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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. OBJECTIVES: 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. [ABSTRACT FROM AUTHOR]

BACKGROUND: The role of neutrophils in exacerbations of asthma is poorly understood. We examined the effect of withdrawal of inhaled corticosteroids on sputum inflammatory indexes in a double-blind study in patients with moderate, stable asthma. METHODS: Following a 2-week run in period, 24 subjects were randomized to receive either budesonide (400 microg bid) or placebo, and the study was continued for another 10 weeks. RESULTS: Loss of asthma control developed in 8 of 12 patients over the 10-week period of steroid withdrawal, whereas only 1 of 10 patients with budesonide treatment had exacerbations. Those with an exacerbation had increased sputum interleukin (IL)-8 (p < 0.0001) and increased sputum neutrophil numbers (p < 0.0001) compared to those without an exacerbation. The significant elevation in sputum IL-8 and neutrophil counts initially occurred 2 weeks prior to an exacerbation. Sputum neutrophilia correlated positively with changes in IL-8 levels (r(2) = 0.76, p = 0.01). CONCLUSIONS: Rapid withdrawal of inhaled corticosteroids results in an exacerbation of asthma that is preceded by an increase in sputum neutrophils and IL-8 concentrations, in contrast to an increase in eosinophils reported in previous studies in which inhaled steroids are slowly tapered. [ABSTRACT FROM AUTHOR]

Rationale: Airway inflammation is characteristic of asthma. Distal inflammation may be particularly important. Objective: To calculate alveolar nitric oxide (NO) concentration (C(alv)) and bronchial flux NO (J(NO)) in children. Methods: We measured C(alv) and J(NO) from the fractional exhaled NO (FeNO(50)) measured at multiple exhalation flow rates in 132 children (aged 4-18 yr) with known atopic status, medication, and asthma control. Measurements and Main Results: Of participants, 85% (112/132) completed all measurements. In 20 of 112, the result did not fit the linear model. Thus, J(NO) and C(alv) were assessed in 92 (70%) subjects. The median (range) values of asthmatic (n = 52), normal (n = 20), and nonasthmatic atopic (n = 20) children were as follows: FeNO(50): 28.1 (4.3-190), 10.35 (3.3-29), 21.8 (8.7-69) ppb, respectively; J(NO): 1,230 (204-9,236), 480 (196-1,913), 1,225 (486-4,119) pl/s, respectively; C(alv): 2.22 (0.44-6.63), 1.63 (0.44-3), 1.21 (0.03-2.85) ppb, respectively. A reproducibility study in 18 other children gave intraclass correlation coefficients (single measures) of 0.99 (J(NO)) and 0.81 (C(alv)). J(NO) and C(alv) were higher in children with asthma than normal children (p = 0.0004 and p = 0.0002, respectively). Children with poorly controlled asthma (n = 27) had higher FeNO(50) measurements than children with good symptom control (n = 25): C(alv): mean (+/- SD), 3.17 +/- 1.62 versus 2.26 +/- 1.30 ppb, p = 0.03; J(NO): mean (+/- SD), 2,634 +/- 2,255 versus 1,193 +/- 1,294 pl/s, p = 0.007, respectively. Conclusions: Measurement of J(NO) and C(alv) is feasible in 70% of school-age children. FeNO(50) and J(NO) give the same information (r = 0.97, p < 0.0001), C(alv) is higher in asthmatic children than in normal children and is affected by asthma control, but not by atopy. C(alv) may possibly reflect alveolar inflammation in asthma. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

STUDY OBJECTIVES: Extracellular adenosine 5'-triphosphate (ATP) causes neurogenic bronchoconstriction, inflammation, and coughs, and may play a mechanistic role in obstructive airway diseases. The aims of this study were to determine the effects of inhaled ATP on airway function, and to compare these effects with those of adenosine 5'-monophosphate (AMP). DESIGN: Prospective, randomized, double-blind study. SETTING: Clinical research laboratory of a postgraduate teaching hospital. METHODS: The effects of inhaled equimolar doses of ATP and AMP on airway caliber, perception of dyspnea quantified by the Borg score, and other symptoms were determined in 10 nonsmokers (age 41 +/- 3 years) and 10 patients with asthma (age 39 +/- 3 years) [+/- SEM]. RESULTS: None of the healthy nonsmokers responded to ATP or AMP. All the patients with asthma responded to ATP, and 90% responded to AMP. The geometric mean of the provocative dose causing a 20% fall in FEV1 (PD20) of ATP was 48.7 micromol/mL and that of PD20 AMP was 113.5 micromol/mL in responsive asthmatics (p < 0.05). In asthmatic patients, the percentage change in FEV1 caused by ATP was greater than that caused by AMP (deltaFEV1 ATP = 29% vs deltaFEV1 AMP = 22%, p < 0.05). Borg score increased significantly in asthmatics after ATP (from 0.1 to 3.3, p < 0.01) and after AMP (from 0.2 to 2.5, p < 0.01). This increase was also greater after ATP than AMP in asthma (deltaBorg ATP = 3.2 vs deltaBorg AMP = 2.3, p < 0.05). ATP induced cough in 16 subjects (80%), while AMP induced cough in 8 subjects (40%) [p < 0.05]; in addition, more subjects had throat irritation after inhalation of ATP than AMP (p < 0.05). CONCLUSIONS: ATP is a more potent bronchoconstrictor and has greater effects on dyspnea and other symptoms than AMP in asthmatic patients. Therefore, ATP could potentially be used as a bronchoprovocator in the clinical setting. [ABSTRACT FROM AUTHOR]

