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Background: Extracellular adenosine 5'-triphosphate (ATP) stimulates vagal C and Aδ fibers in the lung, resulting in pronounced bronchoconstriction and cough mediated by P2X2/3 receptors located on vagal sensory nerve terminals. We investigated the effects of nebulized ATP on cough and symptoms in control subjects, healthy smokers, and patients with COPD and compared these responses to the effects of inhaled adenosine, the metabolite of ATP., Methods: We studied the effects of inhaled ATP and adenosine monophosphate (AMP) on airway caliber, perception of dyspnea assessed by the Borg score, cough sensitivity, and ATP in exhaled breath condensate in healthy nonsmokers (n = 10), healthy smokers (n = 14), and patients with COPD (n = 7)., Results: In comparison with healthy subjects, ATP induced more dyspnea, cough, and throat irritation in smokers and patients with COPD, and the effects of ATP were more pronounced than those of AMP. The concentration of ATP in the exhaled breath condensate of patients with COPD was elevated compared with that of healthy subjects., Conclusions: Smokers and patients with COPD manifest hypersensitivity to extracellular ATP, which may play a mechanistic role in COPD.

Background: Determining the site of airways inflammation may lead to the targeting of therapy. Nitric oxide (NO) is a biomarker of airway inflammation and can be measured at multiple exhalation flow rates to allow partitioning into bronchial (large/central airway maximal nitric oxide flux [J'awno]) and peripheral (peripheral/small airway/alveolar nitric oxide concentration [Cano]) airway contributions by linear regression. This requires a minimum of three exhalations. We developed a simple and practical method to partition NO., Methods: In 29 healthy subjects (FEV1, 97% ± 3% predicted), 13 patients with asthma (FEV1, 90% ± 4% predicted), 14 patients with COPD (FEV1, 59% ± 3% predicted), and 12 patients with cystic fibrosis (CF) (FEV1, 60% ± 3% predicted), we measured the area under the curve of the NO concentration/exhalation time plot (AUC-NO) at exhalation flow rates of 50, 100, 200, and 300 mL/s. We determined the change of the total AUC-NO production (ΔAUC-NO) among the four different exhalation flow rates and compared these levels to Cano and J'awno indices measured conventionally by linear regression., Results: The change in AUC-NO between increasing exhalation flow rates of 50 to 200 mL/s (ΔAUC-NO50-200) was strongly correlated with J'awno in all patient groups as follows: healthy subjects (r = 0.94, P < .001), patients with asthma (r = 0.98, P < .001), patients with COPD (r = 0.93, P < .001), and patients with CF (r = 0.74, P < .05). In all subjects, AUC-NO at an exhalation flow rate of 200 mL/s (AUC-NO200) correlated with Cano (r = 0.69, P < .01)., Conclusions: The bronchial production of NO can be determined by measuring ΔAUC-NO50-200, whereas AUC-NO200 measures its peripheral concentration. This approach is simple, quick, and does not require sophisticated equipment or mathematical models.

Background: COPD is characterized by chronic airflow limitation and inflammation of the respiratory tract. Several inflammatory biomarkers have been evaluated in COPD but are poorly related to disease severity and progression. Osteoprotegerin (OPG) is a glycoprotein mediator that is expressed in the lung and macrophages, so we have studied its concentration in induced sputum and macrophages of patients with COPD., Methods: OPG was measured by enzyme-linked immunosorbent assay in induced sputum of patients with COPD and control subjects., Results: OPG concentrations in induced sputum of patients with COPD (18.7 ± 18.6 ng/mL, n = 39) were significantly higher than those of healthy smokers (8.1 ± 5.6 ng/mL, n = 15), healthy nonsmokers (3.5 ± 3.8 ng/mL, n = 14), or patients with asthma (8.0 ± 5.4 ng/mL, n = 18). Sputum OPG levels in COPD negatively correlated with FEV(1) and positively correlated with residual volume to total lung capacity ratio (RV/TLC) (r = 0.55, P < .05), transfer factor of the lung for carbon monoxide (r = -0.53, P < .05), and carbon monoxide transfer coefficient (r = -0.61, P < .01). By contrast, sputum IL-8 concentrations were related to disease severity but not to RV/TLC or gas diffusion. Airway macrophages and neutrophils were positive for OPG by immunocytochemistry in sputum and peripheral lung tissue. OPG induced matrix metalloproteinase-9 release from sputum macrophages in vitro., Conclusions: Sputum OPG may be a useful biomarker to monitor parenchymal destruction in COPD.

