomography-assessed emphysema phenotypes

Respiratory Research

Russell P Bowler⁹  Katerina Kechris^1,10  Rachel L Zemans⁹  Meilan Han⁴  Alejandro P Comellas¹  Debra A Cockayne⁵  Paula Belloni⁶  Sreekumar G Pillai³  Stephen Rennard⁷  Wanda K O’Neal⁸  Craig P Hersh²  Jarrett Morrow²  Grant Hughes^1,10  Brendan J Carolan⁹ 

[1] Department of Internal Medicine, Division of Pulmonary and Critical Care, University of Michigan Health System, Ann Arbor, MI, USA;Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA;Hoffman La Roche, Nutley, USA;Current address: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA;Department of Internal Medicine, University of Iowa, Iowa City, IA, USA;Genentech, Member of the Roche Group, South San Francisco, CA, USA;Department of Internal Medicine, Pulmonary, Critical Care and Allergy Division, University of Nebraska Medical Center, Omaha, NE, USA;Cystic Fibrosis/Pulmonary Research and Treatment Center, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA;Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA;Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Denver, Aurora, CO, USA

关键词: Emphysema;    CCL20;    ICAM1;    RAGE;    Biomarkers;    COPD;   

Others  :  1137254
DOI  :  10.1186/s12931-014-0127-9

 received in 2014-05-29, accepted in 2014-10-03,  发布年份 2014

【 摘 要 】

Rationale

Chronic obstructive pulmonary disease (COPD) is a phenotypically heterogeneous disease. In COPD, the presence of emphysema is associated with increased mortality and risk of lung cancer. High resolution computed tomography (HRCT) scans are useful in quantifying emphysema but are associated with radiation exposure and high incidence of false positive findings (i.e., nodules). Using a comprehensive biomarker panel, we sought to determine if there was a peripheral blood biomarker signature of emphysema.

Methods

114 plasma biomarkers were measured using a custom assay in 588 individuals enrolled in the COPDGene study. Quantitative emphysema measurements included percent low lung attenuation (%LAA) ≤ −950 HU, ≤ − 910 HU and mean lung attenuation at the 15^th percentile on lung attenuation curve (LP15A). Multiple regression analysis was performed to determine plasma biomarkers associated with emphysema independent of covariates age, gender, smoking status, body mass index and FEV₁. The findings were subsequently validated using baseline blood samples from a separate cohort of 388 subjects enrolled in the Treatment of Emphysema with a Selective Retinoid Agonist (TESRA) study.

Results

Regression analysis identified multiple biomarkers associated with CT-assessed emphysema in COPDGene, including advanced glycosylation end-products receptor (AGER or RAGE, p < 0.001), intercellular adhesion molecule 1 (ICAM, p < 0.001), and chemokine ligand 20 (CCL20, p < 0.001). Validation in the TESRA cohort revealed significant associations with RAGE, ICAM1, and CCL20 with radiologic emphysema (p < 0.001 after meta-analysis). Other biomarkers that were associated with emphysema include CDH1, CDH 13 and SERPINA7, but were not available for validation in the TESRA study. Receiver operating characteristics analysis demonstrated a benefit of adding a biomarker panel to clinical covariates for detecting emphysema, especially in those without severe airflow limitation (AUC 0.85).

Conclusions

Our findings, suggest that a panel of blood biomarkers including sRAGE, ICAM1 and CCL20 may serve as a useful surrogate measure of emphysema, and when combined with clinical covariates, may be useful clinically in predicting the presence of emphysema compared to just using covariates alone, especially in those with less severe COPD. Ultimately biomarkers may shed light on disease pathogenesis, providing targets for new treatments.