Study Objectives: The noninvasive assessment and monitoring of airway inflammation could be important in respiratory disease. The pH of exhaled breath condensate (EBC) is a promising marker. Although pH has been measured in the EBC of adults with inflammatory airway diseases, no study has measured this in children.Design: This study aimed to assess whether there is a change in pH in the EBC of children with cystic fibrosis (CF) and asthma, and to try to determine whether pH could be used as a marker of airway inflammation. Furthermore, the relationships among EBC pH, severity of disease, and oxidative stress were studied.Patients and Methods: We studied 20 children with CF (mean [+/- SEM] age, 7 +/- 3 years), 20 children with asthma (mean age, 7 +/- 2 years), and 15 age-matched healthy children (mean age, 7 +/- 2 years). The pH of EBC was measured using a pH meter.Measurements and Results: Lower pH values were observed in the EBC of children with CF and asthma compared to control subjects (mean pH, 7.23 +/- 0.03 and 7.42 +/- 0.01 vs 7.85 +/- 0.02, respectively). Furthermore, relationships among EBC pH, severity of asthma, and the presence of an infective exacerbation of CF was found. There was a negative correlation between exhaled pH and exhaled leukotriene B(4) concentrations (r = -0.5; p < 0.005).Conclusion: We conclude that the measurement of EBC pH may be useful in the evaluation of airway inflammation in children with asthma and CF. [ABSTRACT FROM AUTHOR]

Cardiac surgery using cardiopulmonary by-pass and, to a greater extent, lung resection, causes acute lung injury that is usually subclinical. Analysis of mediators in exhaled breath condensate is a promising means of monitoring inflammation in a variety of airway diseases but the contribution of the airway lining fluid from the lower respiratory tract is uncertain. We compared the analysis of markers of lung injury in exhaled breath condensate and bronchoalveolar lavage in endotracheally intubated patients before and after coronary artery bypass graft surgery with cardiopulmonary bypass and lobectomy. The neutrophil count and leukotriene B4 concentration in bronchoalveolar lavage fluid rose after coronary artery bypass graft surgery (p < 0.05), but there was no significant change in leukotriene B4, hydrogen peroxide, or hydrogen ion concentrations in exhaled breath condensate. By contrast, after lobectomy, the concentration in exhaled breath condensate of leukotriene B4, hydrogen peroxide and hydrogen ions rose significantly (p < 0.05). Exhaled breath condensate is a safe, noninvasive method of sampling the milieu of the distal lung and is sufficiently sensitive to detect markers of inflammation and oxidative stress in patients after lobectomy, but not after the milder insult associated with cardiac surgery. [ABSTRACT FROM AUTHOR]

Study Objectives: To investigate whether nitric oxide (NO) metabolites would be reduced in children affected by primary ciliary dyskinesia (PCD).Design: Single-center observational study.Patients: Fifteen children with PCD (seven boys; mean [+/- SEM] age, 10.3 +/- 0.7 years; mean FEV(1), 73 +/- 2.1% predicted) were recruited along with 14 healthy age-matched subjects (seven boys; mean age, 11.5 +/- 0.4 years; mean FEV(1), 103 +/- 5% predicted).Interventions: We assessed the levels of nitrite (NO(2)(-)), NO(2)(-)/NO(3)(-) (NO(2)(-)/NO(3)(-)), and S-nitrosothiol in exhaled breath condensate, exhaled NO, and nasal NO from children with PCD compared to those in healthy children.Measurements and Results: The mean exhaled and nasal NO levels were markedly decreased in children with PCD compared to those without PCD (3.2 +/- 0.2 vs 8.5 +/- 0.9 parts per billion [ppb], respectively [p < 0.0001]; 59.6 +/- 12.2 vs 505.5 +/- 66.8 ppb, respectively [p < 0.001]). Despite the lower levels of exhaled NO in children with PCD, no differences were found in the mean levels of NO(2)(-) (2.9 +/- 0.4 vs 3.5 +/- 0.3 microM, respectively), NO(2)(-)/NO(3)(-) (35.2 +/- 5.0 vs 34.3 +/- 4.5 microM, respectively), or S-nitrosothiol (1.0 +/- 0.2 vs 0.6 +/- 0.1 microM, respectively) between children with PCD and healthy subjects.Conclusion: These findings suggest that NO synthase activity may not be decreased as much as might be expected on the basis of low exhaled and nasal NO levels. [ABSTRACT FROM AUTHOR]

