About this Journal Submit a Manuscript Table of Contents
International Journal of Chronic Diseases
Volume 2013 (2013), Article ID 578613, 15 pages
http://dx.doi.org/10.1155/2013/578613
Review Article

Biomarkers in Exhaled Breath Condensate and Serum of Chronic Obstructive Pulmonary Disease and Non-Small-Cell Lung Cancer

1Inflammation and Infection Research Centre, Faculty of Medicine, University of New South Wales, Sydney, NSW 2031, Australia
2Department of Respiratory Medicine, Prince of Wales Hospital, Randwick, Sydney, NSW 2031, Australia

Received 22 April 2013; Accepted 8 July 2013

Academic Editor: Jin-Yuan Shih

Copyright © 2013 Mann Ying Lim and Paul S. Thomas. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Chronic obstructive pulmonary disease (COPD) and lung cancer are leading causes of deaths worldwide which are associated with chronic inflammation and oxidative stress. Lung cancer, in particular, has a very high mortality rate due to the characteristically late diagnosis. As such, identification of novel biomarkers which allow for early diagnosis of these diseases could improve outcome and survival rate. Markers of oxidative stress in exhaled breath condensate (EBC) are examples of potential diagnostic markers for both COPD and non-small-cell lung cancer (NSCLC). They may even be useful in monitoring treatment response. In the serum, S100A8, S100A9, and S100A12 of the S100 proteins are proinflammatory markers. They have been indicated in several inflammatory diseases and cancers including secondary metastasis into the lung. It is highly likely that they not only have the potential to be diagnostic biomarkers for NSCLC but also prognostic indicators and therapeutic targets.

1. Introduction

Chronic obstructive pulmonary disease (COPD) and lung cancer are the leading causes of deaths worldwide which are associated with cigarette smoking. COPD is a preventable and treatable disease characterised by progressive, irreversible airflow obstruction resulting from chronic airway inflammation [13]. It is responsible for 5.8% of all deaths (3.28 million deaths in 2008) and expected to become the third leading cause of death by 2030 [4]. Lung cancer, on the other hand, is defined as cancer which arises from cells of respiratory epithelium [5]. It has been the global leading cause of cancer death (approximately 1.8 million deaths per year) since 1985 [5], accounting for 12.4% of total new cancer cases diagnosed [5] and almost as many deaths as those from prostate, breast, and colon cancer combined [6]. The majority (85%) of lung cancer is non-small-cell lung cancer (NSCLC), and it can be further divided into adenocarcinoma, squamous cell carcinoma, and large cell carcinoma comprising 38.5%, 20%, and 2.9% of all lung cancer cases, respectively [5].

Despite significant advances in 5-year survival rates of other cancers, that of lung cancer remains low at 15.6% (compared to 66% for colon cancer, 94% for melanoma, 90% for breast cancer, and 100% for prostate cancer) [6, 7]. Even more disappointingly, >52% of the patients have distant metastases (stage IV) at the time of diagnosis with a resultant 5-year survival of <3.6% (Figure 1) [5]. This is in stark contrast to the 60%–80% 5-year survival rate for patients with stage I lung cancer [8]. Patients usually present late as lung cancer is silent early in its course of disease and the symptoms are often nonspecific, thereby mistakenly attributed to ageing or smoking [9]. Furthermore, screening procedures such as sputum cytology and chest X-rays have failed to decrease mortality [10, 11]. Although screening CT scans increase the detection rate of early-stage lung cancer or small noncalcified nodules, the effect on mortality rate is still being evaluated, and the benefits need to be weighed against risks including radiation exposure, false positives, and overdiagnosis [1216].

578613.fig.001
Figure 1: Stepwise progression towards lung cancer. Oxidants in cigarette smoking induce inflammation which subjects DNA to mutations. The failure to repair damaged DNA in critical coding regions causes cell proliferation and lung cancer.

Much research has thus been directed towards the hope of finding new, simple, and minimally invasive biomarkers of early diagnosis or screening for COPD and lung cancer. Exhaled breath condensate and serum samples are two such examples.

2. Linking COPD and Lung Cancer

It is well established that both COPD and lung cancer are usually due to tobacco smoking [1722]. The majority (90%) of lung cancers are associated with tobacco smoking [1], and smokers have a 2–30-fold increase in the risk of developing lung cancer [21, 23].

Apart from smoking, COPD is itself an independent risk factor [5, 7, 18, 24] which elevates the risk of lung cancer by 4.5 times [1, 7], and 1% of COPD patients develop lung cancer each year [18] while 40%–70% of lung cancer patients also have COPD [19, 22, 25, 26]. Furthermore, a positive correlation exists between the extent of airflow limitation and incidence of lung cancer [3, 18]. Even emphysema in never smokers (such as that of α 1-antitrypsin deficient carriers) also carries an elevated risk of lung cancer by 2.4-fold [22].

It is also known that COPD patients are at increased risk of developing squamous cell carcinoma with a worse prognosis as they not only develop higher grade tumours but also suffer from a higher rate of recurrence [1, 18, 27, 28].

3. Chronic Inflammation and Oxidative Stress

COPD and lung cancer are both associated with chronic inflammation and oxidative stress, [3, 19, 29, 30] in which oxidants, inflammatory mediators, and antioxidants are key players.

3.1. Oxidants

Oxidants can be generated exogenously or endogenously. Exogenous sources of oxidants include tobacco smoke, infections, and pollutants (such as ozone and nitrogen dioxide) [31, 32]. Of these sources, cigarette smoking is a major contributor as one puff contains up to 1015 oxidants particles and approximately 4700 different compounds [19, 31, 33]. Endogenously, oxidants are not only produced from the lung epithelial cells during respiration but also inflammatory mediators are released from cells such as neutrophils, eosinophils, and activated macrophages during inflammation [3437]. They are generated through the mitochondrial electron transport chain during respiration and peroxidase enzymes such as myeloperoxidase (MPO), eosinophil peroxidase (EPO), and heme peroxidase during inflammation.

Under normal physiological conditions, oxidants have a role in growth regulation, intracellular signaling, and host defence (inflammation) against infection [38]. They comprise reactive oxygen species (ROS) or reactive nitrogen species (RNS). Examples of ROS include superoxide ( ), hydroxyl radicals ( ), and hydrogen peroxide (H2O2) while RNS includes nitric oxide ( ), nitrogen dioxide, and peroxynitrite (ONOO) [32]. Superoxide can be dismutated to hydrogen peroxide. In the presence of redox-active transition metals such as iron or copper, highly unstable hydroxyl radical can be generated from hydrogen peroxide in a reaction known as the Fenton reaction. Meanwhile, nitric oxide readily reacts with ROS to form peroxynitrite which breaks down into nitrite ( ) and nitrate ( ).

Reactive species are very unstable and potentially damaging as their unpaired electrons can exert injurious effects by oxidising DNA, proteins, and lipids [37, 39].

3.2. Inflammation and Oxidative Stress

The introduction of oxidants into the lung from tobacco smoking activates the innate immune cells such as lung epithelial cells whereby damage-associated molecular patterns (DAMPs) are released from injured cells [40]. Following this event, inflammation, which is the body’s normal response to combat toxicants, is triggered [4144] by the activation of transcription factor nuclear factor- B (NF- B) and activator protein 1 (AP-1) in airway epithelial cells and macrophages [29, 45]. The activated transcription factors are then responsible for the transcription of downstream inflammatory cytokines such as interleukin-6 (IL-6), interleukin-8 (IL-8), and tumour necrosis factor α (TNF-α) [34, 4547]. The resultant elevated cytokine levels then attract more neutrophils and macrophages to augment inflammation (Figure 3) [29, 32, 45]. The degree of inflammation as evident by the infiltration of inflammatory cells correlates with disease severity [1, 19, 29].

Following recruitment, neutrophils and macrophages release neutrophil elastase and matrix metalloproteinases-9 which are proteases that degrade lung matrix elastin and collagen [29, 32, 36, 44]. In addition, antiproteinases such as α-1-protease-inhibitor (α-1-PI) and antileukoprotease [32] are inactivated by oxidants [34], leading to a proteinase/antiproteinase imbalance which destroys the alveolar wall, causing airspace enlargement (emphysema) in COPD (Figure 2) [19, 29].

578613.fig.002
Figure 2: Smoking is the major cause of COPD and lung cancer. Oxidants in cigarette smoking are not only a direct cause of lung cancer by DNA damage through protein and lipid peroxidation but also an indirect cause by triggering inflammation. While products of recruited inflammatory mediators cause COPD by degrading lung matrix and promoting mucus hypersecretion, COPD is itself a disease of chronic inflammation which promotes tumorigenesis.
578613.fig.003
Figure 3: EBC consists of particles from ELF of alveoli, bronchi, and mouth, each with an unknown relative contribution.

In addition, injuries during inflammation also lead to goblet cell hyperplasia and squamous metaplasia. This impairs mucociliary clearance, and inflammatory mediators accumulate in the airways as a result, which again amplifies inflammation [1]. The activation of epithelial growth factor receptor (EGFR) in response to neutrophil elastase and oxidative stress is another reason for mucus hypersecretion [1].

Apart from initiating inflammation, oxidants also readily attack polyunsaturated fatty acids of cell membranes to form lipid peroxidation products (LPPs) such as hydroperoxides, endoperoxides, and aldehydes including ethane, pentane, isoprostanoids, malondialdehyde, and 4-hydroxy-2nonenal which are even more reactive [31, 32, 46, 48]. Lipid peroxidation destroys cells by damaging cell membrane [31], and LPPs also react with DNA to cause genomic instability [48].

3.3. Oxidant/Antioxidant Disequilibrium

Under normal conditions, oxidants are counterbalanced by antioxidants which consist of enzymes (superoxide dismutase, catalase, glutathione peroxidase, and glutathione-S-transferase) and nonenzymatic free radical scavengers (glutathione, cysteine, thioredoxin, vitamins C and E, beta-carotene, and uric acid) [46].

