Proteomics-Based Biomarkers in Chronic Obstructive Pulmonary Disease Hong Chen,† Diane Wang,‡ Chunxue Bai,‡ and Xiangdong Wang*,†,‡ Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China, and Biomedical Research Center, Zhongshan Hospital, Fudan University, Shanghai, China Received January 23, 2010
Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease associated with progressive obstruction of airflow affecting peripheral airways. The proteomic analysis highlights ways to identify novel biomarkers for diagnosis, therapy, and prognosis in COPD. Human samples, for example, lung tissue, bronchoalveolar lavage, sputum, and serum, have been used for COPD proteomic research, each with its own merits and demerits. In the present review, we aimed at discussing the feasibility of clinical studies on COPD proteomics and the potential candidates for COPD biomarkers detected in human samples that are sensitive to the progress of COPD, disease-specific to COPD, and associated with the status of the patients. There is an increasing need to be able to perform proteomic studies on patients with COPD that describe the association with disease specificity, severity, progress, and prognosis as well as monitor the efficacy of therapies. There is an urgent need to establish and clarify the criteria for subjects including controls and data analysis and standardize the study design, methodology, and process as this is vital when designing prospective clinical studies on COPD. It is important to clarify the source of the samples, the efficiency, and quality when dealing with large amount of candidates and the specificity of biomarkers according to the severity, therapeutic effects, progress, and prognosis of the disease. Keywords: COPD • proteomics • biomarker • lungs • biopsy
Introduction Chronic obstructive pulmonary disease (COPD) is an inflammatory disease characterized by the progressive deterioration of pulmonary function and increasing airway obstruction.1,2 COPD can be caused by inflammatory responses triggered by noxious particles or gas, most commonly from tobacco smoking,3,4 and is accompanied by chronic bronchitis and emphysema. Progression of COPD is linked with the accumulation of inflammatory mucous exudates in the airway lumen and infiltration of the wall by innate and adaptive inflammatory immune cells that form lymphoid follicles.4 The natural course of COPD is characterized by occasional sudden worsening of symptoms called acute exacerbations, mainly caused by infections or air pollution. Important management strategies are smoking cessation, vaccinations, rehabilitation, and drug therapy (often using inhalers). Some patients go on to require longterm oxygen therapy or lung transplantation.3 COPD was ranked as one of the top five leading causes of death worldwide and is estimated to become the top third cause of mortality by 2020.5 Airway and parenchymal phenotypes of COPD were suggested to be associated with unique * To whom correspondence should be addressed. Xiangdong Wang, M.D., Ph.D. Tel.: +86 21 64041990 ×5420. Fax: +86 21 54961729. E-mail:
[email protected]. † Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University. ‡ Biomedical Research Center, Zhongshan Hospital, Fudan University.
2798 Journal of Proteome Research 2010, 9, 2798–2808 Published on Web 04/14/2010
systemic serum biomarker profiles.6 Inflammation was thought to be the key process in the pathogenesis of COPD as numbers and levels of inflammatory cells and mediators increased in the bronchoalveolar lavage fluid (BALF), sputum, and lung tissues from patients with COPD. There is still some ambiguousness regarding the molecular mechanisms and diseasespecificity of the inflammatory process and acute exacerbation of COPD. The identification of disease-specific, severity-related, and reliable biomarkers is an essential step for diagnostics and the monitoring of therapeutics in patients with COPD. There is a great need for such biomarkers in order to be able to select optimal therapies and develop new therapeutic strategies to prevent and treat the disease. New biomarkers should detect and/or predict the onset and progression of the disease, the efficacy of therapies, and prognosis of the patients. In particular, pharmaceutical industries can take advantage of the discovery of biomarkers to obtain early and specific proof of drugs’ efficacy on the disease. One of the criteria for the validation of biomarkers is that it needs to be specific and sensitive enough to discriminate between clinical end points. Nevertheless, potential biomarkers specific to COPD have not yet been fully identified and validated. The proteomic analysis highlights the ways to investigate protein profiles of cells, biopsies, and fluids; explore proteinbased mechanisms of human diseases; identify novel biomarkers for diagnosis, therapy, and prognosis of multiple diseases; and discover new targets for drug development. Proteomic 10.1021/pr100063r
2010 American Chemical Society
Proteomics-Based Biomarkers in COPD
Figure 1. Basic workflow of proteomics-based methods applied in COPD. Four critical steps should be fully considered in proteomics research, including sample selection and preparation, protein separation and identification, analysis and bioinformatics, and clinical relevance. In COPD proteomics, four kind of clinical samples are available, including lung tissues, BALF, induced sputum, and serum. 2-DE has been suggested as the most common way. LC was coupled with MS or could be supplement to 2-DE. MALDI-TOF, SELDI-TOF, and FTICR have been applied for protein validation in COPD. Various softwares and online databases are always incorporated to deal with global omicsdata. BALF, bronchoalveolar lavage fluid; IS, induced sputum; 2-DE, two-dimensional gel electrophoresis; LC, liquid chromatography; SELDI, surface-enhanced laser desorption/ionization; TOF, time-of-flight; MS, mass spectroscopy; MALDI, Matrixassisted laser desorption/ionization; FTICR, Fourier transform ion cyclotron resonance.