Background: Adenosine 5'-triphosphate (ATP) stimulates pulmonary vagal slow conducting C-fibres and fast conducting Aδ-fibres with rapidly adapting receptors (RARs). Pulmonary C-fibres but not RARs are also sensitive to capsaicin, a potent tussigenic agent in humans. Thus, the aim of this study was to determine the effects of ATP and its metabolite adenosine (given as adenosine 5'-monophosphate, AMP) on capsaicin challenge in asthmatic patients., Methods: Cough (quantified as visual analogue scale, VAS), dyspnoea (quantified as Borg score), and FEV 1 were quantified following bronchoprovocation using capsaicin, adenosine and ATP in healthy non-smokers (age 40±4y, 6 males), smokers (45±4y, 5 males) and asthmatic patients (37±3y, 5 males); n = 10 in each group., Results: None of the healthy non-smokers responded to either AMP or ATP. AMP induced bronchoconstriction in one smoker and eight asthmatics, and ATP in two smokers and all ten asthmatics. The geometric mean of capsaicin causing ≥5 coughs (C5) increased from 134 to 203 μM in non-smokers and from 117 to 287 μM in asthmatics after AMP, whereas it decreased from 203 to 165 μM and 125 to 88 μM, respectively after ATP. AMP decreased C5 from 58 to 29 μM and ATP increased from 33 to 47 μM in smokers. However, due to intergroup variability, these effects of ATP and AMP were not statistically significant (0.125 ≤ p ≤ 0.998). That notwithstanding, in healthy and asthmatic subjects the effects of the ATP showed a tendency to be greater than those of AMP (p < 0.053). Dyspnea, assessed by Borg score, increased after ATP (p < 0.001) and AMP (p < 0.001) only in asthmatic patients. Intensity of cough assessed by VAS increased (p < 0.05) after second capsaicin challenges performed after AMP in all groups, but not after ATP., Conclusions: Asthmatic patients exhibit hypersensitivity to aerosolized AMP and ATP, but aerosolized AMP does not mimic the effects of ATP and the effects of ATP are not mediated by adenosine., (Copyright © 2017. Published by Elsevier Ltd.)

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 &lt; .001), patients with asthma (r = 0.98, P &lt; .001), patients with COPD (r = 0.93, P &lt; .001), and patients with CF (r = 0.74, P &lt; .05). In all subjects, AUC-NO at an exhalation flow rate of 200 mL/s (AUC-NO200) correlated with Cano (r = 0.69, P &lt; .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: Exhaled breath volatile organic compound (VOC) analysis for airway disease monitoring is promising. However, contrary to nitric oxide the method for exhaled breath collection has not yet been standardized and the effects of expiratory flow and breath-hold have not been sufficiently studied. These manoeuvres may also reveal the origin of exhaled compounds., Methods: 15 healthy volunteers (34 ± 7 years) participated in the study. Subjects inhaled through their nose and exhaled immediately at two different flows (5 L/min and 10 L/min) into methylated polyethylene bags. In addition, the effect of a 20 s breath-hold following inhalation to total lung capacity was studied. The samples were analyzed for ethanol and acetone levels immediately using proton-transfer-reaction mass-spectrometer (PTR-MS, Logan Research, UK)., Results: Ethanol levels were negatively affected by expiratory flow rate (232.70 ± 33.50 ppb vs. 202.30 ± 27.28 ppb at 5 L/min and 10 L/min, respectively, p < 0.05), but remained unchanged following the breath hold (242.50 ± 34.53 vs. 237.90 ± 35.86 ppb, without and with breath hold, respectively, p = 0.11). On the contrary, acetone levels were increased following breath hold (1.50 ± 0.18 ppm) compared to the baseline levels (1.38 ± 0.15 ppm), but were not affected by expiratory flow (1.40 ± 0.14 ppm vs. 1.49 ± 0.14 ppm, 5 L/min vs. 10 L/min, respectively, p = 0.14). The diet had no significant effects on the gasses levels which showed good inter and intra session reproducibility., Conclusions: Exhalation parameters such as expiratory flow and breath-hold may affect VOC levels significantly; therefore standardisation of exhaled VOC measurements is mandatory. Our preliminary results suggest a different origin in the respiratory tract for these two gasses.