In response to elevated levels of oxidants, local antioxidants such as superoxide dismutase, catalase, glutathione associated enzymes, and manganese superoxide dismutase may increase in an attempt to counter the insult [4951]. The continuous introduction of oxidants from smoking, however, persistently exposes the lung parenchyma to raised oxidant levels, causing chronic inflammation. This exhausts the buffering capacity of antioxidants, giving rise to an oxidant/anti-oxidant disequilibrium which leads to oxidative stress and cellular damage [32, 42, 45, 52].

3.4. Chronic Inflammation and DNA Damage

Chronic inflammation increases cell turnover and replication errors [19, 42, 44, 5355]. Replication errors which can occur include adduct formation, single or double stranded DNA breaks, promoter hypermethylation, sequence mutations, base insertions and deletions, translocations, microsatellite alterations, oncogene activation, and tumour suppressor gene inactivation [1, 46, 48, 5659]. For smokers with lung cancer, mutations commonly occur in the K-ras oncogene and p53 tumour suppressor genes as well as there being p16 promoter hypermethylation [6065]. The DNA mutations may confer on the cells a survival advantage by allowing cells to escape from apoptosis thereby proliferating uncontrollably [5, 62, 64].

Proofing mechanisms of DNA may attempt to repair or remove the damaged DNA via direct repair, double-strand break repair, cross-link repair, nucleotide excision, and base excision [1]. When damaged beyond repair, the cell usually undergoes apoptosis [5]. However, if any of the steps of reparation fail, or that damage to DNA is too extensive, permanent mutations may occur in the DNA, resulting in oncogenesis.

Apart from direct DNA damage, oxidants also promote tumorigenesis by direct reaction with proteins (protein peroxidation) to impair DNA reparative enzymes such as DNA polymerase [58].

4. Exhaled Breath Condensate

Exhaled breath condensate (EBC) is the cooling of exhaled gas to gain insight into the composition of extracellular lining fluid (ELF) and soluble exhaled gases [35, 6668]. Compounds which have been measured include lipid peroxidation products, products of nitrogen oxide metabolism, hydrogen ions, hydrogen peroxide, cytokines, proteins, and DNA [6971].

EBC has several advantages as an investigational technique. It is noninvasive (unlike bronchoalveolar lavage), inexpensive, easy to collect, and also easily repeatable without causing airway inflammation or dysfunction (unlike bronchoalveolar lavage, transbronchial biopsy or induced sputum analysis) [66, 67, 72, 73]. Furthermore, EBC collection devices are portable, do not induce any patient discomfort, and can thus be used in children and mechanically ventilated patients [67, 71, 7476].

EBC has the potential to be employed in the screening and diagnosis of COPD and lung cancer, disease phenotyping, exacerbations, and treatment response monitoring as well as disease severity measuring and prognosis indicating [66, 68, 72, 77]. For instance, the use of EBC to measure lung antioxidant capacity could enable the monitoring of a response to antioxidant or anti-inflammatory treatment [78, 79]. It may also allow early anti-inflammatory treatment before the development of symptoms and lung function decline in COPD [78, 79].

EBC, however, has a number of limitations which include dilution by water vapour, nonsite specificity, saliva contamination and variable reproducibility. With >99.9% of EBC comprising water vapour [67], concentrations of the mediators of interest can sometimes be close to or below the detection limit of the appropriate assays; thus, assays of sufficient sensitivity are needed to effectively measure biomarkers in EBC [71, 77]. There is currently no standardised assessment of EBC dilution, but such issues can in part be overcome by correcting the dilution with urea, total protein, or cation concentration and conductivity of lyophilized EBC [71, 80, 81]. EBC dilution may also influence the pH. It is thus important to deaerate the sample and monitor the dilution and buffering capacity of EBC when measuring pH [82].

As a result of the collection pathway, EBC also consists of nebulised fluid droplets from the alveoli, bronchi, and mouth, each with an unknown relative contribution (Figure 3). This nonsite specificity is a limitation, and it is inevitable that EBC of patients may consist of a fraction derived from areas not affected by the specific lung disease [67, 81]. EBC from lung cancer patients, for instance, will consist of a large fraction derived from nonmalignant areas. As EBC is collected through the mouth, saliva contamination is another potential problem. It can, however, be minimised by asking subjects to rinse their mouth prior to collection, swallowing accumulated saliva where possible [67] and routinely testing for salivary amylase in EBC samples [71].

While the volume of EBC is reproducible, levels of biomarkers in EBC may vary, and this gives rise to problems in repeatability and reproducibility [71, 81, 83]. This can, however, be overcome by concentrating samples, using assays with a low limit of detection and high sensitivity in many cases [71].

A range of biomarkers have been studied in EBC of COPD and lung cancer patients. The results are as shown in Table 1.

tab1
Table 1: Summary of EBC markers of oxidative stress and antioxidant capacity including S100 proteins in COPD and lung cancer (legend: “↑”: elevated, “”: decreased, “”: no difference, “×”: undetectable).

5. Plasma Proteomics

In addition to EBC, the serum protein profile is another easily collected yet cost-effective tool in detecting and monitoring lung cancer [9, 84, 85]. Elevated levels of C-reactive protein, serum amyloid A (SAA), mucin I, and α-I-antitrypsin can aid in distinguishing between healthy subjects or COPD patients [85] but are however low in sensitivity and/or specificity [86]. As such, novel markers are being described, such as the S100 proteins.

6. S100 Proteins

The S100 proteins are a family of more than 20 low molecular weight acidic proteins of 10–12 kDa which are calcium-binding, and they belong to the EF hand proteins subfamily [8792]. They consist of two EF-hands with different calcium binding affinities joined together by a central hinge region [87, 91, 93]. This explains their role in regulating calcium-dependent intracellular processes [94] including protein phosphorylation, enzyme activity, cytoskeletal components, transcriptional factors, cell growth, and calcium homeostasis [87, 89, 90]. The S100 proteins can form homodimers, heterodimers, and oligomers with varying functions [87, 89, 90]. The majority of their coding genes are found on chromosome 1q21 which is frequently mutated [87, 9597]. They have been implicated in many epithelial and soft tissue cancers including those of lung, breast, oesophagus, bladder, kidney, prostate, thyroid, gastric oral, colorectal, and liver [87, 9597].

6.1. S100A8 and S100A9

S100A8 is also known as calgranulin A or myeloid-related protein 8 while S100A9 is also known as calgranulin B or myeloid-related protein 14. While much of the literature suggests that the S100A8 and S100A9 are proinflammatory, a body of research presents an opposing view. It is possible that the opposing effects of the calgranulins are concentration dependent, being proinflammatory at low concentrations and anti-inflammatory at high concentrations [98, 99].

A100A8 and S100A9 are believed to be anti-inflammatory by being preferentially oxidized, thereby scavenging ROS/RNS. Oxidative modifications by ROS/RNS and posttranslational modifications such as S-nitrosylation and S-glutathionylation are proposed to be the regulatory switches which activate such anti-inflammatory properties [98, 99].

Calgranulins S100A8 and S100A9, however, are also believed to play a role in inflammation by acting as chemokines for neutrophils and monocytes [88, 91, 100102]. They reportedly bind to the receptor for advanced glycation end products (RAGE) and toll-like receptor-4 (TLR4) [88, 90, 103, 104]. This binding activates the NF-κB transcription pathway, subsequent generation of downstream proinflammatory cytokines, and recruitment of inflammatory mediators such as neutrophils and monocytes in a positive feedback loop (Figure 4) [90, 103, 104]. As such, the S100 proteins have implicated many inflammation-related diseases including rheumatoid arthritis, juvenile idiopathic arthritis, cystic fibrosis, and chronic inflammatory bowel disease [88, 91, 93, 105107]. Levels of S100A8 and S100A9 are elevated in the bronchoalveolar fluid of COPD patients compared to smokers, which suggest a potential as diagnostic markers of COPD [108]. Another study comparing acute respiratory distress syndrome (ARDS), cystic fibrosis (CF), and COPD suggests that S100A8 and S100A9 are linked to chronic inflammation while S100A12 is linked to acute inflammation [109].

578613.fig.004
Figure 4: The calgranulins, S100A8, S100A9, and S100A12, are secreted by cells of the myeloid lineage such as neutrophils and monocytes. They bind to TLR4 and RAGE on macrophages and activate the NF- B signalling pathway which leads to the production of proinflammatory cytokines. The production of proinflammatory cytokines then provides a positive feedback by promoting the recruitment of more neutrophils and monocytes. S100A8 and S100A9 are also chemoattractants for MDSCs. MDSCs which move from bone marrow to peripheral blood cause immune suppression and enhance tumourigenesis by impairing cytotoxic CD8+ T cell and NK cell cytotoxicity.

Apart from playing a role in inflammation which promotes tumourigenesis (inflammation-induced cancer) [55], the S100 proteins are also capable of modulating host immune response to promote tumour progression [87].

S100A8 and S100A9 are expressed by cells of myeloid origin, making up 40%–50% of their cytosolic content. Cells expressing S100A8 and S100A9 include granulocytes (e.g., neutrophils), monocytes, and early differentiation stages of macrophages [88, 93, 95, 97, 106, 110]. S100A12 is however only expressed in neutrophils [102, 111]. S100A8 and S100A9 predominantly function as heterodimer complex S100A8/A9 which is also known as calprotectin [88, 112]. Calprotectin is released by neutrophils and activated by monocytes, tumour cells, and myeloid-derived suppressor cells (MDSCs) [113]. It functions to regulate inflammation and inhibit myeloid cell differentiation [114].