approaches have been applied to describe the proteomic profiling in many chronic lung diseases, such as cystic fibrosis, idiopathic pulmonary fibrosis (IPF), sarcoidosis, asthma, and others.7–10 The analysis of protein profiles that are up- or downregulated, modified, secreted, or exudated in the airways during the disease may yield vital evidence to understand the pathogenesis and discover new therapeutic targets for the disease.8 The procedures of proteomic research in pulmonary medicine include sample collection, separation, identification, and bioinformatics study (Figure 1, Table 1). On the basis of the development of the genomic and proteomic techniques, various samples can be employed for COPD study. In this review, we discussed the proteomic-oriented methods mainly used in patients with COPD and diagnostic or prognostic values of potential biomarkers from published proteomics-based results. To understand the disease specificity of proteomic profiles in COPD, we also compared the findings of clinical proteomics in COPD with other chronic lung diseases, for example, sarcoidosis, IPF, and systemic sclerosis.
Sample Selection in COPD Research Lung Tissues. Samples from different compartments of the lungs yield different information on cell numbers, markers of inflammation, and oxidative stress. Biopsies can provide more precise information as well as subjective visualization in the pathological sites. This method has been accepted in proteomics-based COPD research.10–12 In comparison to healthy subjects, higher numbers of macrophages and eosinophils are found in biopsies.13 Tissue remodeling is a potential therapeutic avenue for curing/alleviating COPD.3 Lung tissues can provide in-depth information on the pathogenesis of the disease (Figure 2). Although lung biopsy seems to be the most direct visualiza-
reviews tion in clinical study, it is hard to obtain biopsies from the majority of patients with COPD. Therefore, sampling lung tissues has its limitations when used in clinical proteomics of COPD unlike cases with lung cancer. Proteins and peptides found in lung tissues of patients with COPD are summarized in Table 2. Bronchoalveolar Lavage Fluid. BALF is the most common method used to sample the soluble proteins of the epithelial lining fluid, epithelium-produced elements, and plasma exudation. Many clinical proteomics in BALF from patients with COPD and smokers were studied as shown in Table 1. Investigating BALF can be performed as a routine diagnostic procedure by fibrotic bronchoscope to evaluate upper airway inflammation, allergy, or malignancies. Alveolar epithelial cells are likely to be an important source of the inflammatory mediators in COPD, although the disease specificity in the inflammation of COPD remains unclear.11 Proteins in BALF may be locally released by epithelial cells and inflammatory cells or leaked from the circulation.14 Because of the diverse origins of BALF proteins, analysis of BALF protein profile can provide key evidence to identify disease-specific mediators and enable more accurate characterization of lung diseases at the molecular level9 (Figure 3). Minor components in BALF can be separated by two-dimensional gel electrophoresis (2-DE) and analyzed by mass spectrometry (MS) to obtain the protein profiles and peak identities of the individual spots.8 BALF has been suggested as a promising choice of sample selections, although a number of challenges should be taken into consideration such as the dilution and variation.15 Induced Sputum. Induced sputum by hypertonic saline16 is another alternative used to obtain epithelial lining fluid samples which is less invasive than both BALF and biopsy. This method has been recognized and validated in chronic lung diseases and exacerbation conditions. The percentages of macrophages and neutrophils in the sputum were significantly lower and higher, respectively, than in BALF in chronic lung diseases.13,17–19 The number of lymphocytes in induced sputum and BALF from patients with sarcoidosis and hypersensitivity pneumonitis was significantly higher than those from patients with COPD.20 The percentage of eosinophils in COPD was higher than those found in the healthy controls.13 Induced sputum has been suggested as a useful way to study the role of luminal neutrophils and eosinophils in COPD13 as well as identify the differences between samples from patients with sarcoidosis, healthy subjects, and patients with nongranulomatous interstitial lung diseases.21 However, studies on sputum proteomics are still limited in COPD research due to the difficulty of having controls and lack of general standardization. Serum. Human blood is an easily obtained and useful source of proteins associated with both health and disease. It has been considered that the patterns of serum biomarkers can provide more precise information on the classification and pathogenesis of COPD which would be useful for the development of disease-specific therapies.6 Many lung-specific proteins, such as surfactant protein-A, can be detected in the circulation. A number of proteomic methodologies22 can be used in the assessment of serum biomarkers for COPD. However, few proteomic analyses of the serum are used in COPD as it remains a challenge to identify the large and varied numbers and concentrations of peptides and proteins23 as well as the specificity of serum proteins. It should also be taken into consideration that the information from serum analysis reflects systemic alterations in COPD. Journal of Proteome Research • Vol. 9, No. 6, 2010 2799
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Table 1. Catogories of Study Design and Techniques in COPD Proteomics
ref.