Nitric oxide (NO) production and carbon monoxide (CO) production are increased in inflammatory lung diseases. Although there are some pieces of evidence for hormonal modulation by estrogen, little is known about exhaled NO and CO during the ovarian cycle. In 23 subjects, we measured exhaled NO and CO by an online analyzer. Significantly higher levels of exhaled NO were found at the midcycle compared with those in the premenstrual period or during menstruation. Higher levels of CO were after ovulation and reached a peak in the premenstrual phase. The lowest levels of CO were observed in the first days of the estrogen phase. In males, there was no significant variation in exhaled NO and CO. Exhaled NO and CO levels vary during the ovarian cycle in women, and this fact should be taken into account during serial measurements of these markers in the female population.

Background: Hydrogen peroxide (H2O2) is detectable in exhaled breath condensate (EBC) and has been proposed to be a surrogate marker of oxidative stress in the airways. In this study we tested whether the breathing pattern during EBC collection influences the concentration of exhaled H2O2., Methods: EBC was collected during (1) tidal breathing and (2) breathing with increased tidal volume for 10 min from 16 healthy volunteers. On-line H2O2 measurement was performed by the EcoCheck™ biosensor system. Repeated measurements were also conducted to assess intrasubject reproducibility., Results: Minute ventilation, tidal volume, expiratory flow rate were all increased significantly when subjects were asked to perform breathing with increased tidal volume. In parallel, EBC volume increased (1413±59 vs. 1959±71 μL, p<0.001), whereas exhaled H2O2 levels decreased significantly (1400±170 vs. 840±130 nmol/L, p<0.001). H2O2 levels did not correlate with any individual breathing parameters (p>0.05). Assessment of intersubject variability of H2O2 measurements during the two types of breathing revealed a coefficient of variation of 49 and 54%, respectively. The EBC H2O2 measurement was highly reproducible (888±176 vs. 874±156 nmol/L) as tested during normal breathing., Conclusions: These data demonstrate that the concentration of H2O2 in EBC depends on the ventilatory pattern during sample collection that has to be taken into consideration in all EBC H2O2 assays.

Background: Combination therapy with inhaled corticosteroids (ICS) and long-acting β(2)-adrenergic agonists (LABA) is reported to have superior effects on controlling asthma symptoms to ICS alone; however, there is no molecular-based evidence to explain the clinical effects. Here, the effect of the ICS/LABA combination was compared with ICS on glucocorticoid receptor (GR) activation in sputum macrophages., Methods: In a randomised, double-blind cross-over placebo-controlled 6-visit study, 10 patients with mild asthma were given placebo, formoterol (Oxis(®) 12 μg), budesonide (Pulmicort(®) 200 μg :BUD200, or 800 μg :BUD800), or budesonide/formoterol combination (Symbicort(®)) as a single 100/6 μg (SYM100) or double 200/12 μg (SYM200) dose. Sputum macrophages were separated by plate adhesion from induced sputum. GR binding to the glucocorticoid-response elements on oligonucleotides (GR-GRE binding) was evaluated by ELISA. mRNA expression of MAP-kinase phosphatase (MKP)-1 and IL-8 were measured by quantitative RT-PCR., Results: GR-GRE binding was significantly increased after treatment with SYM100 (3.5 OD/10 μg protein, median, p < 0.05) versus placebo (1.3) and BUD200 (1.6), and the induction was higher than that of BUD800 (2.4). MKP-1 mRNA was increased and IL-8 mRNA was significantly inhibited by BUD800, SYM100 and SYM200 versus placebo., Conclusions: The effects of SYM100 and SYM200 on GR activation were not different from that of BUD800 and superior to BUD200. Thus, it has been confirmed at a molecular level that inhaled combination therapy with a lower dose of budesonide has an equivalent effect to a high dose of budesonide alone. In addition, GR-GRE binding is found to be a valuable pharmacodynamic marker for steroid efficacy in clinical studies., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

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.