MDSCs are precursors of macrophages, granulocytes, and dendritic cells [113] which increase in number during inflammation, cancer, and infection [115]. They suppress natural killer CD4+ and CD8+ T cell immunity against cancer by inhibiting dendritic cell differentiation to compromise antigen presentation (Figure 4) [112, 115120]. MDSCs suppress this innate immunity through the induction of FOXP3+ T regulatory cells by secreting interleukin-10 (IL-10), interferon-gamma (IFN-γ) and high levels of ROS, peroxynitrite, and nitric oxide [116].

In tumorigenesis, MDSCs are attracted from bone marrow to peripheral blood by inflammatory cytokines (e.g., interleukin-1β, interleukin-6, prostaglandin E2), chemokines, tumour-derived growth factors, and myeloid-related proteins such as S100A9 and S100A8 [116, 117]. The production of proinflammatory S100A8/9 then sustains MDSC accumulation by an autocrine feedback through TLR4 and RAGE which activates the NF- B pathway and mitogen-activated protein kinase [113, 116, 117, 121]. Hence, similar to the positive feedback loop of oxidants, S100A8/A9 which is released by myeloid cells also promotes the recruitment of yet more leukocytes [122, 123].

S100A8/A9-positive myeloid cells are not only early infiltrating cells in the inflammatory process [97] but are also upregulated in epithelial malignancies including that of the prostate [124, 125], gastric [126], colon, and rectum [127, 128]. As such, S100A9 is suggested to be a potential marker in differentiating prostate cancer from benign prostate hyperplasia or healthy controls [125].

In lung cancer, a recent study found that the expression of S100A8 and S100A9 is increased in patients with NSCLC [116]. NSCLC patients with an overexpression of S100A9 are usually associated with poorly differentiated tumours [129, 130], lower 5-year survival rate [108], and higher rate of relapse [129]. Moreover, S100A9 in CD11b+CD14+ monocytic MDSC correlates with tumour response to platinum-based chemotherapy with low CD11b+CD14+S100A9+ having longer progression-free survival [116]. These suggest the possibility of S100A8 and S100A9 as prognostic markers of NSCLC.

Lastly, S100A8 and S100A9 also play a role in cell proliferation and metastasis of primary tumours into the lung [87]. Their expression is increased in pulmonary myeloid and endothelial cells through the production of vascular endothelial growth factor-A, transforming growth factor-β, and TNF-α by primary tumours before metastasis occurs [87, 131, 132]. S100A8 and S100A9 not only promote the recruitment of CD11b+ myeloid cells but also act as chemoattractants which draw tumour cells to premetastatic sites in the lungs [87, 110]. They recruit CD11b+ myeloid cells by activating p38 mitogen-activated protein kinase (MAPK) which promotes migration [110]. SAA3, which is induced by S100A8, interacts with TLR4 to stimulate the NF- B pathway in promoting CD11b+ myeloid cell accumulation [110, 133]. In addition, S100A8 and S100A9 also increase cancer cell motility through p38-mediated activation of pseudopodia [87, 131]. This makes S100A8/A9 a potential target for inhibiting lung metastasis.

7. Future Directions

Early Diagnosis, Predicting Prognosis, and Personalised Medicine. EBC and serum are noninvasive and minimally invasive techniques which are cost effective and easily sampled. If EBC markers of oxidative stress and serum proinflammatory S100 proteins or other candidate entities are diagnostic for COPD and NSCLC, it could greatly improve survival outcome by allowing early diagnosis and thus treatment.

As many NSCLC patients do not behave as predicted based on tumour staging, new markers are also needed to more accurately predict prognosis [134]. Prognostic biomarkers indicative of metastatic potential, response to treatment, and patient survival could aid in deciding treatments. For example, using CD11b+CD14+S100A9+ to predict response to chemotherapy could be used to decide if patients should be given adjuvant or neoadjuvant chemotherapy or any chemotherapy at all.

Furthermore, it will be beneficial to discover more specific and sensitive serum biomarkers for lung cancer as well as to personalise anticancer therapies. For instance, knowing the reduced overall survival of patients with an overexpression of S100A9 may not only identify patients who are at high risk of a poor outcome [134] but also allow the administration of personalised anticancer therapy which targets S100A9 specifically to optimise outcome [64].

The S100 proteins have a great potential to be the new diagnostic tumour markers, prognostic predictor, and possibly therapeutic targets for NSCLC.

Conflict of Interests

The authors do not have any financial conflict of interests related to this paper.