Rationale: Nitric oxide (NO) is increased in the lung periphery of patients with chronic obstructive pulmonary disease (COPD). However, expression of the NO synthase(s) responsible for elevated NO has not been identified in the peripheral lung tissue of patients with COPD of varying severity., Methods: Protein and mRNA expression of nitric oxide synthase type I (neuronal NOS [nNOS]), type II (inducible NOS [iNOS]), and type III (endothelial NOS [eNOS]) were quantified by Western blotting and reverse transcription-polymerase chain reaction, respectively, in specimens of surgically resected lung tissue from nonsmoker control subjects, patients with COPD of varying severity, and smokers without COPD, and in a lung epithelial cell line (A549). The effects of nitrative/oxidative stress on NOS expression and activity were also evaluated in vitro in A549 cells. nNOS nitration was quantified by immunoprecipitation and dimerization of nNOS was detected by low-temperature SDS-PAGE/Western blot in the presence of the peroxynitrite generator, 3-morpholinosydnonimine-N-ethylcarbamide (SIN1), in vitro and in vivo., Measurements and Main Results: Lung tissue from patients with severe and very severe COPD had graded increases in nNOS (mRNA and protein) compared with nonsmokers and normal smokers. Hydrogen peroxide (H(2)O(2)) and SIN1 as well as the cytokine mixture (IFN-gamma, IL-1beta, and tumor necrosis factor-alpha) increased mRNA expression and activity of nNOS in A549 cells in a concentration-dependent manner compared with nontreated cells. Tyrosine nitration resulted in an increase in nNOS activity in vitro, but did not affect its dimerization., Conclusions: Patients with COPD have a significant increase in nNOS expression and activity that reflects the severity of the disease and may be secondary to oxidative stress.

Background: Nitric oxide (NO) is produced by resident and inflammatory cells in the respiratory tract by the enzyme NO synthase (NOS), which exists in three isoforms: neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS. NO production is increased in patients with COPD, and the production of NO under oxidative stress conditions generates reactive nitrogen species that may amplify the inflammatory response in COPD., Methods: To examine the role of increased NO in COPD, we administered a relatively selective iNOS inhibitor, aminoguanidine, by nebulization in a double-blind, placebo-controlled study in COPD patients, healthy smokers, and healthy nonsmoking subjects. We investigated whether aminoguanidine had any effect on exhaled NO produced in the central lung (flux of NO from the airways [Jno] and peripheral lungs (concentration of NO in peripheral lung [Calv], on NO metabolites (nitrite [NO(2)(-)]/nitrate [NO(3)(-)], peroxinitrite [ONOO(-)], nitrotyrosine), and on a marker of oxidative stress (8-isoprostane) in exhaled breath condensate (EBC) and in sputum., Results: Aminoguanidine administration resulted in a significant reduction in Jno compared with administration of the saline solution control in healthy subjects, smokers, and COPD patients. Calv in smokers and in COPD patients was not completely inhibited 1 h after aminoguanidine inhalation, in marked contrast to previous results in asthma. Moreover, ONOO(-) and NO(2)(-)/NO(3)(-) levels were also increased in EBC and in sputum of smokers and COPD and were not completely inhibited following aminoguanidine inhalation. 8-Isoprostane levels were also increased in smokers and in COPD patients but were not reduced after aminoguanidine inhalation., Conclusions: These results suggest that the constitutive NOS isoform as well as iNOS might be involved in NO release and contribute to the high Calv and ONOO(-) production in patients with COPD., Trial Registration: Clinicaltrials.gov Identifier: NCT00180635.