【 授权许可】

   
2014 Carolan et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Vestbo J, Hurd SS, Agusti AG, Jones PW, Vogelmeier C, Anzueto A, Barnes PJ, Fabbri LM, Martinez FJ, Nishimura M, Stockley RA, Sin DD, Rodriguez-Roisin R: Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2013, 187(4):347-365.
• [2]Fletcher CM, Gilson JG, Hugh-Jones P, Scadding JG: Terminology, definitions, and classification of chronic pulmonary emphysema and related conditions. Thorax 1959, 14:286-299.
• [3]Mohamed Hoesein FA, Zanen P, Boezen HM, Groen HJ, van Ginneken B, de Jong PA, Postma DS, Lammers JW: Lung function decline in male heavy smokers relates to baseline airflow obstruction severity. Chest 2012, 142(6):1530-1538.
• [4]Li Y, Swensen SJ, Karabekmez LG, Marks RS, Stoddard SM, Jiang R, Worra JB, Zhang F, Midthun DE, de Andrade M, Song Y, Yang P: Effect of emphysema on lung cancer risk in smokers: a computed tomography-based assessment. Cancer Prev Res (Phila) 2011, 4(1):43-50.
• [5]de Torres JP, Bastarrika G, Wisnivesky JP, Alcaide AB, Campo A, Seijo LM, Pueyo JC, Villanueva A, Lozano MD, Montes U, Montuenga L, Zulueta JJ: Assessing the relationship between lung cancer risk and emphysema detected on low-dose CT of the chest. Chest 2007, 132(6):1932-1938.
• [6]Haruna A, Muro S, Nakano Y, Ohara T, Hoshino Y, Ogawa E, Hirai T, Niimi A, Nishimura K, Chin K, Mishima M: CT scan findings of emphysema predict mortality in COPD. Chest 2010, 138(3):635-640.
• [7]Bastarrika G, Wisnivesky JP, Pueyo JC, Diaz L, Arraiza M, Villanueva A, Alcaide AB, Campo A, Seijo L, de Torres JP, Zulueta JJ: Low-dose volumetric computed tomography for quantification of emphysema in asymptomatic smokers participating in an early lung cancer detection trial. J Thorac Imaging 2009, 24(3):206-211.
• [8]Kirby M, Coxson HO: Computed tomography biomarkers of pulmonary emphysema. COPD 2013, 10(4):547-550.
• [9]Schroeder JD, McKenzie AS, Zach JA, Wilson CG, Curran-Everett D, Stinson DS, Newell JD Jr, Lynch DA: Relationships between airflow obstruction and quantitative CT measurements of emphysema, air trapping, and airways in subjects with and without chronic obstructive pulmonary disease. AJR Am J Roentgenol 2013, 201(3):W460-W470.
• [10]Mendoza CS, Washko GR, Ross JC, Diaz AA, Lynch DA, Crapo JD, Silverman EK, Acha B, Serrano C, Estepar RS: Emphysema Quantification in a Multi-Scanner Hrct Cohort Using Local Intensity Distributions.Proc IEEE Int Symp Biomed Imaging 2013: 474–477.
• [11]Parr DG, Dirksen A, Piitulainen E, Deng C, Wencker M, Stockley RA: Exploring the optimum approach to the use of CT densitometry in a randomised placebo-controlled study of augmentation therapy in alpha 1-antitrypsin deficiency. Respir Res 2009, 10:75. BioMed Central Full Text
• [12]Stoller JK, Aboussouan LS: A review of alpha1-antitrypsin deficiency. Am J Respir Crit Care Med 2012, 185(3):246-259.
• [13]Cheng DT, Kim DK, Cockayne DA, Belousov A, Bitter H, Cho MH, Duvoix A, Edwards LD, Lomas DA, Miller BE, Reynaert N, Tal-Singer R, Wouters EF, Agusti A, Fabbri LM, Rames A, Visvanathan S, Rennard SI, Jones P, Parmar H, MacNee W, Wolff G, Silverman EK, Mayer RJ, Pillai SG: Systemic soluble receptor for advanced glycation endproducts is a biomarker of emphysema and associated with AGER genetic variants in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2013, 188(8):948-957.
• [14]Carolan BJ, Kim YI, Williams AA, Kechris K, Lutz S, Reisdorph N, Bowler RP: The association of adiponectin with computed tomography phenotypes in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2013, 188(5):561-566.
• [15]Miller M, Ramsdell J, Friedman PJ, Cho JY, Renvall M, Broide DH: Computed tomographic scan-diagnosed chronic obstructive pulmonary disease-emphysema: eotaxin-1 is associated with bronchodilator response and extent of emphysema. J Allergy Clin Immunol 2007, 120(5):1118-1125.