References

  1. I. M. Adcock, G. Caramori, and P. J. Barnes, “Chronic Obstructive pulmonary disease and lung cancer: new molecular insights,” Respiration, vol. 81, no. 4, pp. 265–284, 2011. View at Publisher · View at Google Scholar · View at Scopus
  2. K. F. Rabe, S. Hurd, A. Anzueto et al., “Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary,” American Journal of Respiratory and Critical Care Medicine, vol. 176, no. 6, pp. 532–555, 2007. View at Publisher · View at Google Scholar · View at Scopus
  3. I. A. Yang, V. Relan, C. M. Wright et al., “Common pathogenic mechanisms and pathways in the development of COPD and lung cancer,” Expert Opinion on Therapeutic Targets, vol. 15, no. 4, pp. 439–456, 2011. View at Publisher · View at Google Scholar · View at Scopus
  4. WHO, “Chronic Obstructive Pulmonary Disease (COPD),” 2013, http://www.who.int/respiratory/copd/en/index.html.
  5. C. S. D. Cruz, L. T. Tanoue, and R. A. Matthay, “Lung cancer: epidemiology, etiology, and prevention,” Clinics in Chest Medicine, vol. 32, no. 4, pp. 605–644, 2011. View at Publisher · View at Google Scholar · View at Scopus
  6. R. Siegel, E. Ward, O. Brawley, and A. Jemal, “Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths,” CA Cancer Journal for Clinicians, vol. 61, no. 4, pp. 212–236, 2011. View at Publisher · View at Google Scholar · View at Scopus
  7. R. P. Young and R. J. Hopkins, “How the genetics of lung cancer may overlap with COPD,” Respirology, vol. 16, no. 7, pp. 1047–1055, 2011. View at Publisher · View at Google Scholar · View at Scopus
  8. L. Dominioni, A. Imperatori, F. Rovera, A. Ochetti, G. Torrigiotti, and M. Paolucci, “Stage I nonsmall cell lung carcinoma: analysis of survival and implications for screening,” Cancer, vol. 89, no. 11, supplement, pp. 2334–2344, 2000. View at Google Scholar · View at Scopus
  9. A. Amann, M. Corradi, P. Mazzone, and A. Mutti, “Lung cancer biomarkers in exhaled breath,” Expert Review of Molecular Diagnostics, vol. 11, no. 2, pp. 207–217, 2011. View at Publisher · View at Google Scholar · View at Scopus
  10. E. F. Patz, P. C. Goodman, and G. Bepler, “Screening for lung cancer,” The New England Journal of Medicine, vol. 343, no. 22, pp. 1627–1633, 2000. View at Publisher · View at Google Scholar · View at Scopus
  11. S. Sone, T. Nakayama, T. Honda et al., “Long-term follow-up study of a population-based 1996-1998 mass screening programme for lung cancer using mobile low-dose spiral computed tomography,” Lung Cancer, vol. 58, no. 3, pp. 329–341, 2007. View at Publisher · View at Google Scholar · View at Scopus
  12. D. R. Aberle, F. Abtin, and K. Brown, “Computed tomography screening for lung cancer: has it finally arrived? implications of the national lung screening trial,” Journal of Clinical Oncology, vol. 31, no. 8, pp. 1002–1008, 2013. View at Google Scholar
  13. L. Paleari, P. Granone, A. Cesario, and P. Russo, “Computed tomography screening for lung cancer: review of screening principles and update on current status,” Cancer, vol. 112, no. 11, pp. 2520–2521, 2008. View at Publisher · View at Google Scholar · View at Scopus
  14. S. Senan, M. A. Paul, and F. J. Lagerwaard, “Treatment of early-stage lung cancer detected by screening: surgery or stereotactic ablative radiotherapy?” The Lancet Oncology, vol. 14, no. 7, pp. e270–e274, 2013. View at Google Scholar
  15. C. I. Henschke, “Early lung cancer action project: overall design and findings from baseline screening,” Cancer, vol. 89, no. 11, supplement, pp. 2474–2482, 2000. View at Google Scholar · View at Scopus
  16. P. B. Bach, J. R. Jett, U. Pastorino, M. S. Tockman, S. J. Swensen, and C. B. Begg, “Computed tomography screening and lung cancer outcomes,” Journal of the American Medical Association, vol. 297, no. 9, pp. 953–961, 2007. View at Google Scholar
  17. D. M. Skillrud, K. P. Offord, and D. W. Miller, “Higher risk of lung cancer in chronic obstructive pulmonary disease. A prospective, matched, controlled study,” Annals of Internal Medicine, vol. 105, no. 4, pp. 503–507, 1986. View at Google Scholar · View at Scopus
  18. Y. Sekine, H. Katsura, E. Koh, K. Hiroshima, and T. Fujisawa, “Early detection of COPD is important for lung cancer surveillance,” European Respiratory Journal, vol. 39, no. 5, pp. 1230–1240, 2012. View at Publisher · View at Google Scholar · View at Scopus
  19. H. Yao and I. Rahman, “Current concepts on the role of inflammation in COPD and lung cancer,” Current Opinion in Pharmacology, vol. 9, no. 4, pp. 375–383, 2009. View at Publisher · View at Google Scholar · View at Scopus
  20. M. S. Tockman, N. R. Anthonisen, and E. C. Wright, “Airways obstruction and the risk for lung cancer,” Annals of Internal Medicine, vol. 106, no. 4, pp. 512–518, 1987. View at Google Scholar · View at Scopus
  21. J. Koshiol, M. Rotunno, D. Consonni et al., “Chronic obstructive pulmonary disease and altered risk of lung cancer in a population-based case-control study,” PLoS One, vol. 4, no. 10, Article ID e7380, 2009. View at Publisher · View at Google Scholar · View at Scopus
  22. M. C. Turner, Y. Chen, D. Krewski, E. E. Calle, and M. J. Thun, “Chronic obstructive pulmonary disease is associated with lung cancer mortality in a prospective study of never smokers,” American Journal of Respiratory and Critical Care Medicine, vol. 176, no. 3, pp. 285–290, 2007. View at Publisher · View at Google Scholar · View at Scopus
  23. M. E. Mattson, E. S. Pollack, and J. W. Cullen, “What are the odds that smoking will kill you?” American Journal of Public Health, vol. 77, no. 4, pp. 425–431, 1987. View at Google Scholar · View at Scopus
  24. D. M. Mannino, S. M. Aguayo, T. L. Petty, and S. C. Redd, “Low lung function and incident lung cancer in the United States: data from the First National Health and Nutrition Examination Survey follow-up,” Archives of Internal Medicine, vol. 163, no. 12, pp. 1475–1480, 2003. View at Publisher · View at Google Scholar · View at Scopus
  25. R. S. Loganathan, D. E. Stover, W. Shi, and E. Venkatraman, “Prevalence of COPD in women compared to men around the time of diagnosis of primary lung cancer,” Chest, vol. 129, no. 5, pp. 1305–1312, 2006. View at Publisher · View at Google Scholar · View at Scopus
  26. J. Congleton and M. F. Muers, “The incidence of airflow obstruction in bronchial carcinoma, its relation to breathlessness, and response to bronchodilator therapy,” Respiratory Medicine, vol. 89, no. 4, pp. 291–296, 1995. View at Publisher · View at Google Scholar · View at Scopus
  27. A. Papi, G. Casoni, G. Caramori et al., “COPD increases the risk of squamous histological subtype in smokers who develop non-small cell lung carcinoma,” Thorax, vol. 59, no. 8, pp. 679–681, 2004. View at Publisher · View at Google Scholar · View at Scopus
  28. B. M. Smith, K. Schwartzman, B. Kovacina et al., “Lung cancer histologies associated with emphysema on computed tomography,” Lung Cancer, vol. 76, no. 1, pp. 61–66, 2012. View at Publisher · View at Google Scholar · View at Scopus
  29. P. J. Barnes, “Immunology of asthma and chronic obstructive pulmonary disease,” Nature Reviews Immunology, vol. 8, no. 3, pp. 183–192, 2008. View at Publisher · View at Google Scholar · View at Scopus
  30. A. Punturieri, E. Szabo, T. L. Croxton, S. D. Shapiro, and S. M. Dubinett, “Lung cancer and chronic obstructive pulmonary disease: needs and opportunities for integrated research,” Journal of the National Cancer Institute, vol. 101, no. 8, pp. 554–559, 2009. View at Publisher · View at Google Scholar · View at Scopus
  31. L. Nagorni-Obradović, D. Pesut, V. Skodrić-Trifunović, and T. Adzić, “Influence of tobacco smoke on the appearance of oxidative stress in patients with lung cancer and chronic obstructive pulmonary diseases,” Vojnosanitetski Pregled, vol. 63, no. 10, pp. 893–895, 2006. View at Google Scholar · View at Scopus
  32. I. Rahman and W. MacNee, “Role of oxidants/antioxidants in smoking-induced lung diseases,” Free Radical Biology and Medicine, vol. 21, no. 5, pp. 669–681, 1996. View at Publisher · View at Google Scholar · View at Scopus
  33. W. A. Pryor and K. Stone, “Oxidants in cigarette smoke: radicals, hydrogen peroxide, peroxynitrate, and peroxynitrite,” Annals of the New York Academy of Sciences, vol. 686, pp. 12–28, 1993. View at Google Scholar · View at Scopus
  34. K. Kostikas, G. Papatheodorou, K. Psathakis, P. Panagou, and S. Loukides, “Oxidative stress in expired breath condensate of patients with COPD,” Chest, vol. 124, no. 4, pp. 1373–1380, 2003. View at Publisher · View at Google Scholar · View at Scopus
  35. N. Louhelainen, M. Myllärniemi, I. Rahman, and V. L. Kinnula, “Airway biomarkers of the oxidant burden in asthma and chronic obstructive pulmonary disease: current and future perspectives,” International Journal of COPD, vol. 3, no. 4, pp. 585–603, 2008. View at Google Scholar · View at Scopus
  36. C. A. Owen, “Proteinases and oxidants as targets in the treatment of chronic obstructive pulmonary disease,” Proceedings of the American Thoracic Society, vol. 2, no. 4, pp. 373–385, 2005. View at Publisher · View at Google Scholar · View at Scopus
  37. I. Rahman, S. K. Biswas, and A. Kode, “Oxidant and antioxidant balance in the airways and airway diseases,” European Journal of Pharmacology, vol. 533, no. 1–3, pp. 222–239, 2006. View at Publisher · View at Google Scholar · View at Scopus