Background: In COPD patients, there is reduced vascularity and inflammation of the bronchi, which may have opposite effects on bronchial blood flow (QAW). We studied the relationship of QAW with the fraction of exhaled nitric oxide (FENO), which is a potent vasodilator. We also investigated the vascular response to budesonide and a beta(2)-agonist., Methods: We measured QAW in 17 patients with COPD (mean [+/- SEM] age, 67 +/- 3 years; 10 male patients; mean FEV(1), 57 +/- 3% predicted; mean FEV(1)/FVC ratio, 54 +/- 4%), all of whom were ex-smokers, and in 16 age-matched nonsmoking volunteers (mean age, 64 +/- 4 years) and compared this to FENO. QAW was measured using the acetylene dilution method., Results: Mean QAW was similar in patients with COPD (34.29 +/- 1.09 microL/mL/min) compared to healthy subjects (35.50 +/- 1.74 microL/mL/min; p > 0.05) and was not affected by long-term treatment (35.89 +/- 1.63 microL/mL/min) or short-term treatment (32.50 +/- 1.24 microL/mL/min; p < 0.05) with inhaled budesonide. QAW positively correlated with the diffusion of carbon monoxide (ie, carbon monoxide transfer coefficient: r = 0.74; p < 0.05). FENO levels were mildly elevated in steroid-treated patients (10.89 +/- 0.87 parts per billion [ppb]) and untreated patients (9.40 +/- 0.86 ppb) compared to the control group (8.22 +/- 0.57 ppb; p < 0.05) and were correlated with QAW (r = 0.6; p < 0.05). Ten minutes after the inhalation of 200 microg of albuterol, QAW was more elevated in healthy control subjects (59.33 +/- 2.40 microL/mL/min) compared to COPD patients (38.00 +/- 0.58 microL/mL/min; p < 0.05), indicating that COPD patients may have a reduced bronchial vascular reactivity., Conclusions: QAW is normal in COPD patients and is not affected by therapy with inhaled corticosteroids or beta(2)-agonists. In addition, QAW correlates with levels of FENO, which may have a regulatory role.

Endotoxin, or lipopolysaccharide (LPS), is a constituent of the outer cell membrane of Gram-negative bacteria. LPS is a highly potent proinflammatory substance, that, when inhaled, dose-dependently causes fever, chills, and bronchoconstriction. These symptoms are accompanied by a proinflammatory response in sputum and bronchoalveolar lavage fluid with elevation of neutrophils, macrophages and certain cytokines/chemokines. This response can be partially modified with certain drugs. Similar inflammatory changes are observed both in the stable state of chronic obstructive lung disease (COPD) and during exacerbations of this disease. Cigarette smoke, which contains bioactive LPS, is the most common cause of COPD and may also precipitate exacerbations. In addition, the presence of Gram-negative bacteria in the lower airways is a distinguishing feature both of stable COPD and of exacerbations. Based on this knowledge we argue here that inhaled LPS provocation of healthy volunteers can be used as a model or COPD as well as for exacerbations of this disease.

Assessing airway and lung inflammation is important for investigating the underlying mechanisms of asthma and COPD. Yet these cannot be measured directly in clinical research and practice because of the difficulties in monitoring inflammation. Noninvasive monitoring may assist in early recognition of asthma and COPD, assessment of its severity, and response to treatment, especially during disease exacerbations. There is increasing evidence that breath analysis may have an important place in clinical management of asthma and COPD. The article reviews the role of current noninvasive measurements of exhaled gases, such as nitric oxide (NO), inflammatory markers in exhaled breath condensate (EBC), and exhaled breath temperature, as well as novel methods in monitoring and management of asthma and COPD.