total identified proteins
12
11
893
42
41
10
105 113 381 377 26
7 9 8
481
type of subjects (n ) subject numbers)
samples
country
methods
NS(5) COPD II-III(4) COPD IV(4) AATD(5) IPF(3) NS(8) HS(7) COPD(7)
Biopsy
Korea
2D-PAGE immunohistochemistry Western blot
Biopsy
Finland
COPD(10) HS(8) NS(8)
BALF
Germany
NS(20) Asthma(24) COPD(24) CF (28) Bronchiectasis(19) NS(3) HS(3) Ex-smokers(3) NS(18) HS(29) NS(18) HS(30) HS (3) NS(4)
Sputum
UK
Biopsy
USA
BALF
Sweden
BALF
USA and Sweden Sweden
2D-PAGE MALDI-TOF-MS Western blot immunohistochemistry SELDI-MS RP-HPLC Nano LC-MS/MS MALDI-TOF-MS SELDI-TOF-MS MALDI-TOF-MS Tandom MS/MS ELISA Western blot 2-DE MALDI-TOF-MS Western blot 2-DE MS Shotgun sequencing LC-LTQ MS 2-DE MALDI-TOF MS
BALF
a BALF, bronchoalveolar lavage fluid; 2-DE, two-dimensional gel electrophoresis; SELDI, surface-enhanced laser desorption/ionization; TOF, time-of-flight; MS, mass spectroscopy; MALDI, Matrix-assisted laser desorption/ionization; RP-HPLC, reversed-phase high-performance liquid chromatography; LTQ MS, on-line linear ion trap quadropole mass spectrometry; COPD, chronic obstructive pulmonary disease; CF, Cystic fibrosis; IPF, idiopathic pulmonary fibrosis; AATD, alpha-antitrypsin deficiency; HS, healthy smokers; NS, nonsmokers.
Figure 2. Hypothesis of possible signaling pathway of potential biomarkers detected in COPD lung tissues. Lung tissues can provide in-depth information on the pathogenesis of the disease. Upon tobacco smoking, epithelial cells could produce inflammatory mediators, such as IL-1 and IL-8. Both of them could activate and recruit neutrophils in the tissue. Some proteins released by neutrophils like MMP-13, thioredoxin, and elastin might take part in tissue damage and remodeling. Other proteins may be up-regulated in epithelial cells by p38/MAPK-NF-κB signaling pathway. SP-A is important in tissue repair process. Some proteins detected in COPD proteomics, such as cathepsin D, calgranulin C, and gelsolin, may play a role in pathogenesis, although the mechanism remains unclear. NF-κB, nuclear factor κB; MAPK, mitogen-activated protein kinase; IL-1, interleukin-1; IL-8, interleukin-8; MMP-13, matrix metalloproteinase 13; SP-A, pulmonary surfactant A.
Exhaled Breath. Exhaled breath condensate is an interesting and important source of biomarkers that is a relatively pure aqueous solution almost free of any protein interfering solutes. The proteins are collected by cooling exhaled air during natural 2800
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breathing through an easy and noninvasive procedure.24 There is, however, no proteomic analysis of the exhaled breath condensate in COPD, which may be feasible and useful in clinical practice.