  38. H. Sauer, M. Wartenberg, and J. Hescheler, “Reactive oxygen species as intracellular messengers during cell growth and differentiation,” Cellular Physiology and Biochemistry, vol. 11, no. 4, pp. 173–186, 2001. View at Publisher · View at Google Scholar · View at Scopus
  39. K. Garber, “A radical treatment,” Nature, vol. 489, no. 7417, pp. S4–S6, 2012. View at Google Scholar
  40. G. G. Brusselle, G. F. Joos, and K. R. Bracke, “New insights into the immunology of chronic obstructive pulmonary disease,” The Lancet, vol. 378, no. 9795, pp. 1015–1026, 2011. View at Publisher · View at Google Scholar · View at Scopus
  41. A. Emmendoerffer, M. Hecht, T. Boeker, M. Mueller, and U. Heinrich, “Role of inflammation in chemical-induced lung cancer,” Toxicology Letters, vol. 112-113, pp. 185–191, 2000. View at Publisher · View at Google Scholar · View at Scopus
  42. E. A. Engels, “Inflammation in the development of lung cancer: epidemiological evidence,” Expert Review of Anticancer Therapy, vol. 8, no. 4, pp. 605–615, 2008. View at Publisher · View at Google Scholar · View at Scopus
  43. S. D. Shapiro and E. P. Ingenito, “The pathogenesis of chronic obstructive pulmonary disease: advances in the past 100 years,” American Journal of Respiratory Cell and Molecular Biology, vol. 32, no. 5, pp. 367–372, 2005. View at Publisher · View at Google Scholar · View at Scopus
  44. R. Medzhitov, “Origin and physiological roles of inflammation,” Nature, vol. 454, no. 7203, pp. 428–435, 2008. View at Publisher · View at Google Scholar · View at Scopus
  45. E. M. Drost, K. M. Skwarski, J. Sauleda et al., “Oxidative stress and airway inflammation in severe exacerbations of COPD,” Thorax, vol. 60, no. 4, pp. 293–300, 2005. View at Publisher · View at Google Scholar · View at Scopus
  46. A. Federico, F. Morgillo, C. Tuccillo, F. Ciardiello, and C. Loguercio, “Chronic inflammation and oxidative stress in human carcinogenesis,” International Journal of Cancer, vol. 121, no. 11, pp. 2381–2386, 2007. View at Publisher · View at Google Scholar · View at Scopus
  47. C. Gessner, R. Scheibe, M. Wötzel et al., “Exhaled breath condensate cytokine patterns in chronic obstructive pulmonary disease,” Respiratory Medicine, vol. 99, no. 10, pp. 1229–1240, 2005. View at Publisher · View at Google Scholar · View at Scopus
  48. L. J. Marnett, “Oxyradicals and DNA damage,” Carcinogenesis, vol. 21, no. 3, pp. 361–370, 2000. View at Google Scholar · View at Scopus
  49. V. L. Kinnula, “Focus on antioxidant enzymes and antioxidant strategies in smoking related airway diseases,” Thorax, vol. 60, no. 8, pp. 693–700, 2005. View at Publisher · View at Google Scholar · View at Scopus
  50. C. B. Gilks, K. Price, J. L. Wright, and A. Churg, “Antioxidant gene expression in rat lung after exposure to cigarette smoke,” American Journal of Pathology, vol. 152, no. 1, pp. 269–278, 1998. View at Google Scholar · View at Scopus
  51. K. McCusker and J. Hoidal, “Selective increase of antioxidant enzyme activity in the alveolar macrophages from cigarette smokers and smoke-exposed hamsters,” American Review of Respiratory Disease, vol. 141, no. 3, pp. 678–682, 1990. View at Google Scholar · View at Scopus
  52. I. Rahman and W. MacNee, “Oxidant/antioxidant imbalance in smokers and chronic obstructive pulmonary disease,” Thorax, vol. 51, no. 4, pp. 348–350, 1996. View at Google Scholar · View at Scopus
  53. F. Balkwill and A. Mantovani, “Cancer and inflammation: implications for pharmacology and therapeutics,” Clinical Pharmacology and Therapeutics, vol. 87, no. 4, pp. 401–406, 2010. View at Publisher · View at Google Scholar · View at Scopus
  54. L. M. Coussens and Z. Werb, “Inflammation and cancer,” Nature, vol. 420, no. 6917, pp. 860–867, 2002. View at Publisher · View at Google Scholar · View at Scopus
  55. C. Porta, P. Larghi, M. Rimoldi et al., “Cellular and molecular pathways linking inflammation and cancer,” Immunobiology, vol. 214, no. 9-10, pp. 761–777, 2009. View at Publisher · View at Google Scholar · View at Scopus
  56. D. I. Feig, T. M. Reid, and L. A. Loeb, “Reactive oxygen species in tumorigenesis,” Cancer Research, vol. 54, no. 7, supplement, pp. 1890s–1894s, 1994. View at Google Scholar · View at Scopus
  57. J. E. Klaunig and L. M. Kamendulis, “The role of oxidative stress in carcinogenesis,” Annual Review of Pharmacology and Toxicology, vol. 44, pp. 239–267, 2004. View at Publisher · View at Google Scholar · View at Scopus
  58. N. Azad, Y. Rojanasakul, and V. Vallyathan, “Inflammation and lung cancer: roles of reactive oxygen/nitrogen species,” Journal of Toxicology and Environmental Health B, vol. 11, no. 1, pp. 1–15, 2008. View at Publisher · View at Google Scholar · View at Scopus
  59. C. Szabó and H. Ohshima, “DNA damage induced by peroxynitrite: subsequent biological effects,” Nitric Oxide, vol. 1, no. 5, pp. 373–385, 1997. View at Publisher · View at Google Scholar · View at Scopus
  60. S. A. Belinsky, “Role of the cytosine DNA-methyltransferase and p16(INK4a) genes in the development of mouse lung tumors,” Experimental Lung Research, vol. 24, no. 4, pp. 463–479, 1998. View at Google Scholar · View at Scopus
  61. W. P. Bennett, T. V. Colby, W. D. Travis et al., “p53 Protein accumulates frequently in early bronchial neoplasia,” Cancer Research, vol. 53, no. 20, pp. 4817–4822, 1993. View at Google Scholar · View at Scopus
  62. S. S. Hecht, “Cigarette smoking and lung cancer: chemical mechanisms and approaches to prevention,” Lancet Oncology, vol. 3, no. 8, pp. 461–469, 2002. View at Publisher · View at Google Scholar · View at Scopus
  63. M. Volm, G. Van Kaick, and J. Mattern, “Analysis of c-fos, c-jun, c-erbB1, c-erbB2 and c-myc in primary lung carcinomas and their lymph node metastases,” Clinical and Experimental Metastasis, vol. 12, no. 4, pp. 329–334, 1994. View at Publisher · View at Google Scholar · View at Scopus
  64. S. Dubey and C. A. Powell, “Update in lung cancer 2007,” American Journal of Respiratory and Critical Care Medicine, vol. 177, no. 9, pp. 941–946, 2008. View at Publisher · View at Google Scholar · View at Scopus
  65. S. S. Hecht, “Lung carcinogenesis by tobacco smoke,” International Journal of Cancer, vol. 131, no. 12, pp. 2724–2732, 2012. View at Google Scholar
  66. P. O'Reilly and W. Bailey, “Clinical use of exhaled biomarkers in COPD,” International Journal of COPD, vol. 2, no. 4, pp. 403–408, 2007. View at Google Scholar · View at Scopus
  67. G. M. Mutlu, K. W. Garey, R. A. Robbins, L. H. Danziger, and I. Rubinstein, “Collection and analysis of exhaled breath condensate in humans,” American Journal of Respiratory and Critical Care Medicine, vol. 164, no. 5, pp. 731–737, 2001. View at Google Scholar · View at Scopus
  68. Z. L. Borrill, K. Roy, and D. Singh, “Exhaled breath condensate biomarkers in COPD,” European Respiratory Journal, vol. 32, no. 2, pp. 472–486, 2008. View at Publisher · View at Google Scholar · View at Scopus
  69. H. P. Chan, C. Lewis, and P. S. Thomas, “Exhaled breath analysis: novel approach for early detection of lung cancer,” Lung Cancer, vol. 63, no. 2, pp. 164–168, 2009. View at Publisher · View at Google Scholar · View at Scopus
  70. S. S. Y. Ai, K. Hsu, C. Herbert et al., “Mitochondrial DNA mutations in exhaled breath condensate of patients with lung cancer,” Respiratory Medicine, vol. 107, no. 6, pp. 911–918, 2013. View at Publisher · View at Google Scholar
  71. I. Horváth, J. Hunt, P. J. Barnes et al., “Exhaled breath condensate: methodological recommendations and unresolved questions,” European Respiratory Journal, vol. 26, no. 3, pp. 523–548, 2005. View at Publisher · View at Google Scholar · View at Scopus
  72. S. A. Kharitonov and P. J. Barnes, “Biomarkers of some pulmonary diseases in exhaled breath,” Biomarkers, vol. 7, no. 1, pp. 1–32, 2002. View at Publisher · View at Google Scholar · View at Scopus
  73. P. P. Rosias, C. M. Robroeks, H. J. Niemarkt et al., “Breath condenser coatings affect measurement of biomarkers in exhaled breath condensate,” European Respiratory Journal, vol. 28, no. 5, pp. 1036–1041, 2006. View at Publisher · View at Google Scholar · View at Scopus
  74. E. Baraldi, L. Ghiro, V. Piovan, S. Carraro, F. Zacchello, and S. Zanconato, “Safety and success of exhaled breath condensate collection in asthma,” Archives of Disease in Childhood, vol. 88, no. 4, pp. 358–360, 2003. View at Publisher · View at Google Scholar · View at Scopus
  75. I. Korovesi, E. Papadomichelakis, S. E. Orfanos et al., “Exhaled breath condensate in mechanically ventilated brain-injured patients with no lung injury or sepsis,” Anesthesiology, vol. 114, no. 5, pp. 1118–1129, 2011. View at Publisher · View at Google Scholar · View at Scopus
  76. P. P. R. Rosias, C. M. Robroeks, K. D. van de Kant et al., “Feasibility of a new method to collect exhaled breath condensate in pre-school children,” Pediatric Allergy and Immunology, vol. 21, no. 1, pp. e235–244, 2010. View at Google Scholar · View at Scopus
  77. O. Holz, “Catching breath: monitoring airway inflammation using exhaled breath condensate,” European Respiratory Journal, vol. 26, no. 3, pp. 371–372, 2005. View at Publisher · View at Google Scholar · View at Scopus
  78. P. Montuschi, “Analysis of exhaled breath condensate in respiratory medicine: methodological aspects and potential clinical applications,” Therapeutic Advances in Respiratory Disease, vol. 1, no. 1, pp. 5–23, 2007. View at Publisher · View at Google Scholar · View at Scopus
  79. P. Montuschi, “Indirect monitoring of lung inflammation,” Nature Reviews Drug Discovery, vol. 1, no. 3, pp. 238–242, 2002. View at Google Scholar · View at Scopus