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: Exhaled NO (FE(NO)) is a useful biomarker for the monitoring of asthma control and response to therapy. However, there is a lack of data on FE(NO) levels and their interpretation in Primary Care asthma population depending on their treatment and smoking habit. Besides, the majority of current FE(NO) tests have been done by stationary chemiluminescence analysers whose use is limited to research laboratories., Methods: FE(NO) measurements by the novel hand-held NO monitoring device (NIOX MINO) were made in 96 asthma patients (32 males, mean age 53+/-12) at five local General Practices during their scheduled 15-20 min visits for lung function assessment., Results: Success rate was 78% and the intra-subject coefficient of variation was 8.7%. Inhaled corticosteroid treatment had an overall reducing effect on the FE(NO) value (30.5 [19.8-49.8]) vs. patients not on the ICS (26.5 [19-94]) (p<0.044). FE(NO) levels in the ICS treated current or ex-smokers group of patients were still significantly above the normal values (p<0.0001). FE(NO) levels were similar in patients receiving ICS whether there were current, ex-smokers or non-smokers. The highest FE(NO) levels (94 [15.8-151]) were found in asthmatic current smokers and not receiving treatment with ICS. The most "normalised" FE(NO) levels (35.3 [13.5-35.3]) were seen in ex-smokers., Conclusions: FE(NO) measurements performed with a new hand-held monitoring device are reproducible and feasible in General Practice in the majority of patients of different ages and asthma severities. A high percentage of patients with different severities of asthma and regardless of their treatment with ICS and current smoking habit (current and/or ex-smokers) had highly elevated FE(NO) values, suggesting that their current therapy was possibly insufficient to control the underlying degree of airway inflammation and asthma symptoms.

Background: Whereas increased airway hyperresponsiveness (AHR) and airway inflammation are well documented in adult elite athletes, it remains uncertain whether the same airway changes are present in adolescents involved in elite sport., Objective: To investigate airway responsiveness and airway inflammation in adolescent elite swimmers., Methods: We performed a cross-sectional study on adolescent elite swimmers (n = 33) and 2 control groups: unselected adolescents (n = 35) and adolescents with asthma (n = 32). The following tests were performed: questionnaire, exhaled nitric oxide (FeNO), spirometry, induced sputum, methacholine challenge, eucapnic voluntary hyperpnea (EVH) test, and exhaled breath condensate pH., Results: There were no differences in FeNO, exhaled breath condensate pH, cellular composition in sputum, or prevalence of AHR to either EVH or methacholine among the 3 groups. When looking at airway responsiveness as a continuous variable, the swimmers were more responsive to EVH than unselected subjects, but less responsive to methacholine compared with subjects with asthma. We found no differences in the prevalence of respiratory symptoms between the swimmers and the unselected adolescents. There was no difference in FeNO, cellular composition of sputum, airway reactivity, or prevalence of having AHR to methacholine and/or EVH between swimmers with and without respiratory symptoms., Conclusion: Adolescent elite swimmers do not have significant signs of airway damage after only a few years of intense training and competition. This leads us to believe that elite swimmers do not have particularly susceptible airways when they take up competitive swimming when young, but that they develop respiratory symptoms, airway inflammation, and AHR during their swimming careers.

Nitric oxide (NO) is produced by a variety of cells within the respiratory tract, particularly airway epithelial cells, and its increased concentration in asthma is likely to derive from inducible NO synthase (iNOS) expressed in inflamed airways. To evaluate whether an increased bronchial flux of NO (ie, airway wall NO flux [Jno] in picoliters per second) produced in the large airways is due to an enzyme overexpression, we administered a relatively selective iNOS inhibitor, aminoguanidine, by nebulization in a double-blind, placebo-controlled manner in asthmatic and healthy subjects and also investigated whether the same concentration of inhibitor has any effect on NO produced in the peripheral lungs (ie, alveolar NO concentration [Calv] in parts per billion [ppb]) or on the diffusing capacity of NO (Dno) [in picoliters per second(-1) per ppb(-1)) in the airways. Aminoguanidine administration resulted in a significant reduction in Jno compared with administration of the saline solution control in eight healthy subjects and in eight patients with asthma but caused no significant changes in Calv or in Dno in either group. No rise in BP, fall in FEV(1), or adverse effects were observed in either group. These results indicate that iNOS from larger airways is the predominant source of elevated large airway-derived NO in patients with asthma, and that exhaled NO from peripheral lungs is not affected by a nebulized iNOS inhibitor and, therefore, is more likely to be derived form constitutive forms of NO synthase.