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Table 2. Summary of Potential Biomarkers Detected in Lung Tissues in COPD proteins
COPD§
Surfactant protein-A, SP-A Matrix metalloproteinase-13, MMP-13 Thioredoxin-like 2 Transcription factor AP-4, TFAP-4 Peroxiredoxin 6 NEFA-interacting nuclear protein, NIP 30 Hepatoma-derived growth factor Regulator of G-protein signaling 16 Histamine-releasing factor R -soluble-N ethylmaleimide-sensitive fusion attachment protein, alpha-SNAP Centrin-3 Calmodulin-like protein, CaLP Calreticulin Protein disulfide-isomerase, PDI 78kD glucose-regulated protein, GRP 78 Thioredoxin-dependent peroxide reductase ATP synthase subunit β Glyceraldehydes-3-phosphate dehydrogenase, GAPDH Malate dehydrogenase Actin, cytoplasmic 1 Tubulin β-2 chain Microfibril-associated glycoprotein Gelsolin Annexin A2 Cofilin-1 60S acidic ribosomal protein P2 Elongation factor 1β Elongation factor 1δ Cathepsin D Heat shock protein 27 14-3-3 protein sigma (epithelial cell marker protein 1,stratifin) Reticulocalbin-1 Rho GDP-dissociation inhibitor 1 Major vault protein (lung resistance-related protein) Heme-binding protein 2 Apolipoprotein A-1 Albumin Serotransferrin Calgranulin C
v v v v v v v v v V
COPD*
healthy smokers§
ref.
12 11 11 11 11 11 11 11 11 11
v v v V v v
V V v v v v v v v v v v v v v v v v v v v v v v v V V V V
11 11 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10
also indicated in other diseases
IPFv94 asthmav96
CFv, 97asthmav84 sacroidosisv98
CFv93 IPFv95
a The symbols * and § stand for the comparison with healthy smokers and healthy nonsmokers, respectively. The arrows v and V stand for the up-regulated and down-regulated indications, respectively.
Separation and Identification of Potential Biomarkers Gel-Based Separation and Liquid Chromatography. 2-DE has been used as the first step for the analysis of protein profiles in BALF and sputum, although BALF may contain a low concentration of proteins and a relatively high abundance of albumin, immunoglobulins, and mucopolysaccharides. 2-DE has been applied in COPD studies, as shown in Table 1, though the exact quantification of proteins from 2-DE analysis remains to be questioned. Fluorescence two-dimensional differential gel electrophoresis (2D-DIGE) is a new development in protein detection for 2-DE25 where the proteins are labeled with fluorescent dyes and then separated by 2D-PAGE. Liquid chromatography (LC), especially reversed-phase high-performance liquid chromatography (RP-HPLC), can be used as a purification step before or after 2-DE. LC-LC-MS-MS (tandem mass spectrometry)-based techniques might have the upper hand over gel-based techniques in terms of the speed, sensitivity, reproducibility, and applicability to different samples and conditions.26 Proteomic analysis in BALF can identify proteins above 10 kDa by 2-DE14,27,28 and below 8 kDa by nano tandem
mass spectrometry.11 LC as the automated operation is easier to perform than 2-DE analysis and with less influence from artificial factors. Mass Spectrometry. A number of analytic methodologies, for example, MS, including matrix-assisted laser desorption/ ionization (MALDI), surface-enhanced laser desorption/ionization (SELDI),29 and time-of-flight (TOF) MS, are used to identify the protein profiles in tissue samples, blood, urine, and other clinical samples for the identification and validation of diseasespecific biomarker discovery.30,31 SELDI-TOF MS uses protein chip arrays to capture individual targets from a complex protein sample in a high-throughput way,32 although some difficulties when identifying the proteins in the mass profile might occur.33 SELDI-TOF MS is used to analyze protein profiles of BALF samples from patients with sarcoidosis.34 It is, however, possible that results based on SELDI MS could be influenced by assays,35 sample collections,36 different laboratories,37 and analytical and preanalytical biases.38 Its reliability and reproducibility were biased by artifacts related to the nature of the clinical samples, MS instrument, and/or bioinformatic analyJournal of Proteome Research • Vol. 9, No. 6, 2010 2801
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Figure 3. Interaction between potential biomarkers detected in BALF in patients with COPD. These candidate biomarkers may take part in different stages and some signaling pathways remain unknown as indicated as the question mark. Because of the diverse origins of BAL proteins, analysis of BALF protein profile can provide the important evidence to identify disease-specific mediators. Many of these proteins could reflect the molecular mechanism in the development of COPD. Cytokines (MCP-1, IL-8, IL-1, TNF-R) are up-regulated upon stimulus in airway epithelial cells, leading to activation and recruitment of effector cells. In COPD, local macrophage and neutrophils are major inflammatory cells and abundant in lung tissue and BALF. ROS in leukocytes could result in apoptosis and local inflammation. Some candidate biomarkers by neutrophils incorporate in different stages in COPD, i.e., damage and repair. NF-κB, nuclear factor κB; MCP-1, monocyte chemoattractant protein-1; TNF-R, tumor necrosis factor-R; MAPK, mitogen-activated protein kinase; IL-1, interleukin1; IL-8, interleukin-8; ROS, reactive oxygen species; MMPs, matrix metalloproteinases.