  80. R. M. Effros, M. B. Dunning III, J. Biller, and R. Shaker, “The promise and perils of exhaled breath condensates,” American Journal of Physiology. Lung Cellular and Molecular Physiology, vol. 287, no. 6, pp. L1073–L1080, 2004. View at Publisher · View at Google Scholar · View at Scopus
  81. Y. Liang, S. M. Yeligar, and L. A. S. Brown, “Exhaled breath condensate: a promising source for biomarkers of lung disease,” The Scientific World Journal, vol. 2012, Article ID 217518, 7 pages, 2012. View at Publisher · View at Google Scholar
  82. A. Bikov, G. Galffy, L. Tamasi, Z. Lazar, G. Losonczy, and I. Horvath, “Exhaled breath condensate pH is influenced by respiratory droplet dilution,” Journal of Breath Research, vol. 6, no. 4, Article ID 046002, 2012. View at Publisher · View at Google Scholar
  83. S. Chow, D. H. Yates, and P. S. Thomas, “Reproducibility of exhaled breath condensate markers,” European Respiratory Journal, vol. 32, no. 4, pp. 1124–1126, 2008. View at Publisher · View at Google Scholar · View at Scopus
  84. T. Okano, T. Kondo, T. Kakisaka et al., “Plasma proteomics of lung cancer by a linkage of multi-dimensional liquid chromatography and two-dimensional difference gel electrophoresis,” Proteomics, vol. 6, no. 13, pp. 3938–3948, 2006. View at Publisher · View at Google Scholar · View at Scopus
  85. W.-M. Gao, R. Kuick, R. P. Orchekowski et al., “Distinctive serum protein profiles involving abundant proteins in lung cancer patients based upon antibody microarray analysis,” BMC Cancer, vol. 5, article 110, 2005. View at Publisher · View at Google Scholar · View at Scopus
  86. A. M. Rodríguez-Piñeiro, S. Blanco-Prieto, N. Sánchez-Otero, F. J. Rodríguez-Berrocal, and M. P. de la Cadena, “On the identification of biomarkers for non-small cell lung cancer in serum and pleural effusion,” Journal of Proteomics, vol. 73, no. 8, pp. 1511–1522, 2010. View at Publisher · View at Google Scholar · View at Scopus
  87. I. Salama, P. S. Malone, F. Mihaimeed, and J. L. Jones, “A review of the S100 proteins in cancer,” European Journal of Surgical Oncology, vol. 34, no. 4, pp. 357–364, 2008. View at Publisher · View at Google Scholar · View at Scopus
  88. T. Vogl, A. L. Gharibyan, and L. A. Morozova-Roche, “Pro-inflammatory S100A8 and S100A9 proteins: self-assembly into multifunctional native and amyloid complexes,” International Journal of Molecular Sciences, vol. 13, no. 3, pp. 2893–2917, 2012. View at Publisher · View at Google Scholar · View at Scopus
  89. K. Hsu, C. Champaiboon, B. D. Guenther et al., “Anti-infective protective properties of S100 calgranulins,” Anti-Inflammatory and Anti-Allergy Agents in Medicinal Chemistry, vol. 8, no. 4, pp. 290–305, 2009. View at Publisher · View at Google Scholar · View at Scopus
  90. I. Marenholz, C. W. Heizmann, and G. Fritz, “S100 proteins in mouse and man: from evolution to function and pathology (including an update of the nomenclature),” Biochemical and Biophysical Research Communications, vol. 322, no. 4, pp. 1111–1122, 2004. View at Publisher · View at Google Scholar · View at Scopus
  91. J. Goyette and C. L. Geczy, “Inflammation-associated S100 proteins: new mechanisms that regulate function,” Amino Acids, vol. 41, no. 4, pp. 821–842, 2011. View at Publisher · View at Google Scholar · View at Scopus
  92. B. W. Schafer, R. Wicki, D. Engelkamp, M.-G. Mattei, and C. W. Heizmann, “Isolation of a YAC clone covering a cluster of nine S100 genes on human chromosome 1q21: rationale for a new nomenclature of the S100 calcium-binding protein family,” Genomics, vol. 25, no. 3, pp. 638–643, 1995. View at Publisher · View at Google Scholar · View at Scopus
  93. D. Foell, H. Wittkowski, T. Vogl, and J. Roth, “S100 proteins expressed in phagocytes: a novel group of damage-associated molecular pattern molecules,” Journal of Leukocyte Biology, vol. 81, no. 1, pp. 28–37, 2007. View at Publisher · View at Google Scholar · View at Scopus
  94. R. J. Passey, K. Xu, D. A. Hume, and C. L. Geczy, “S100A8: emerging functions and regulation,” Journal of Leukocyte Biology, vol. 66, no. 4, pp. 549–556, 1999. View at Google Scholar · View at Scopus
  95. C. Kerkhoff, M. Klempt, and C. Sorg, “Novel insights into structure and function of MRP8 (S100A8) and MRP14 (S100A9),” Biochimica et Biophysica Acta, vol. 1448, no. 2, pp. 200–211, 1998. View at Publisher · View at Google Scholar · View at Scopus
  96. J. Roth, T. Vogl, C. Sorg, and C. Sunderkötter, “Phagocyte-specific S100 proteins: a novel group of proinflammatory molecules,” Trends in Immunology, vol. 24, no. 4, pp. 155–158, 2003. View at Publisher · View at Google Scholar · View at Scopus
  97. C. Gebhardt, J. Németh, P. Angel, and J. Hess, “S100A8 and S100A9 in inflammation and cancer,” Biochemical Pharmacology, vol. 72, no. 11, pp. 1622–1631, 2006. View at Publisher · View at Google Scholar · View at Scopus
  98. S. Y. Lim, M. J. Raftery, and C. L. Geczy, “Oxidative modifications of DAMPs suppress inflammation: the case for S100A8 and S100A9,” Antioxidants and Redox Signaling, vol. 15, no. 8, pp. 2235–2248, 2011. View at Publisher · View at Google Scholar · View at Scopus
  99. Y. L. Su, M. J. Raftery, J. Goyette, K. Hsu, and C. L. Geczy, “Oxidative modifications of S100 proteins: functional regulation by redox,” Journal of Leukocyte Biology, vol. 86, no. 3, pp. 577–587, 2009. View at Publisher · View at Google Scholar · View at Scopus
  100. P. Rouleau, K. Vandal, C. Ryckman et al., “The calcium-binding protein S100A12 induces neutrophil adhesion, migration, and release from bone marrow in mouse at concentrations similar to those found in human inflammatory arthritis,” Clinical Immunology, vol. 107, no. 1, pp. 46–54, 2003. View at Publisher · View at Google Scholar · View at Scopus
  101. C. Ryckman, K. Vandal, P. Rouleau, M. Talbot, and P. A. Tessier, “Proinflammatory activities of S100: proteins S100A8, S100A9, and S100A8/A9 induce neutrophil chemotaxis and adhesion,” Journal of Immunology, vol. 170, no. 6, pp. 3233–3242, 2003. View at Google Scholar · View at Scopus
  102. Z. Yang, T. Tao, M. J. Raftery, P. Youssef, N. Di Girolamo, and C. L. Geczy, “Proinflammatory properties of the human S100 protein S100A12,” Journal of Leukocyte Biology, vol. 69, no. 6, pp. 986–994, 2001. View at Google Scholar · View at Scopus
  103. M. A. Hofmann, S. Drury, C. Fu et al., “RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides,” Cell, vol. 97, no. 7, pp. 889–901, 1999. View at Publisher · View at Google Scholar · View at Scopus
  104. H.-L. Hsieh, B. W. Schäfer, N. Sasaki, and C. W. Heizmann, “Expression analysis of S100 proteins and RAGE in human tumors using tissue microarrays,” Biochemical and Biophysical Research Communications, vol. 307, no. 2, pp. 375–381, 2003. View at Publisher · View at Google Scholar · View at Scopus
  105. D. Foell and J. Roth, “Proinflammatory S100 proteins in arthritis and autoimmune disease,” Arthritis and Rheumatism, vol. 50, no. 12, pp. 3762–3771, 2004. View at Publisher · View at Google Scholar · View at Scopus
  106. C. W. Heizmann, G. Fritz, and B. W. Schäfer, “S100 proteins: structure, functions and pathology,” Frontiers in Bioscience, vol. 7, pp. 1356–1368, 2002. View at Google Scholar · View at Scopus
  107. D. Foell, T. Kucharzik, M. Kraft et al., “Neutrophil derived human S100A12 (EN-RAGE) is strongly expressed during chronic active inflammatory bowel disease,” Gut, vol. 52, no. 6, pp. 847–853, 2003. View at Publisher · View at Google Scholar · View at Scopus
  108. D. Merkel, W. Rist, P. Seither, A. Weith, and M. C. Lenter, “Proteomic study of human bronchoalveolar lavage fluids from smokers with chronic obstructive pulmonary disease by combining surface-enhanced laser desorption/ionization-mass spectrometry profiling with mass spectrometric protein identification,” Proteomics, vol. 5, no. 11, pp. 2972–2980, 2005. View at Publisher · View at Google Scholar · View at Scopus
  109. E. Lorenz, M. S. Muhlebach, P. A. Tessier et al., “Different expression ratio of S100A8/A9 and S100A12 in acute and chronic lung diseases,” Respiratory Medicine, vol. 102, no. 4, pp. 567–573, 2008. View at Publisher · View at Google Scholar · View at Scopus
  110. G. Srikrishna, “S100A8 and S100A9: new insights into their roles in malignancy,” Journal of Innate Immunity, vol. 4, no. 1, pp. 31–40, 2011. View at Publisher · View at Google Scholar · View at Scopus
  111. T. Vogl, C. Pröpper, M. Hartmann et al., “S100A12 is expressed exclusively by granulocytes and acts independently from MRP8 and MRP14,” Journal of Biological Chemistry, vol. 274, no. 36, pp. 25291–25296, 1999. View at Publisher · View at Google Scholar · View at Scopus
  112. G. Srikrishna and H. H. Freeze, “Endogenous damage-associated molecular pattern molecules at the crossroads of inflammation and cancer,” Neoplasia, vol. 11, no. 7, pp. 615–628, 2009. View at Publisher · View at Google Scholar · View at Scopus
  113. M. K. Srivastava, Å. Andersson, L. Zhu et al., “Myeloid suppressor cells and immune modulation in lung cancer,” Immunotherapy, vol. 4, no. 3, pp. 291–304, 2012. View at Publisher · View at Google Scholar · View at Scopus
  114. R. Donato, “S100: a multigenic family of calcium-modulated proteins of the EF-hand type with intracellular and extracellular functional roles,” International Journal of Biochemistry and Cell Biology, vol. 33, no. 7, pp. 637–668, 2001. View at Publisher · View at Google Scholar · View at Scopus