• [16]Thomsen M, Dahl M, Lange P, Vestbo J, Nordestgaard BG: Inflammatory biomarkers and comorbidities in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012, 186(10):982-988.
• [17]Gaki E, Kontogianni K, Papaioannou AI, Bakakos P, Gourgoulianis KI, Kostikas K, Alchanatis M, Papiris S, Loukides S: Associations between BODE index and systemic inflammatory biomarkers in COPD. COPD 2011, 8(6):408-413.
• [18]Rosenberg SR, Kalhan R: Biomarkers in chronic obstructive pulmonary disease. Transl Res 2012, 159(4):228-237.
• [19]Regan EA, Hokanson JE, Murphy JR, Make B, Lynch DA, Beaty TH, Curran-Everett D, Silverman EK, Crapo JD: Genetic epidemiology of copd (copedgene) study design. COPD 2010, 7:32-43.
• [20]Jones PW: Tesra (treatment of emphysema with selective retinoid agonist) study results. Am J Respir Crit Care Med 2011, 183:A6418.
• [21]Han MK, Kazerooni EA, Lynch DA, Liu LX, Murray S, Curtis JL, Criner GJ, Kim V, Bowler RP, Hanania NA, Anzueto AR, Make BJ, Hokanson JE, Crapo JD, Silverman EK, Martinez FJ, Washko GR: Chronic obstructive pulmonary disease exacerbations in the COPDGene study: associated radiologic phenotypes. Radiology 2011, 261(1):274-282.
• [22]O'Neal WK, Anderson W, Basta PV, Carretta EE, Doerschuk CM, Barr RG, Bleecker ER, Christenson SA, Curtis JL, Han MK, Hansel NN, Kanner RE, Kleerup EC, Martinez FJ, Miller BE, Peters SP, Rennard SI, Scholand MB, Tal-Singer R, Woodruff PG, Couper DJ, Davis SM: Comparison of serum, EDTA plasma and P100 plasma for luminex-based biomarker multiplex assays in patients with chronic obstructive pulmonary disease in the SPIROMICS study. J Transl Med 2014, 12:9. BioMed Central Full Text
• [23]Stouffer SA, Suchman EA, DeVinney LC, Star SA, Williams RM Jr: The American Soldier, Vol. 1: Adjustment during Army Life. Princeton University Press, Princeton; 1949.
• [24]Murdoch DR, O'Brien KL, Scott JA, Karron RA, Bhat N, Driscoll AJ, Knoll MD, Levine OS: Breathing new life into pneumonia diagnostics. J Clin Microbiol 2009, 47(11):3405-3408.
• [25]Buckley ST, Ehrhardt C: The receptor for advanced glycation end products (RAGE) and the lung. J Biomed Biotechnol 2010, 2010:917108.
• [26]Pullerits R, Bokarewa M, Dahlberg L, Tarkowski A: Decreased levels of soluble receptor for advanced glycation end products in patients with rheumatoid arthritis indicating deficient inflammatory control. Arthritis Res Ther 2005, 7(4):R817-R824. BioMed Central Full Text
• [27]Falcone C, Bozzini S, Guasti L, D'Angelo A, Capettini AC, Paganini EM, Falcone R, Moia R, Gazzaruso C, Pelissero G: Soluble RAGE plasma levels in patients with coronary artery disease and peripheral artery disease. Scientific World Journal 2013, 2013:584504.
• [28]Alexiou P, Chatzopoulou M, Pegklidou K, Demopoulos VJ: RAGE: a multi-ligand receptor unveiling novel insights in health and disease. Curr Med Chem 2010, 17(21):2232-2252.
• [29]Uchida T, Shirasawa M, Ware LB, Kojima K, Hata Y, Makita K, Mednick G, Matthay ZA, Matthay MA: Receptor for advanced glycation end-products is a marker of type I cell injury in acute lung injury. Am J Respir Crit Care Med 2006, 173(9):1008-1015.
• [30]Smith DJ, Yerkovich ST, Towers MA, Carroll ML, Thomas R, Upham JW: Reduced soluble receptor for advanced glycation end-products in COPD. Eur Respir J 2011, 37(3):516-522.
• [31]Cockayne DA, Cheng DT, Waschki B, Sridhar S, Ravindran P, Hilton H, Kourteva G, Bitter H, Pillai SG, Visvanathan S, Muller KC, Holz O, Magnussen H, Watz H, Fine JS: Systemic biomarkers of neutrophilic inflammation, tissue injury and repair in COPD patients with differing levels of disease severity. PLoS One 2012, 7(6):e38629.
• [32]Miniati M, Monti S, Basta G, Cocci F, Fornai E, Bottai M: Soluble receptor for advanced glycation end products in COPD: relationship with emphysema and chronic cor pulmonale: a case–control study. Respir Res 2011, 12:37. BioMed Central Full Text