sis.39 The question is whether these challenges, that have been encountered in the search of cancer biomarkers, will also be encountered in the study of COPD which could constrain the clinical application.33,39
Potential Proteomics-Based Biomarkers
MALDI MS and MS/MS or linear quadrupole ion trap (LTQ) MS were used to accurately identify sensitive proteins contained in intermediates such as phosphopeptides.40 The differences in protein expression seen by LTQ MS analysis could be confirmed by 2-DE.9 2-DE coupled with MALDI-TOF was commonly used in COPD proteomics,8,10,11,41,42 showing more preferable and suitable than SELDI. The application of highresolution Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS) in combination with gel-electrophoretic separation provided efficient identification of proteins of medium and low abundance.43 FTICR-MS may be more useful in the research of COPD proteomics due to the substantially lower tolerance and low sequence coverage.44–47 Other Methods. Bon et al.6 successfully used cytometric bead assay to investigate the relationship between serum cytokine pattern and COPD phenotypes. The LabMap technology combines the principle of a sandwich immunoassay with the fluorescent-bead-based technology allowing individual and multiplex analysis of up to 100 different analysts in a single microtiter well.48 Such protein-chip array allows simultaneous identification and quantification of a large number of proteins from a small volume of any given sample within a single run.49 This exciting technology may be an option for COPD proteomics in the future. Conventional methods like ELISA, western blot, and immunohistopathology could be supplemented to validate proteomics results.11,12,41 It seems that BALF and induced sputum are more competitive than other samples due to the minimal invasion and more accurate reflection of the lung damage that has occurred. LC-MS-based proteome analy-
Oxidant-Antioxidant and Protease-Antiprotease System. This review included the recent clinical studies on COPD proteomics and analyzed feasible data regarding biomarker candidates in comparison to other chronic lung diseases like idiopathic pulmonary fibrosis and chronic fibrosis as well as identified the COPD-specific biomarkers. Oxidative stress, inflammation, tissue damage, and tissue repair (remodeling) are parts of the complex procedure in COPD. The increased oxidative stress in patients with COPD could be a result of increased amounts of reactive oxygen species (ROS) from various inflammatory, immune, and epithelial cells in the airways.50 Processes that contribute to the pathogenesis of COPD could be, for example, oxidative inactivation of antiproteases and surfactants, mucus hypersecretion, membrane lipid peroxidation, mitochondrial respiration, alveolar epithelial injury, remodeling of extracellular matrix, and apoptosis.51 Multiple proteases, causing both elastin and collagen degradation, are important in the pathogenesis of pulmonary emphysema.52 The activation of matrix metalloproteinases (MMPs), thioredoxin, and myeloperoxidase was found to increase in patients with COPD as well as in nicotine exposed people11,42,53 (Table 2). On the other hand, thioredoxin activity was downregulated in other chronic lung diseases54 (Table 3) and levels of MMP-2, -8, -13, and -14, mainly in active forms, were elevated in BALF from chronic inflammatory airway diseases.55 Other proteins, for example, MMP-9 and 12, spotted by conventional methods in animal models,56,57 have not been reported in human proteomic studies.
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sis may be more extensive in the analysis of samples from patients with COPD.