There has been increasing interest in using pulmonary biomarkers to understand and monitor the inflammation in the respiratory tract of patients with chronic obstructive pulmonary disease (COPD). In this Pulmonary Perspective we discuss the merits of the various approaches by reviewing the current literature on pulmonary biomarkers in COPD and underscore the need for more systematic studies in the future. Bronchial biopsies and bronchoalveolar lavage provide valuable information about inflammatory cells and mediators, but are invasive, so that repeated measurements have to be very limited in assessing any interventions. Induced sputum has provided considerable information about the inflammatory process, including mediators and proteinases in COPD, but selectively samples proximal airways and may not closely reflect distal inflammatory processes. Exhaled gases and breath condensate are noninvasive procedures, so repeated measurements are possible, but for some assays the variability is relatively high. There is relatively little information about how any of these biomarkers relate to other clinical outcomes, such as progression of the disease, severity of disease, clinical subtypes, or response to therapy. More information is also needed about the variability in these measurements. In the future, pulmonary biomarkers may be useful in predicting disease progression, indicating disease instability, and in predicting response to current therapies and novel therapies, many of which are now in development.

Nitric oxide (NO), a simple free radical gas, elicits a diverse range of physiological and pathophysiological effects, and plays an important role in pulmonary diseases. Nitrosative stress and nitration of proteins in airway epithelium maybe responsible for steroid resistance in asthma and their ineffectiveness in chronic obstructive pulmonary disease (COPD), supporting the potential role of future therapeutic strategies aimed at regulating NO synthesis in asthma and COPD. Here, we have reviewed the potential role of NO modulators (NO synthase inhibitors and NO donors), which if given on a regular basis may have clinical benefit in asthma and COPD.

Background: Leukotriene (LT) B4 concentrations are increased and prostaglandin (PG) E2 concentrations are decreased in exhaled breath condensate (EBC) in patients with chronic obstructive pulmonary disease (COPD). A study was undertaken to investigate the short term effects of cyclo-oxygenase (COX) inhibition on exhaled LTB4 and PGE2 concentrations in patients with COPD and to identify the COX isoform responsible for exhaled PGE2 production., Methods: Two studies were performed. A double blind, crossover, randomised, placebo controlled study with ibuprofen (400 mg qid for 2 days), a non-selective COX inhibitor, was undertaken in 14 patients with stable COPD, and an open label study with oral rofecoxib (25 mg once a day for 5 days), a selective COX-2 inhibitor, was undertaken in a different group of 16 COPD patients. EBC was collected before and after drug treatment. Exhaled LTB4 and PGE2 concentrations were measured with specific immunoassays., Results: All patients complied with treatment as indicated by a reduction in ex vivo serum thromboxane B2 concentrations (ibuprofen) and a reduction in lipopolysaccharide induced increase in ex vivo plasma PGE2 values (rofecoxib) of more than 80%. Exhaled LTB4 was increased after ibuprofen (median 175.5 (interquartile range 128.8-231.5) pg/ml v 84.0 (70.0-98.5) pg/ml, p < 0.001) and exhaled PGE2 was reduced (93.5 (84.0-105-5) pg/ml v 22.0 (15.0-25.5) pg/ml, p < 0.0001). Rofecoxib had no effect on exhaled LTB4 (p = 0.53) or PGE2 (p = 0.23)., Conclusions: Non-selective COX inhibition decreases PGE2 and increases LTB4 in EBC, whereas selective COX-2 inhibition has no effect on these eicosanoids. PGE2 in EBC is primarily derived from COX-1 activity, and COX inhibition may redirect arachidonic acid metabolism towards the 5-lipoxygenase pathway.