  115. D. I. Gabrilovich and S. Nagaraj, “Myeloid-derived suppressor cells as regulators of the immune system,” Nature Reviews Immunology, vol. 9, no. 3, pp. 162–174, 2009. View at Publisher · View at Google Scholar · View at Scopus
  116. P. H. Feng, K. Y. Lee, Y. L. Chang et al., “CD14+S100A9+ monocytic myeloid-derived suppressor cells and their clinical relevance in non-small cell lung cancer,” American Journal of Respiratory & Critical Care Medicine, vol. 186, no. 10, pp. 1025–1036, 2012. View at Google Scholar
  117. P. Sinha, C. Okoro, D. Foell, H. H. Freeze, S. Ostrand-Rosenberg, and G. Srikrishna, “Proinflammatory S100 proteins regulate the accumulation of myeloid-derived suppressor cells,” Journal of Immunology, vol. 181, no. 7, pp. 4666–4675, 2008. View at Google Scholar · View at Scopus
  118. S. Nagaraj and D. I. Gabrilovich, “Myeloid-derived suppressor cells in human cancer,” Cancer Journal, vol. 16, no. 4, pp. 348–353, 2010. View at Publisher · View at Google Scholar · View at Scopus
  119. L. Dolcetti, I. Marigo, B. Mantelli, E. Peranzoni, P. Zanovello, and V. Bronte, “Myeloid-derived suppressor cell role in tumor-related inflammation,” Cancer Letters, vol. 267, no. 2, pp. 216–225, 2008. View at Publisher · View at Google Scholar · View at Scopus
  120. P. Serafini, I. Borrello, and V. Bronte, “Myeloid suppressor cells in cancer: recruitment, phenotype, properties, and mechanisms of immune suppression,” Seminars in Cancer Biology, vol. 16, no. 1, pp. 53–65, 2006. View at Publisher · View at Google Scholar · View at Scopus
  121. S. Ostrand-Rosenberg, “Cancer and complement,” Nature Biotechnology, vol. 26, no. 12, pp. 1348–1349, 2008. View at Publisher · View at Google Scholar · View at Scopus
  122. G. Zwadlo, J. Bruggen, G. Gerhards, R. Schlegel, and C. Sorg, “Two calcium-binding proteins associated with specific stages of myeloid cell differentiation are expressed by subsets of macrophages in inflammatory tissues,” Clinical and Experimental Immunology, vol. 72, no. 3, pp. 510–515, 1988. View at Google Scholar · View at Scopus
  123. K. Odink, N. Cerletti, J. Bruggen et al., “Two calcium-binding proteins in infiltrate macrophages of rheumatoid arthritis,” Nature, vol. 330, no. 6143, pp. 80–82, 1987. View at Google Scholar · View at Scopus
  124. A. Hermani, B. De Servi, S. Medunjanin, P. A. Tessier, and D. Mayer, “S100A8 and S100A9 activate MAP kinase and NF-κB signaling pathways and trigger translocation of RAGE in human prostate cancer cells,” Experimental Cell Research, vol. 312, no. 2, pp. 184–197, 2006. View at Publisher · View at Google Scholar · View at Scopus
  125. A. Hermani, J. Hess, B. De Servi et al., “Calcium-binding proteins S100A8 and S100A9 as novel diagnostic markers in human prostate cancer,” Clinical Cancer Research, vol. 11, no. 14, pp. 5146–5152, 2005. View at Publisher · View at Google Scholar · View at Scopus
  126. H.-Y. Yong and A. Moon, “Roles of calcium-binding proteins, S100A8 and S100A9, in invasive phenotype of human gastric cancer cells,” Archives of Pharmacal Research, vol. 30, no. 1, pp. 75–81, 2007. View at Google Scholar · View at Scopus
  127. J. Stuli'k, J. Osterreicher, K. Koupilova' et al., “The analysis of S100A9 and S100A8 expression in matched sets of macroscopically normal colon mucosa and colorectal carcinoma: the S100A9 and S100A8 positive cells underlie and invade tumor mass,” Electrophoresis, vol. 20, no. 4-5, pp. 41047–41554, 1999. View at Google Scholar
  128. H.-J. Kim, H. J. Kang, H. Lee et al., “Identification of S100A8 and S100A9 as serological markers for colorectal cancer,” Journal of Proteome Research, vol. 8, no. 3, pp. 1368–1379, 2009. View at Publisher · View at Google Scholar · View at Scopus
  129. H. Kawai, Y. Minamiya, and N. Takahashi, “Prognostic impact of S100A9 overexpression in non-small cell lung cancer,” Tumor Biology, vol. 32, no. 4, pp. 641–646, 2011. View at Publisher · View at Google Scholar · View at Scopus
  130. K. Arai, “Immunohistochemical investigation of S100A9 expression in pulmonary adenocarcinoma: S100A9 expression is associated with tumor differentiation,” Oncology Reports, vol. 8, no. 3, pp. 591–596, 2001. View at Google Scholar · View at Scopus
  131. S. Rafii and D. Lyden, “S100 chemokines mediate bookmarking of premetastatic niches,” Nature Cell Biology, vol. 8, no. 12, pp. 1321–1323, 2006. View at Publisher · View at Google Scholar · View at Scopus
  132. S. Hiratsuka, A. Watanabe, H. Aburatani, and Y. Maru, “Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis,” Nature Cell Biology, vol. 8, no. 12, pp. 1369–1375, 2006. View at Publisher · View at Google Scholar · View at Scopus
  133. S. Hiratsuka, A. Watanabe, Y. Sakurai et al., “The S100A8-serum amyloid A3-TLR4 paracrine cascade establishes a pre-metastatic phase,” Nature Cell Biology, vol. 10, no. 11, pp. 1349–1355, 2008. View at Publisher · View at Google Scholar · View at Scopus
  134. S. Kwiatkowska, K. Noweta, M. Zieba, D. Nowak, and P. Bialasiewicz, “Enhanced exhalation of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in patients with COPD exacerbation: a prospective study,” Respiration, vol. 84, no. 3, pp. 231–241, 2012. View at Publisher · View at Google Scholar
  135. H. P. Chan, V. Tran, C. Lewis, and P. S. Thomas, “Elevated levels of oxidative stress markers in exhaled breath condensate,” Journal of Thoracic Oncology, vol. 4, no. 2, pp. 172–178, 2009. View at Publisher · View at Google Scholar · View at Scopus
  136. P. N. R. Dekhuijzen, K. K. H. Aben, I. Dekker et al., “Increased exhalation of hydrogen peroxide in patients with stable and unstable chronic obstructive pulmonary disease,” American Journal of Respiratory and Critical Care Medicine, vol. 154, no. 3, pp. 813–816, 1996. View at Google Scholar · View at Scopus
  137. H. Inonu, S. Doruk, S. Sahin et al., “Oxidative stress levels in exhaled breath condensate associated with COPD and smoking,” Respiratory Care, vol. 57, no. 3, pp. 413–419, 2012. View at Publisher · View at Google Scholar · View at Scopus
  138. D. Nowak, M. Kasielski, A. Antczak, T. Pietras, and P. Bialasiewicz, “Increased content of thiobarbituric acid-reactive substances and hydrogen peroxide in the expired breath condensate of patients with stable chronic obstructive pulmonary disease: no significant effect of cigarette smoking,” Respiratory Medicine, vol. 93, no. 6, pp. 389–396, 1999. View at Publisher · View at Google Scholar · View at Scopus
  139. M. Corradi, M. Majori, G. C. Cacciani, G. F. Consigli, E. De'Munari, and A. Pesci, “Increased exhaled nitric oxide in patients with stable chronic obstructive pulmonary disease,” Thorax, vol. 54, no. 7, pp. 572–575, 1999. View at Google Scholar · View at Scopus
  140. C.-Y. Liu, C.-H. Wang, T.-C. Chen, H.-C. Lin, C.-T. Yu, and H.-P. Kuo, “Increased level of exhaled nitric oxide and up-regulation of inducible nitric oxide synthase in patients with primary lung cancer,” British Journal of Cancer, vol. 78, no. 4, pp. 534–541, 1998. View at Google Scholar · View at Scopus
  141. J. Liu, A. Sandrini, M. C. Thurston, D. H. Yates, and P. S. Thomas, “Nitric oxide and exhaled breath nitrite/nitrates in chronic obstructive pulmonary disease patients,” Respiration, vol. 74, no. 6, pp. 617–623, 2007. View at Publisher · View at Google Scholar · View at Scopus
  142. F. A. Masri, S. A. A. Comhair, T. Koeck et al., “Abnormalities in nitric oxide and its derivatives in lung cancer,” American Journal of Respiratory and Critical Care Medicine, vol. 172, no. 5, pp. 597–605, 2005. View at Publisher · View at Google Scholar · View at Scopus
  143. W. Maziak, S. Loukides, S. Culpitt, P. Sullivan, S. A. Kharitonov, and P. J. Barnes, “Exhaled nitric oxide in chronic obstructive pulmonary disease,” American Journal of Respiratory and Critical Care Medicine, vol. 157, no. 3, pp. 998–1002, 1998. View at Google Scholar · View at Scopus
  144. P. Montuschi, S. A. Kharitonov, and P. J. Barnes, “Exhaled carbon monoxide and nitric oxide in COPD,” Chest, vol. 120, no. 2, pp. 496–501, 2001. View at Publisher · View at Google Scholar · View at Scopus
  145. C. Gessner, S. Hammerschmidt, H. Kuhn et al., “Breath condensate nitrite correlates with hyperinflation in chronic obstructive pulmonary disease,” Respiratory Medicine, vol. 101, no. 11, pp. 2271–2278, 2007. View at Publisher · View at Google Scholar · View at Scopus
  146. V. Rihák, P. Zatloukal, J. Chládková, A. Zimulová, Z. Havlínová, and J. Chládek, “Nitrite in exhaled breath condensate as a marker of nitrossative stress in the airways of patients with asthma, COPD, and idiopathic pulmonary fibrosis,” Journal of Clinical Laboratory Analysis, vol. 24, no. 5, pp. 317–322, 2010. View at Publisher · View at Google Scholar · View at Scopus
  147. M. Corradi, A. Pesci, R. Casana et al., “Nitrate in exhaled breath condensate of patients with different airway diseases,” Nitric Oxide, vol. 8, no. 1, pp. 26–30, 2003. View at Publisher · View at Google Scholar · View at Scopus
  148. C. Brindicci, K. Ito, O. Torre, P. J. Barnes, and S. A. Kharitonov, “Effects of aminoguanidine, an inhibitor of inducible nitric oxide synthase, on nitric oxide production and its metabolites in healthy control subjects, healthy smokers, and COPD patients,” Chest, vol. 135, no. 2, pp. 353–367, 2009. View at Publisher · View at Google Scholar · View at Scopus