Background: The majority of asthmatic patients achieve control of their illness; others do not. It is therefore crucial to validate/develop strategies that help the clinician monitor the disease, improving the response to treatment., Methods: We have quantified the inflammation in central and peripheral airways by measuring exhaled nitric oxide (NO) at multiple exhalation flows in 56 asthmatics at different levels of severity (mild, n = 10; moderate stable, n = 17; moderate during exacerbation, n = 11; severe, n = 18, 7 of whom were receiving oral corticosteroids) and 18 healthy control subjects. The reproducibility of the measurement was also assessed., Results: Bronchial NO (Jno) in patients with mild asthma (2,363 +/- 330 pL/s) [mean +/- SD] was higher than in patients with moderate stable asthma (1,300 +/- 59 pL/s, p < 0.0005), in patients with severe asthma receiving inhaled corticosteroids (ICS) [1,015 +/- 67 pL/s, p < 0.0005], and healthy control subjects (721 +/- 22 pL/s, p < 0.0001). There were no differences between Jno in patients with mild asthma compared to patients with severe asthma receiving ICS and oral corticosteroids (2,225 +/- 246 pL/s). Patients with exacerbations showed a higher Jno (3,475 +/- 368.9 pL/s, p < 0.05) compared to the other groups. Alveolar NO was higher in patients with severe asthma receiving oral corticosteroids (3.0 +/- 0.1 parts per billion [ppb], p < 0.0001) than in the other groups but was not significantly higher than in patients with moderate asthma during exacerbation (2.8 +/- 0.3 ppb). No differences were seen in NO diffusion levels between the different asthma groups. All the measurements were highly reproducible and free of day-to-day and diurnal variations., Conclusions: Differential flow analysis of exhaled NO provides additional information about the site of inflammation in asthma and may be useful in assessing the response of peripheral inflammation to therapy.

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.

Air pollution and cigarette smoke are recognized health risks. A method was developed for the measurement of the deposition fraction (DF) of polydisperse particulate matter (PM) in human airways. Ten normal volunteers [three females, age range 18-67 years, mean age (SD) 43.9 (14)] made single breath exhalations after inhalation to total lung capacity. The exhaled breath was diverted to a multichannel laser diffraction chamber where the particulate profiler measured 0.3 - 1.0-microm particles. DF was inversely related to expiration flow-rate, 0.69 (0.02) at 4 l min-1 and 0.5 (0.01) at 13 l min-1, respectively (p<0.05), and was influenced by the inhalation flow-rate [0.70 (0.02) at 3 l min-1 and 0.59 (0.02) at 13 l min-1, respectively (p<0.05)], while no differences were found between nasal and oral inhalation (0.68 (0.05) versus 0.67 (0.06), p>0.05). Higher breath holding times were associated with elevated DF [0.74 (0.02) at 20 s, and 0.62 (0.05) without breath holding (p<0.01)]. When the expiratory flow was controlled and the breath hold time standardized, DF was reproducible (CV = 4.85%). PM can be measured in the exhaled breath and its DF can be quantified using a portable device. These methods may be useful in studies investigating the health effects of air pollution and tobacco smoke.

Background: It has been suggested that cysteinyl leukotrienes (cysLTs) play an important role in airway remodeling. Previous reports have indicated that cysLTs augment human airway smooth muscle cell proliferation. Recently, cysLTs have been measured in exhaled breath condensate (EBC). The aim of this study was to evaluate the relationship between cysLTs in EBC and another marker of airway remodeling, reticular basement membrane (RBM) thickening, in endobronchial biopsies in children., Methods: 29 children, aged 4-15 years, with moderate to severe persistent asthma, who underwent bronchoscopy as part of their clinical assessment, were included. Subjects underwent spirometry and EBC collection for cysLTs analysis, followed by bronchoscopy and endobronchial biopsy within 24 hours., Results: EBC cysLTs were significantly lower in asthmatic children who were treated with montelukast than in those who were not (median (interquartile range) 36.62 (22.60-101.05) versus 249.1 (74.21-526.36) pg/ml, p = 0.004). There was a significant relationship between EBC cysLTs and RBM thickness in the subgroup of children who were not treated with montelukast (n = 13, r = 0.75, p = 0.003)., Conclusion: EBC cysLTs appear to be associated with RBM thickening in asthma.

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: Sputum induction is increasingly used to study both cellular and biochemical composition of the airways. However, there is a significant rise in the percentage of neutrophils at 8 h after inhalation with hypertonic saline., Objective: The aim of this study was to assess whether markers of inflammation in exhaled air and exhaled air condensate change after sputum induction in normal and asthmatic subjects., Methods: We measured leukotriene B(4) (LTB(4)) and a marker of oxidative stress, 8-isoprostane, (by enzyme immunoassay) in exhaled air condensate and exhaled nitric oxide (NO; by chemiluminescence analyzer) in 15 healthy subjects (8 females, mean age 35 +/- 4 years, FEV(1) 97.4% predicted) and in 8 mild asthmatic subjects (5 males, mean age 34 +/- 2 years, FEV(1) 70.5% predicted)., Results: LTB(4) was significantly higher compared with baseline at 6 h but did not remain increased at 24 h after sputum induction (134.3 +/- 30.15 and 75.4 +/- 14.32 vs. 64.6 +/- 11.6 pg/ml at baseline; p < 0.02 and p > 0.05, respectively) in healthy subjects. An inverse correlation between LTB(4) and exhaled NO at 6 h after sputum induction was observed in healthy subjects (r = -0.66, p < 0.03). No increase in LTB(4) levels was observed in asthmatic patients. Baseline 8-isoprostane levels were higher in asthmatic patients than in healthy subjects (47.3 +/- 37.1 vs. 17.5 +/- 8.8 pg/ml; p < 0.01). A trend towards increased levels of 8-isoprostane could be observed at 6 and 24 h after inhalation in healthy subjects (26.2 +/- 3.7 and 26.7 +/- 3.9 pg/ml; p = 0.09 and p = 0.07, respectively). In healthy subjects, exhaled NO was significantly higher compared with baseline at 6 h and remained increased 24 h after sputum induction (7.96 +/- 3.5 vs. 5.61 +/- 1.86 ppb; p < 0.01 and p < 0.05, respectively). Exhaled NO levels were increased in asthmatic patients but did not further increase after sputum induction., Conclusions: Sputum induction with hypertonic saline causes an inflammatory response which should be considered when using the technique to monitor airway inflammation., (Copyright (c) 2005 S. Karger AG, Basel.)