Single constant flow exhaled nitric oxide (eNO) cannot distinguish between the sources of NO. The present study measured eNO at multiple expired flows (MEFeNO) to partition NO into alveolar (Calv,NO) and bronchial (Jaw,NO) fractions to investigate peripheral lung contribution to eNO in chronic obstructive lung disease (COPD). MEFeNO were made in 81 subjects including 18 nonsmokers, 16 smokers and 47 COPD patients of different severity by the classification of the Global Initiative for Chronic Obstructive Lung Disease (GOLD): 0 (n = 14), 1 (n = 7), 2 (n = 11), 3 (n = 8) and 4 (n = 7). COPD severity was correlated with an increased Calv,NO regardless of the patient's smoking habit or current treatment. The levels of Calv,NO (in ppb) were 1.4+/-0.09 in nonsmokers, 2.1+/-0.1 in smokers categorised as GOLD stage 0 (smokers-GOLD0), 3.3+/-0.18 in GOLD1-2 and 3.4+/-0.1 in GOLD3-4. Jaw,NO levels (pL x s(-1)) were higher in nonsmokers than smokers-GOLD0 (716.2+/-33.3 versus 464.7+/-41.8), GOLD3-4 (609.4+/-71). Diffusion of NO in the airways (Daw,NO pL x ppb(-1) s(-1)) was higher (p<0.05) in GOLD3-4 than in nonsmokers (15+/-1.2 versus 11+/-0.5) and smokers-GOLD0 (11.6+/-0.5). MEFeNO measurements were reproducible, free from day-to-day and diurnal variation and were not affected by bronchodilators. In conclusion, chronic obstructive pulmonary disease is associated with elevated alveolar nitric oxide. Measurements of nitric oxide at multiple expired flows may be useful in monitoring inflammation and progression of chronic obstructive pulmonary disease, and the response to anti-inflammatory treatment.

Background: Hyperoxia increases oxidative stress through the generation of reactive oxygen species and may therefore enhance inflammation in the lungs. The aim of this study was to investigate whether short term supplementary oxygen (28%) increases oxidative stress and inflammation in the airways by measuring 8-isoprostane and interleukin 6 (IL-6) concentrations in exhaled breath condensate., Methods: Twenty three healthy subjects (12 men, mean (SD) age 48 (7) years) and 23 patients with chronic obstructive pulmonary disease (COPD; 15 men, mean (SD) age 56 (5) years) were studied. 8-isoprostane and IL-6 concentrations were measured by immunoassay., Results: Increased concentrations of 8-isoprostane and IL-6 were found in all subjects after breathing 28% oxygen for 1 hour. In healthy subjects the concentrations of 8-isoprostane and IL-6 were 10.9 (2.9) pg/ml and 4.9 (0.8) pg/ml, respectively, compared with baseline concentrations of 6.1 (1.3) pg/ml and 2.9 (0.6) pg/ml, and in patients with COPD the concentrations were 27.9 (3.1) pg/ml and 8.3 (1.2) pg/ml), respectively, compared with baseline concentrations of 18.9 (3.6) pg/ml and 6.3 (0.6) pg/ml. By contrast, breathing air through the same face mask for 1 hour had no significant effects on 8-isoprostane or IL-6 concentrations in normal subjects or those with COPD., Conclusions: These findings suggest that short term supplementary oxygen may enhance oxidative stress and inflammation in the airways. Whether this happens with long term oxygen therapy needs to be determined.

Exhaled breath analysis may be used to quantify inflammation and oxidative stress in the respiratory tract, in the differential diagnosis of airway diseases, and in the monitoring of therapy. The greatest progress has been made with standardized measurement of exhaled nitric oxide (NO). Bronchial NO is increased in asthma, correlated with other markers of inflammation, and reduced by treatment with corticosteroids and antileukotrienes. Alveolar NO is increased in chronic obstructive pulmonary disease (COPD), reflecting disease severity and progression. Exhaled carbon monoxide and ethane are increased in both asthma and COPD. Increased concentrations of 8-isoprostane, hydrogen peroxide, nitrite, and nitrotyrosine are found in exhaled breath condensate from patients with inflammatory lung diseases. Increased levels of lipid mediators are also found, and the pattern depends on the nature of the disease process. Additional biomarkers are exhaled breath temperature, which is elevated in asthma and reduced in COPD, and bronchial blood flow. It is likely that smaller and more sensitive analyzers will extend the discriminatory value of exhaled breath analysis and that new techniques will become available to diagnose and monitor respiratory diseases in the family practice and home settings.