  149. G. O. Osoata, T. Hanazawa, C. Brindicci et al., “Peroxynitrite elevation in exhaled breath condensate of COPD and its inhibition by fudosteine,” Chest, vol. 135, no. 6, pp. 1513–1520, 2009. View at Publisher · View at Google Scholar · View at Scopus
  150. P. Montuschi, J. V. Collins, G. Ciabattoni et al., “Exhaled 8-isoprostane as an in vivo biomarker of lung oxidative stress in patients with COPD and healthy smokers,” American Journal of Respiratory and Critical Care Medicine, vol. 162, no. 3, pp. 1175–1177, 2000. View at Google Scholar · View at Scopus
  151. F. W. S. Ko, C. Y. K. Lau, T. F. Leung, G. W. K. Wong, C. W. K. Lam, and D. S. C. Hui, “Exhaled breath condensate levels of 8-isoprostane, growth related oncogene α and monocyte chemoattractant protein-1 in patients with chronic obstructive pulmonary disease,” Respiratory Medicine, vol. 100, no. 4, pp. 630–638, 2006. View at Publisher · View at Google Scholar · View at Scopus
  152. E. Dalaveris, T. Kerenidi, A. Katsabeki-Katsafli et al., “VEGF, TNF-α and 8-isoprostane levels in exhaled breath condensate and serum of patients with lung cancer,” Lung Cancer, vol. 64, no. 2, pp. 219–225, 2009. View at Publisher · View at Google Scholar · View at Scopus
  153. M. Corradi, I. Rubinstein, R. Andreoli et al., “Aldehydes in exhaled breath condensate of patients with chronic obstructive pulmonary disease,” American Journal of Respiratory and Critical Care Medicine, vol. 167, no. 10, pp. 1380–1386, 2003. View at Publisher · View at Google Scholar · View at Scopus
  154. A. Gönenç, Y. Özkan, M. Torun, and B. Şmşek, “Plasma malondialdehyde (MDA) levels in breast and lung cancer patients,” Journal of Clinical Pharmacy and Therapeutics, vol. 26, no. 2, pp. 141–144, 2001. View at Publisher · View at Google Scholar · View at Scopus
  155. H. Ahmadzai, S. Huang, R. Hettiarachchi, J. L. Lin, P. S. Thomas, and Q. Zhang, “Exhaled breath condensate: a comprehensive update,” Clinical Chemistry and Laboratory Medicine, pp. 1343–1361, 2013. View at Publisher · View at Google Scholar
  156. G. E. Carpagnano, G. P. Palladino, D. Lacedonia, A. Koutelou, S. Orlando, and M. P. Foschino-Barbaro, “Neutrophilic airways inflammation in lung cancer: the role of exhaled LTB-4 and IL-8,” BMC Cancer, vol. 11, article 226, 2011. View at Publisher · View at Google Scholar · View at Scopus
  157. J.-L. Corhay, M. Henket, D. Nguyen, B. Duysinx, J. Sele, and R. Louis, “Leukotriene B4 contributes to exhaled breath condensate and sputum neutrophil chemotaxis in COPD,” Chest, vol. 136, no. 4, pp. 1047–1054, 2009. View at Publisher · View at Google Scholar · View at Scopus
  158. P. Montuschi, S. A. Kharitonov, G. Ciabattoni, and P. J. Barnes, “Exhaled leukotrienes and prostaglandins in COPD,” Thorax, vol. 58, no. 7, pp. 585–588, 2003. View at Publisher · View at Google Scholar · View at Scopus
  159. K. Kostikas, M. Gaga, G. Papatheodorou, T. Karamanis, D. Orphanidou, and S. Loukides, “Leukotriene B4 in exhaled breath condensate and sputum supernatant in patients with COPD and asthma,” Chest, vol. 127, no. 5, pp. 1553–1559, 2005. View at Publisher · View at Google Scholar · View at Scopus
  160. A. Antczak, W. Piotrowski, J. Marczak, M. Ciebiada, P. Gorski, and P. J. Barnes, “Correlation between eicosanoids in bronchoalveolar lavage fluid and in exhaled breath condensate,” Disease Markers, vol. 30, no. 5, pp. 213–220, 2011. View at Publisher · View at Google Scholar · View at Scopus
  161. E. Chan, T. Sivagnanam, Q. Zhang, C. R. Lewis, and P. S. Thomas, “Tumour necrosis factor alpha and oxidative stress in the breath condensate of those with non-small cell lung cancer,” Journal of Cancer Therapy, vol. 3, no. 4A, pp. 460–466, 2012. View at Publisher · View at Google Scholar
  162. E. Bucchioni, S. A. Kharitonov, L. Allegra, and P. J. Barnes, “High levels of interleukin-6 in the exhaled breath condensate of patients with COPD,” Respiratory Medicine, vol. 97, no. 12, pp. 1299–1302, 2003. View at Publisher · View at Google Scholar · View at Scopus
  163. G. E. Carpagnano, O. Resta, M. P. Foschino-Barbaro, E. Gramiccioni, and F. Carpagnano, “Interleukin-6 is increased in breath condensate of patients with non-small cell lung cancer,” International Journal of Biological Markers, vol. 17, no. 2, pp. 141–145, 2002. View at Google Scholar · View at Scopus
  164. A.-R. Koczulla, S. Noeske, C. Herr et al., “Acute and chronic effects of smoking on inflammation markers in exhaled breath condensate in current smokers,” Respiration, vol. 79, no. 1, pp. 61–67, 2009. View at Publisher · View at Google Scholar · View at Scopus
  165. G. E. Carpagnano, G. P. Palladino, D. Martinelli, D. Lacedonia, S. Orlando, and M. P. Foschino-Barbaro, “Exhaled matrix metalloproteinase-9 in lung cancer,” Rejuvenation Research, vol. 15, no. 4, pp. 359–365, 2012. View at Publisher · View at Google Scholar
  166. P. Carratu, C. Scoditti, M. Maniscalco et al., “Exhaled and arterial levels of endothelin-1 are increased and correlate with pulmonary systolic pressure in COPD with pulmonary hypertension,” BMC Pulmonary Medicine, vol. 8, article 20, 2008. View at Publisher · View at Google Scholar · View at Scopus
  167. G. E. Carpagnano, M. P. Foschino-Barbaro, O. Restaa, E. Gramiccioni, and F. Carpagnano, “Endothelin-1 is increased in the breath condensate of patients with non-small-cell lung cancer,” Oncology, vol. 66, no. 3, pp. 180–184, 2004. View at Publisher · View at Google Scholar · View at Scopus
  168. L. Chen, H.-L. Zhu, and X. Zhang, “Clinical significance of measuring endothelin-1 in exhaled breath condensate of patients with non-small cell lung cancer,” Journal of Xi'an Jiaotong University, vol. 32, no. 4, pp. 458–461, 2011. View at Google Scholar · View at Scopus
  169. P. Paredi, S. A. Kharitonov, D. Leak, S. Ward, D. Cramer, and P. J. Barnes, “Exhaled ethane, a marker of lipid peroxidation, is elevated chronic obstructive pulmonary disease,” American Journal of Respiratory and Critical Care Medicine, vol. 162, no. 2, pp. 369–373, 2000. View at Google Scholar · View at Scopus
  170. M. Phillips, K. Gleeson, J. M. B. Hughes et al., “Volatile organic compounds in breath as markers of lung cancer: a cross-sectional study,” Lancet, vol. 353, no. 9168, pp. 1930–1933, 1999. View at Publisher · View at Google Scholar · View at Scopus
  171. G. Song, T. Qin, H. Liu et al., “Quantitative breath analysis of volatile organic compounds of lung cancer patients,” Lung Cancer, vol. 67, no. 2, pp. 227–231, 2010. View at Publisher · View at Google Scholar · View at Scopus
  172. B. Antus and I. Barta, “Exhaled breath condensate pH in patients with lung cancer,” Lung Cancer, vol. 75, no. 2, pp. 178–180, 2012. View at Publisher · View at Google Scholar · View at Scopus
  173. W. MacNee, S. I. Rennard, J. F. Hunt et al., “Evaluation of exhaled breath condensate pH as a biomarker for COPD,” Respiratory Medicine, vol. 105, no. 7, pp. 1037–1045, 2011. View at Publisher · View at Google Scholar · View at Scopus
  174. K. Kostikas, G. Papatheodorou, K. Ganas, K. Psathakis, P. Panagou, and S. Loukides, “pH in expired breath condensate of patients with inflammatory airway diseases,” American Journal of Respiratory and Critical Care Medicine, vol. 165, no. 10, pp. 1364–1370, 2002. View at Publisher · View at Google Scholar · View at Scopus
  175. W. Lee, H. Loo, and P. S. Thomas, “Airway antioxidant capacity and pH in chronic obstructive pulmonary disease,” Oxidants and Antioxidants in Medical Science, vol. 1, no. 3, pp. 153–160, 2012. View at Google Scholar
  176. G. E. Carpagnano, M. P. Foschino-Barbaro, G. Mulé et al., “3p microsatellite alterations in exhaled breath condensate from patients with non-small cell lung cancer,” American Journal of Respiratory and Critical Care Medicine, vol. 172, no. 6, pp. 738–744, 2005. View at Publisher · View at Google Scholar · View at Scopus
  177. C. Gessner, H. Kuhn, K. Toepfer, S. Hammerschmidt, J. Schauer, and H. Wirtz, “Detection of p53 gene mutations in exhaled breath condensate of non-small cell lung cancer patients,” Lung Cancer, vol. 43, no. 2, pp. 215–222, 2004. View at Publisher · View at Google Scholar · View at Scopus
  178. C. Gessner, “Nachweis von mutationen des K-ras-Cens im atemkondensat von patienten mit nicht-kleinzelligem lungenkarzinom (NSCLC) als mögliche nicht-invasive screeningmethode,” Pneumologie, vol. 52, no. 7, pp. 426–427, 1998. View at Google Scholar · View at Scopus
  179. D. Zhang, N. Takigawa, N. Ochi et al., “Detection of the EGFR mutation in exhaled breath condensate from a heavy smoker with squamous cell carcinoma of the lung,” Lung Cancer, vol. 73, no. 3, pp. 379–380, 2011. View at Publisher · View at Google Scholar · View at Scopus
  180. W. Han, T. Wang, A. A. Reilly, S. M. Keller, and S. D. Spivack, “Gene promoter methylation assayed in exhaled breath, with differences in smokers and lung cancer patients,” Respiratory Research, vol. 10, article 86, 2009. View at Publisher · View at Google Scholar · View at Scopus
  181. G. E. Carpagnano, A. Koutelou, M. I. Natalicchio et al., “HPV in exhaled breath condensate of lung cancer patients,” British Journal of Cancer, vol. 105, no. 8, pp. 1183–1190, 2011. View at Publisher · View at Google Scholar · View at Scopus
  182. G. E. Carpagnano, D. Lacedonia, G. P. Palladino et al., “Could exhaled ferritin and SOD be used as markers for lung cancer and prognosis prediction purposes?” European Journal of Clinical Investigation, vol. 42, no. 5, pp. 478–486, 2012. View at Publisher · View at Google Scholar · View at Scopus