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Proteomics-Based Biomarkers in COPD *
Table 3. Summary of Potential Biomarkers Detected in BALF in COPD proteins
Surfant Protein-A Salivary Proline-rich peptide P-C Salivary proline-rich peptide P-D Clara cell phospholipid-binding protein, CC-10 Lysozyme C Neutrophil defensin 1 Neutrophil defensin 2 Calgranulin A Calgranulin B Ceruloplasmin R1-B-glycoprotein Complement C3β Complement factor B Complement C3 Complement factor I R1-Antitrypsin R1-antitrypsin(dimer) R1-antichymotrypsin Haptoglobin β Haptoglobin β (Ci) R1-antiplasmin R2-antiplasmin Apolipoprotein A-1 β2-microglobulin Prothrombin Amyloid P Calcyphosin Thioredoxin Peroximal antioxidant enzyme, AOPP R2-macroglobulin Cyclophilin A Translationally controlled tumor protein, TCTP/p23 Cytidylate kinase A-FABP, fatty acid binding protein E-FABP L-FABP Thioredoxin peroxidase 2 Macrophage migratioin inhibitor factor, MIF Galectin 1 Ubiquitin Serum retinal binding protein, SRBP Transthiretin Cathepsin D Haptoglobin R1-chain Hepatoglobin R Immunoglobulin A S chain Intestinal trefoil factor Ubiquitin-like protein Tropomyosin Calreticulin Calvasculin Calcyclin Saposin D chain Cyclohydrolase feedback regulatory protein Rho-GDP dissociation inhibitor protein Hemopexin
COPD*
HS§
S#
S§
v
v
SSc#
IPF§
V
v V V V v v v v
v
f
V V v v v v v v v v v v v v
v
v v V V V V V V V V V V V V V V V V v v
v
v V v v v
v
v v v
v
v
v
v
v
v v v v
14 42 42 42 42 42 42 14, 42, 54 42, 54 54, 102 54 54 54 54, 102 54 9, 14, 54 54 54 54 54, 102 54 102 14, 54 14, 54 54 54 54 54 54
also indicated in other diseases
IPFv99 CFv100,101IPFv99
54
V v v
v
v
V
V V V
ref.
v
v
V V V v v
v v v v v v v v v v v v v
v v
54 54 54 14 14 54 54 54 54 54 54 14, 54, 102 9, 14 14 102 102 14 14 14 14 14 14 14 14 9 102
* The symbols *, §, and # stand for the comparison with healthy smokers, healthy nonsmokers, and patients with idiopathic pulmonary fibrosis, respectively. The arrows v, V, and f stand for the up-regulated, down-regulated, and no change, respectively. HS, healthy smokers; S, sacroidosis; IPF, idiopathic pulmonary fibrosis; SSc, systemic sclerosis.
Calcium-Binding Proteins. In proteomics-based study, calcium-binding proteins, such as cathepsins and calgranulins, were up-regulated in healthy smokers and patients with COPD42 (Table 2), cystic fibrosis41 (Table 4), bronchiectasis41 (Table 4), sarcoidosis and IPF14 (Table 3). Cathepsin has been
suggested as a promising biomarker for COPD through nonproteomic methods. Cathepsin B detected in human lung tissue is only localized within macrophages.58 Interleukin-18 (IL-18) overproduction in the lungs can induce lung diseases such as pulmonary inflammation, lung fibrosis and COPD.59 The levels Journal of Proteome Research • Vol. 9, No. 6, 2010 2803
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Table 4. Summary of Potential Biomarkers Detected in Induced Sputum in COPD* proteins
Calgranulin A Calgranulin B Calgranulin C Clara cell secretory protein, CCSP Surfactant protein-A Myeloperoxidase R1-antitrypsin IgG
COPD§
CF §
V
v v§ v§ VV§
bronchiectasis§
v v v VV
v v* v* V*
asthma§
ref.
V
41 41 41 41 12 53 53 53
* The symbols * and § stand for the comparison with healthy nonsmokers and healthy smokers, respectively.The arrows v, V, and VV stand for the up-regulated, down-regulated, and greatly down-regulated, respectively. CF: Cystic fibrosis.