Background: Chronic obstructive pulmonary disease (COPD) is characterised by chronic inflammation of the respiratory tract., Methods: We investigated the presence of interleukin-6 (IL-6: a cytokine secreted by monocytes/macrophages, T cells, B cells, fibroblasts, bone marrow stromal cells, keratinocytes and endothelial cells) in the exhaled breath condensate of 16 exsmokers with moderate COPD, 12 healthy non-smokers. IL-6 was measured by means of a specific enzyme immunoassay., Results: IL-6 levels were detectable in all of the subjects, but were higher in the COPD patients (8.0 +/- 0.1 pg/ml; P < 0.0001) than in the healthy non-smokers (4.9 +/- 0.2 pg/ml) with a correlation in this group between age and IL-6 levels (r = 0.597; P < 0.05)., Conclusions: The increased IL-6 levels in exhaled breath condensate may reflect airway inflammation in patients with COPD.

Background: The role of eicosanoids, including leukotrienes (LTs) and prostaglandins (PGs), in chronic obstructive pulmonary disease (COPD) is uncertain. The aim of this study was to investigate whether eicosanoids are measurable in exhaled breath condensate (EBC), a non-invasive method of collecting airway secretions, in patients with stable mild to moderate COPD, and to show possible differences in their concentrations compared with control subjects., Methods: LTB(4), LTE(4), PGE(2), PGD(2)-methoxime, PGF(2alpha), and thromboxane B(2) (TxB(2)) were measured in EBC in 15 healthy ex-smokers, 20 steroid naïve patients with COPD who were ex-smokers, and in 25 patients with COPD who were ex-smokers and who were treated with inhaled corticosteroids. The study was of cross sectional design and all subjects were matched for age and smoking habit., Results: LTB(4) and PGE(2) concentrations were increased in steroid naïve (LTB(4): median 100.6 (range 73.5-145.0) pg/ml, p<0.001; PGE(2): 98.0 (range 57.0-128.4) pg/ml, p<0.001) and steroid treated patients with COPD (LTB(4): 99.0 (range 57.9-170.5) pg/ml, p<0.001; PGE(2): 93.6 (range 52.8-157.0) pg/ml, p<0.001) compared with control subjects (LTB(4): 38.1 (range 31.2-53.6) pg/ml; PGE(2): 44.3 (range 30.2-52.1) pg/ml). Both groups of patients had similar concentrations of exhaled LTB(4) (p=0.43) and PGE(2) (p=0.59). When measurable, LTE(4) and PGD(2)-methoxime concentrations were similar in COPD patients and controls, whereas PGF(2alpha) concentrations were increased in the former. TxB(2)-LI was undetectable in any of the subjects., Conclusions: There is a selective increase in exhaled LTB(4) and PGE(2) in patients with COPD which may be relatively resistant to inhaled corticosteroid therapy.

Background: Exacerbations are an important feature of chronic obstructive pulmonary disease (COPD), accounting for a large proportion of health care costs. They are associated with increased airway inflammation and oxidative stress., Methods: Concentrations of leukotriene B4 (LTB4), a marker of inflammation, and 8-isoprostane, a marker of oxidative stress, were measured in the exhaled breath condensate of 21 patients (11 M) with COPD during an exacerbation and 2 weeks after treatment with antibiotics. In 12 patients who had no further exacerbations these markers were also measured after 2 months., Results: LTB4 concentrations were raised during the COPD exacerbation (mean (SE) 15.8 (1.1) pg/ml and fell after treatment with antibiotics to 9.9 (0.9) pg/ml (p<0.0001). In 12 patients the level of LTB4 fell further from 10.6 (1.1) pg/ml to 8.5 (0.8) pg/ml (p<0.005) after 2 months. In 12 normal age matched subjects the LTB4 levels were 7.7 (0.5) pg/ml. Concentrations of 8-isoprostane were also increased during the exacerbation (13.0 (0.9) pg/ml) and fell after antibiotic treatment to 9.0 (0.6) pg/ml (p<0.0001). In 12 patients there was a further fall from 9.3 (0.7) pg/ml to 6.0 (0.7) pg/ml (p<0.001) after 2 months compared with normal subjects (6.2 (0.4) pg/ml)., Conclusions: Non-invasive markers of inflammation and oxidative stress are increased during an infective exacerbation of COPD and only slowly recover after treatment with antibiotics.