• [33]Wu L, Ma L, Nicholson LF, Black PN: Advanced glycation end products and its receptor (RAGE) are increased in patients with COPD. Respir Med 2011, 105(3):329-336.
• [34]Stogsdill MP, Stogsdill JA, Bodine BG, Fredrickson AC, Sefcik TL, Wood TT, Kasteler SD, Reynolds PR: Conditional overexpression of receptors for advanced glycation end-products in the adult murine lung causes airspace enlargement and induces inflammation. Am J Respir Cell Mol Biol 2013, 49(1):128-134.
• [35]Di Stefano A, Maestrelli P, Roggeri A, Turato G, Calabro S, Potena A, Mapp CE, Ciaccia A, Covacev L, Fabbri LM, Saetta M: Upregulation of adhesion molecules in the bronchial mucosa of subjects with chronic obstructive bronchitis. Am J Respir Crit Care Med 1994, 149(3 Pt 1):803-810.
• [36]El-Deek SE, Makhlouf HA, Saleem TH, Mandour MA, Mohamed NA: Surfactant protein D, soluble intercellular adhesion molecule-1 and high-sensitivity C-reactive protein as biomarkers of chronic obstructive pulmonary disease. Med Princ Pract 2013, 22(5):469-474.
• [37]Huang H, Jiang H, Kong X, Liu T, Tan Z, Chen P, Luo H: Association of intercellular adhesion molecule-1 gene K469E polymorphism with chronic obstructive pulmonary disease. Zhong Nan Da Xue Xue Bao Yi Xue Ban 2012, 37(1):78-83.
• [38]Lopez-Campos JL, Calero C, Arellano-Orden E, Marquez-Martin E, Cejudo-Ramos P, Ortega Ruiz F, Montes-Worboys A: Increased levels of soluble ICAM-1 in chronic obstructive pulmonary disease and resistant smokers are related to active smoking. Biomark Med 2012, 6(6):805-811.
• [39]Aaron CP, Schwartz JE, Tracy R, Hoffman EA, Austin JHM, Oelsner EC, Donohue KM, Kalhan R, Jacobs D, Barr RG: Intercellular Adhesion Molecule (icam)1 And Longitudinal Change In Percent Emphysema And Lung Function: The MESA Lung Study. Am J Respir Crit Care Med 2013, 187:A1523.
• [40]Dieu-Nosjean MC, Massacrier C, Homey B, Vanbervliet B, Pin JJ, Vicari A, Lebecque S, Dezutter-Dambuyant C, Schmitt D, Zlotnik A, Caux C: Macrophage inflammatory protein 3alpha is expressed at inflamed epithelial surfaces and is the most potent chemokine known in attracting Langerhans cell precursors. J Exp Med 2000, 192(5):705-718.
• [41]Meuronen A, Majuri ML, Alenius H, Mantyla T, Wolff H, Piirila P, Laitinen A: Decreased cytokine and chemokine mRNA expression in bronchoalveolar lavage in asymptomatic smoking subjects. Respiration 2008, 75(4):450-458.
• [42]Bracke KR, D'Hulst AI, Maes T, Moerloose KB, Demedts IK, Lebecque S, Joos GF, Brusselle GG: Cigarette smoke-induced pulmonary inflammation and emphysema are attenuated in CCR6-deficient mice. J Immunol 2006, 177(7):4350-4359.
• [43]Gall TM, Frampton AE: Gene of the month: E-cadherin (CDH1). J Clin Pathol 2013, 66(11):928-932.
• [44]Milara J, Peiro T, Serrano A, Cortijo J: Epithelial to mesenchymal transition is increased in patients with COPD and induced by cigarette smoke. Thorax 2013, 68(5):410-420.
• [45]Tsuduki KNH, Nakajima T, Tsujimura S, Yoshida S, Takahashi E, Nakamura M, Minematsu N, Tateno H, Ishizaka A: Genetic polymorphism of e-cadherin and COPD. Am J Respir Crit Care Med 2009, 179:A2999.
• [46]Kasahara DI, Williams AS, Benedito LA, Ranschr B, Kobzik L, Hug C, Shore SA: Role of the adiponectin binding protein, t-cadherin (cdh13), in pulmonaryt responses to subacute ozone. PLoS One 2013, 8:e65829.
• [47]Takeuchi T, Misaki A, Fujita J, Sonobe H, Ohtsuki Y: T-cadherin (cdh13, h-cadherin) expression downtregulated surfactant protein d in bronchioloalveolar cells. Virchows Arch 2001, 438:370-375.
• [48]Faner R, Tal-Singer R, Riley JH, Celli B, Vestbo J, MacNee W, Bakke P, Calverley PM, Coxson H, Crim C, Edwards LD, Locantore N, Lomas DA, Miller BE, Rennard SI, Wouters EF, Yates JC, Silverman EK, Agusti A: Lessons from ECLIPSE: a review of COPD biomarkers. Thorax 2013, 69(7):666-672.
• [49]Agusti A, Sin DD: Biomarkers in COPD. Clin Chest Med 2014, 35(1):131-141.