Study Objectives: In some patients with asthma treated with inhaled corticosteroids, suppression of inflammation is incomplete. This may be because the effect of corticosteroids on cysteinyl-leukotriene (cys-LT) biosynthesis is limited. Montelukast is a cys-LT antagonist that significantly improves asthma control in corticosteroid-treated asthmatic patients. However, not all patients treated with cys-LT antagonists show a clinical improvement., Design: We have studied the effect of treatment for 4 weeks with montelukast (10 mg/d) on exhaled cys-LTs and leukotriene B4 (LTB4), exhaled nitric oxide, asthma quality of life (AQL), and respiratory function in patients with stable asthma., Setting: Asthma clinics in general practice., Patients: We studied 50 patients (30 men; mean +/- SEM age, 53 +/- 2 years) who were treated with inhaled corticosteroids., Measurements and Results: We detected cys-LTs in exhaled breath condensate in 25 of 50 patients; however, in the normal nonasthmatic subjects, cys-LTs were below the limit of detection. After treatment with montelukast, there was a fall in cys-LT concentrations from 14.6 +/- 3.3 to 8.5 +/- 2.6 pg/mL after 2 weeks (p > 0.05) and to 3.9 +/- 1.3 pg/mL after 4 weeks (p < 0.01). Exhaled LTB4 levels were also elevated. After treatment with montelukast, LTB4 levels fell from 33.0 +/- 3.9 to 20.4 +/- 2.5 pg/mL after 2 weeks of treatment (p < 0.05), and to 17.0 +/- 2.2 pg/mL after 4 weeks of treatment (p < 0.01). These changes in exhaled cys-LT and LTB4 were associated with significant improvements in AQL scores., Conclusions: It appears that in some patients with stable asthma treated with inhaled corticosteroids, the suppression of inflammation is incomplete. Adding a leukotriene receptor antagonist can provide a complementary effect of controlling inflammation, with a significant improvement in quality of life.

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.

Study Objectives: Airway neutrophil levels are increased in patients with severe asthma and during asthma exacerbations. Long-acting beta2-agonists (LABAs), such as formoterol, reduce the number of asthma exacerbations. While beta2-agonists may affect neutrophil function in vitro, it is uncertain whether they have effects on neutrophilic inflammation in asthmatic patients in vivo., Design: In a double-blind randomized crossover study, we evaluated the effects of 4 weeks of treatment with formoterol (Turbuhaler), 24 microg bid, compared to placebo on sputum neutrophil numbers and interleukin (IL)-8 levels in asthmatic patients. Therapy with budesonide (administered via Turbuhaler), 400 microg bid for 4 weeks, was added at the end as a "gold standard" antiinflammatory effect comparison., Patients: We studied 15 steroid-naïve nonsmoking patients who ranged from 19 to 51 years of age and had mild persistent asthma., Results: Formoterol therapy significantly reduced sputum IL-8 levels and neutrophil numbers compared to placebo. There was a significant correlation between the reduction in sputum IL-8 levels and the number of neutrophils, indicating that formoterol may attenuate neutrophilic airway inflammation by inhibiting IL-8 production., Conclusions: Our data suggest that the LABA formoterol reduces neutrophilic airway inflammation in patients with mild asthma and that this might be beneficial in preventing asthma exacerbations.