Nitric oxide (NO), a simple free-radical gas, elicits a diverse range of physiologic and pathophysiologic effects, and plays an important role in pulmonary diseases. Nitrosative stress and nitration of proteins in airway epithelium may be responsible for steroid resistance in asthma and their ineffectiveness in chronic obstructive pulmonary disease (COPD), supporting the potential role of future therapeutic strategies aimed at regulating NO synthesis in asthma and COPD. In this article, we review the potential role of NO modulators (NO synthase inhibitors and NO donors), which, if given on a regular basis, may have clinical benefit in asthma and COPD.

In chronic obstructive pulmonary disease (COPD) there is decreased vascularity of the bronchi and inflammation of the airways that may have opposite effects on the regulation of heat loss. Exhaled air temperature increase (delta(e) T) was measured in 23 patients with moderate COPD (18 male, mean age +/- SEM 70 +/- 1 yrs; forced expiratory volume in one second (FEV1) 45 +/- 3%, FEV1/forced vital capacity 54 +/- 4%) and 16 normal volunteers (64 +/- 4 yr) and compared to exhaled nitric oxide (eNO) and inflammatory cells in induced sputum as a marker of airway inflammation. Delta(e) T was measured during a flow- and pressure-controlled single exhalation with a fast-response thermometer. delta(e) T was reduced in patients with COPD (1.86 +/- 0.15 delta C x s(-1)) compared to normal subjects (4.00 +/- 0.26 delta C x s(-1)). There was no difference in delta(e) T between patients treated with inhaled steroids and those who were steroid naïve. Delta(e) T was correlated with eNO (r=0.60) but not with sputum neutrophilia. In COPD patients, delta(e) T was increased (2.26 +/- 0.16 delta C x s(-1)) after the inhalation of 200 microg of albuterol, which is a known vasodilator, indicating that delta(e) T and bronchial blood flow may be correlated. Exhaled temperature increase is reduced in chronic obstructive pulmonary disease patients and is increased by the inhalation of vasodilators and therefore may be related to changes of bronchial blood flow and tissue remodelling.

Chronic inflammation is a critical feature of chronic obstructive pulmonary disease, cystic fibrosis, and asthma. This inflammation is associated with the increased production of reactive oxygen species or oxidative stress in the lungs. Oxidative stress may have several adverse effects and may amplify the inflammatory process; however, monitoring oxidative stress is difficult and may not be reflected by changes in blood markers. We have therefore developed several noninvasive markers in the exhaled breath that may indicate oxidative stress in the lungs, and we studied these in relationship to the severity of chronic inflammatory lung diseases. We analyzed the exhaled breath for the content of nitric oxide as a marker of inflammation, carbon monoxide as a marker of oxidative stress, and ethane, which is one of the end products of lipid peroxidation. In addition, we measured the concentration of markers of oxidative stress such as isoprostanes in exhaled breath condensate. Our results confirm that there are increased inflammation, oxidative stress, and lipid peroxidation in lung disease, as shown by elevated levels of nitric oxide, carbon monoxide, and ethane, respectively. The finding of lower levels of these gases in patients on steroid treatment and of higher levels in those with more severe lung disease, as assessed by lung function tests and clinical symptoms, reinforces the hypothesis that the noninvasive measurement of exhaled gases maybe useful in monitoring the underlying pathologic pathways of lung disease. Longitudinal studies are required to assess the clinical usefulness of these measurements in the monitoring of chronic inflammatory lung disease.