of IL-18 and cathepsin B increased in pulmonary macrophages from smokers and patients with COPD.59,60 The neutrophil elastase and cathepsin G were found to increase in the sputum from patients with COPD exacerbation.61 Cathepsin C was also involved in GM-CSF-induced neutrophil activation.62 An experimental study demonstrated that IL-13 and interferongamma stimulated MMPs and cathepsin-based proteolytic pathways in the lung.63,64 COPD patients had greater levels of cathepsin S in the BALF.63 Inhibitors of cathepsins were suggested as potential therapeutic approaches for COPD.65–67 However, a proteomics study showed that cathepsin D only increased in healthy smokers (Tables 2 and 3) rather than in patients with COPD.9,10 Proteins Derived from Inflammatory Cells. The levels of mediators derived from inflammatory cells may reflect different stages of COPD. Imbalance between inflammatory mediators produced by neutrophils and their natural inhibitors was suggested to be responsible for the local destruction in lung disease.62 By conventional methods, serum monocyte chemoattractant protein-1 (MCP-1) was suggested as a critical and important biomarker to differentiate COPD subjects from healthy smokers and classify COPD severity.68,69 The elastase, cathepsin G, proteinase 3, and defensins were found to be involved in the development of neutrophil-dominated inflammation and tissue damage. Both neutrophil elastase and defensins could induce the release of the neutrophil chemoattractant chemokine from epithelial cells.70 Merkel et al.42 observed that neutrophil defensin 1 and 2 were up-regulated more in COPD than in healthy smokers (Table 3). A recent study revealed that airway and parenchymal phenotypes of COPD are associated with unique systemic serum biomarker profiles.6 Lung Specific Proteins. Pulmonary surfactants (SPs) are divided into four forms, A, B, C, and D.71,72 As members of collectins, hydrophilic SP-A and SP-D share much in common in terms of structural feature while SP-B and SP-C, smaller and nonpolar, exhibit entirely different properties. Growing evidence revealed that SP-B and SP-C might play a key role in the host defense of patients with COPD.73,74 The levels of SP-A and SP-D in BALF decreased in smokers and patients with COPD compared to those in nonsmokers,74–76 although no report agreed with this conclusion in COPD proteomics (Table 3). SPs may have a long-term protective effect on chronic smoking and elastase-induced COPD77 of which SP-A, as a lung-specific secretary protein detected in serum, is responsible for the integrity of the lung epithelium.78,79 An experimental study indicated that increased SP-D might play a protective 2804
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role in the development of smoking-induced emphysema.80 Circulating SP-D levels may be a useful biomarker to track the outcomes of COPD patients,81,82 but no available proteomics has yet evidenced the importance of SP-D in COPD. SP-A levels were found elevated at an early state of COPD.12 A proteomics study demonstrated that lung tissue levels of SP-A were higher in patients with COPD, although this was not the case for SPB, SP-C, and SP-D12 (Table 2). Compared to the healthy subjects, BALF level of SP-A was not changed in patients with IPF.12 It seems that SP-A may be associated with the pathogenesis of COPD and could be considered as a potential biomarker for COPD. Clara cell related proteins, including clara cell phospholipid-binding protein, binding protein and clara cell secretory protein, are also found to be down-regulated in healthy smokers (Table 3) and COPD patients41,42 (Table 4). It is possible that those alterations may result from the destruction of airway epithelium caused by tobacco stimulus and inflammation. Other Related Proteins. Gelsolin, the most likely protein to sever actin filament,83 was up-regulated in lung tissues of healthy smokers10 (Table 2). It could weaken and break the noncovalent bonds between actin filaments. The concentrations of both IL-4 and gelsolin were elevated in the BALF of patients with asthma, suggesting that gelsolin might improve the fluidity of airway surface liquid in asthma by breaking down filamentous actin that may be released in large amounts by dying cells during inflammation.84 COPD is characterized by the degradation of elastin which is the major insoluble protein of lung tissues. The two abundant and studied elastin crosslinkers are desmosine and isodesmosine. There was a significant and rapid decrease in the urinary level of desmosine and isodesmosine in patients with COPD, as compared to healthy nonsmokers.85 Alveolar elastin was overexpressed in patients with severe COPD.86 MS can be used to detect the minimal concentrations of desmosine and isodesmosine in urine, plasma, or sputum and may also be employed to understand their values in monitoring therapeutic efficacy in COPD.87 It would also be important to map the changed inflammatory mediators using antibody