Unlabelled: Several nasal nitric oxide (NO) measurement techniques have been described, but there is not a widespread measurement technique for measurement of nasal NO. In this study we evaluated the repeatability of one technique of nasal NO measurements using the nasal application of the NIOX system., Methods: Three nasal NO measurements (NIOX Nitric Oxide Monitoring System, Aerocrine, Sweden) were made on a single occasion in 22 healthy subjects and 27 patients with asthma, aged 5-69 years. Nasal NO was sampled during breath hold from one nostril at a flow rate of 5 ml/s., Results: The repeatability of nasal NO assessed by the coefficient of variation (CV) was 12.5% (95% Confidence interval (CI) 11.0-14.7%) for the total population. Healthy adults had a significantly better repeatability than healthy children (P<0.008). The mean NO level for the total population was 837 ppb. The mean NO levels in children were lower than in the adults (751 and 897 ppb, respectively). The mean breath hold length needed to obtain a steady NO plateau for all subject categories combined was 20.4+/-6.01 s. The average number of attempts needed to obtain three approved NO measurements was 5.4 (range 3-13) for the total population. There were no significant differences between the different subject categories. When using two measurements per session instead of three, the overall CV was 10.5% (95% CI 8.8-13.1%). Most subjects found the measurements easy to perform and all of them would accept to do the examination as a routine., Conclusions: Nasal NO measurements in NIOX may provide a useful reliable clinical tool to assess and monitor upper airways in different diseases, for example PCD and rhinitis, and are acceptable by both healthy and asthmatic adults and children, as a part of their routine visit to a physician.

Background: Exhaled breath condensate (EBC) is a non-invasive method to assess airway inflammation and oxidative stress and may be useful in the assessment of childhood asthma., Methods: Exhaled 8-isoprostane, a stable marker of oxidative stress, was measured in EBC, in children (5-17 years) with asthma (13 steroid-naïve and 12 inhaled steroid-treated) and 11 healthy control., Results: Mean exhaled 8-isoprostane concentration was significantly elevated in steroid-naïve asthmatic children compared to healthy children 9.3 (SEM 1.7) vs. 3.8 (0.6) pg/ml, p < 0.01. Children on inhaled steroids also had significantly higher 8-isoprostane levels than those of normal subjects 6.7 (0.7) vs. 3.8 (0.6) pg/ml, p < 0.01. Steroid-naïve asthmatics had higher exhaled nitric oxide (eNO) than those of controls 28.5 (4.7) vs. 12.6 (1.5) ppb, p < 0.01. eNO in steroid-treated asthmatics was similar to control subjects 27.5(8.8) vs. 12.6(1.5) ppb. Exhaled 8-isoprostane did not correlate with duration of asthma, dose of inhaled steroids or eNO., Conclusion: We conclude that 8-isoprostane is elevated in asthmatic children, indicating increased oxidative stress, and that this does not appear to be normalized by inhaled steroid therapy. This suggests that 8-isoprostane is a useful non-invasive measurement of oxidative stress in children and that antioxidant therapy may be useful in the future.

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.

Nitrosative stress and nitration of proteins in airway epithelium maybe responsible for steroid resistance in asthma and steroid ineffectiveness in chronic obstructive pulmonary disease (COPD), supporting the potential role of future therapeutic strategies aimed at regulating NO synthesis in asthma and COPD (for example, combination treatment with NOS inhibitors and corticosteroids). Here, the potential role of NO modulators (NO synthase inhibitors and NO donors) has been reviewed, which if are given on a regular basis may have clinical benefit in asthma and COPD.

In asthma elevated rates of exhaled breath temperature changes (Deltae degrees T) and bronchial blood flow (Qaw) may be due to increased vascularity of the airway mucosa as a result of inflammation.We investigated the relationship of Deltae degrees T with Qaw and airway inflammation as assessed by exhaled nitric oxide (NO). We also studied the anti-inflammatory and vasoactive effects of inhaled corticosteroid and beta2-agonist.Deltae degrees T was confirmed to be elevated (7.27 +/- 0.6 Delta degrees C/s) in 19 asthmatic subjects (mean age +/- SEM, 40 +/- 6 yr; 6 male, FEV1 74 +/- 6 % predicted) compared to 16 normal volunteers (4.23 +/- 0.41 Delta degrees C/s, p < 0.01) (30 +/- 2 yr) and was significantly increased after salbutamol inhalation in normal subjects (7.8 +/- 0.6 Delta degrees C/ s, p < 0.05) but not in asthmatic patients. Qaw, measured using an acetylene dilution method was also elevated in patients with asthma compared to normal subjects (49.47 +/- 2.06 and 31.56 +/- 1.6 mul/ml/min p < 0.01) and correlated with exhaled NO (r = 0.57, p < 0.05) and Deltae degrees T (r = 0.525, p < 0.05). In asthma patients, Qaw was reduced 30 minutes after the inhalation of budesonide 400 mug (21.0 +/- 2.3 mul/ml/min, p < 0.05) but was not affected by salbutamol.Deltae degrees T correlates with Qaw and exhaled NO in asthmatic patients and therefore may reflect airway inflammation, as confirmed by the rapid response to steroids.

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.