microarray since a large number of clinical studies demonstrated the increase of cytokines in COPD.88 C-reactive protein and fibrinogens, as systemic acutephase proteins, are uncommonly seen in COPD proteomics. However, C-reactive protein and fibrinogen in serum were found as potential candidates to predict the rapid decline of forced expiratory volume in the first second in COPD and exacerbation COPD patients.89–91 Besides the impairment of lung function, systemic inflammation manifested by elevated levels of fibrinogen was found to be an independent risk factor for exacerbations of COPD.92 Disease Specificity. Despite the complexity of COPD, several studies performed have revealed candidate protein markers with potential clinical relevance. These biomarkers would be valuable if they could indicate disease specificity and progression. Most proteins found in COPD proteomics (Table 2) have not been reported in other chronic lung diseases which suggests that proteomics has its merits in biomarker hunting, for example, MMP-13, thioredoxin-like 2, transcription factor AP-4, peroxiredoxin 6, NEFA-interacting nuclear protein, regulator of G-protein signaling 16, R-soluble-N ethylmaleimidesensitive fusion attachment protein, centrin-3 and calmodulinlike protein. Other candidate proteins such as hepatomaderived growth factor, histamine-releasing factor, cathepsin D,
Proteomics-Based Biomarkers in COPD and heat shock protein 27 (Table 2) were also detected in other diseases like cystic fibrosis,93 IPF94,95 or asthma.96
Future Perspectives As a biomarker for COPD, it is expected to be detected in human lung fluids or tissues, sensitive to the progress of COPD, disease-specific to COPD and associated with the status of patients. There is a need to perform proteomic studies on patients with COPD, describing the association with the disease in terms of specificity, severity, progress and prognosis and monitoring the efficacy of therapies. There is a need to establish and clarify the criteria for subjects including controls, data analysis and standardization of the study design, methodology and process. These factors are vital and will form the foundation of well designed prospective clinical studies on COPD. There is a bright future for identifying and validating diseasespecific multibiomarkers as well as for developing a digital mode to predict the progress and prognosis of COPD. An important goal of proteomics studies is to understand the biological roles of specific proteins and develop new drug targets.49 The main value of biomarkers in COPD would be in early diagnosis and to provide the early proof of efficacy of drugs during the treatment.15 Although the number of clinical studies on COPD is limited, they still serve as the outstanding initiation for proteomic research in such a complex disease. We have learned the importance of clarifying the resources of samples, efficiency and quality to deal with large amount of candidates as well as the value of specificity of biomarkers to the severity, therapeutic effects, progress and prognosis of the disease.
Acknowledgment. The study was sponsored by the grants from the Science and Technology Commission of Shanghai Municipality (08PJ1402900, 08DZ2293104 and 09540702600), Fudan University and Zhongshan Hospital Grant for Distinguished Professor, and Shanghai Leading Academic Discipline Project (T0206, B115). References (1) Celli, B. R.; MacNee, W. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur. Respir. J. 2004, 23 (6), 932–46. (2) Pauwels, R. A.; Rabe, K. F. Burden and clinical features of chronic obstructive pulmonary disease (COPD). Lancet 2004, 364 (9434), 613–20. (3) Hogg, J. C.; Chu, F.; Utokaparch, S.; Woods, R.; Elliott, W. M.; Buzatu, L.; Cherniack, R. M.; Rogers, R. M.; Sciurba, F. C.; Coxson, H. O.; Pare, P. D. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N. Engl. J. Med. 2004, 350 (26), 2645–53. (4) Rabe, K. F.; Hurd, S.; Anzueto, A.; Barnes, P. J.; Buist, S. A.; Calverley, P.; Fukuchi, Y.; Jenkins, C.; Rodriguez-Roisin, R.; van Weel, C.; Zielinski, J. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am. J. Respir. Crit. Care Med. 2007, 176 (6), 532–55. (5) Lopez, A. D.; Murray, C. C. The global burden of disease, 19902020. Nat. Med. 1998, 4 (11), 1241–3. (6) Bon, J. M.; Leader, J. K.; Weissfeld, J. L.; Coxson, H. O.; Zheng, B.; Branch, R. A.; Kondragunta, V.; Lee, J. S.; Zhang, Y.; Choi, A. M.; Lokshin, A. E.; Kaminski, N.; Gur, D.; Sciurba, F. C. The influence of radiographic phenotype and smoking status on peripheral blood biomarker patterns in chronic obstructive pulmonary disease. PLoS One 2009, 4 (8), e6865. (7) Plymoth, A.; Lofdahl, C. G.; Ekberg-Jansson, A.; Dahlback, M.; Broberg, P.; Foster, M.; Fehniger, T. E.; Marko-Varga, G. Protein expression patterns associated with progression of chronic obstructive pulmonary disease in bronchoalveolar lavage of smokers. Clin. Chem. 2007, 53 (4), 636–44.
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