Different Relationships between FENO and COPD Characteristics in Smokers and Ex-Smokers.

Exhaled nitric oxide (FENO) is a marker of type-2 inflammation in asthma and is used in its management. However, smokers and ex-smokers have lower FENO values, and the clinical use of FENO values in COPD patients is unclear. Therefore, we investigated if FENO had a relationship to different COPD characteristics in smoking and ex-smoking subjects. Patients with COPD (n = 533, 58% females) were investigated while in stable condition. Measurements of FENO50, blood cell counts, IgE sensitisation and lung function were performed. Medication reconciliation was used to establish medication usage. Smokers (n = 150) had lower FENO50 9 (8, 10) ppb (geometric mean, 95% confidence interval) than ex-smokers did (n = 383) 15 (14, 16) ppb, p < 0.001. FENO50 was not associated with blood eosinophil or neutrophil levels in smokers, but in ex-smokers significant associations were found (r = 0.23, p < 0.001) and (r = -0.18, p = 0.001), respectively. Lower FENO values were associated with lower FEV1% predicted in both smokers (r = 0.17, p = 0.040) and ex-smokers (r = 0.20, p < 0.001). Neither the smokers nor ex-smokers with reported asthma or IgE sensitisation were linked to an increase in FENO50. Ex-smokers treated with inhaled corticosteroids (ICS) had lower FENO50 14 (13, 15) ppb than non-treated ex-smokers 17 (15, 19) ppb, p = 0.024. This was not found in smokers (p = 0.325). FENO is associated with eosinophil inflammation and the use of ICS in ex-smoking COPD subjects, but not in smoking subjects suggesting that the value of FENO as an inflammatory marker is more limited in smoking subjects. The association found between low FENO values and low lung function requires further investigation.

Allergen extract vs. component sensitization and airway inflammation, responsiveness and new-onset respiratory disease.

BACKGROUND: The absence of IgE sensitization to allergen components in the presence of sensitization to the corresponding extract has been reported, but its clinical importance has not been studied. OBJECTIVE: To evaluate the clinical significance of IgE sensitization to three aeroallergen extracts and the corresponding components in relation to the development of respiratory disease. METHODS: A total of 467 adults participated in the European Community Respiratory Health Survey (ECRHS) II and 302 in ECRHS III, 12 years later. IgE sensitization to allergen extract and components, exhaled nitric oxide (FeNO) and bronchial responsiveness to methacholine were measured in ECRHS II. Rhinitis and asthma symptoms were questionnaire-assessed in both ECRHS II and III. RESULTS: A good overall correlation was found between IgE sensitization to extract and components for cat (r = 0.83), timothy (r = 0.96) and birch (r = 0.95). However, a substantial proportion of subjects tested IgE positive for cat and timothy allergen extracts but negative for the corresponding components (48% and 21%, respectively). Subjects sensitized to both cat extract and components had higher FeNO (P = 0.008) and more bronchial responsiveness (P = 0.002) than subjects sensitized only to the extract. Further, subjects sensitized to cat components were more likely to develop asthma (P = 0.005) and rhinitis (P = 0.007) than subjects sensitized only to cat extract. CONCLUSION: Measurement of IgE sensitization to cat allergen components would seem to have a higher clinical value than extract-based measurement, as it related better to airway inflammation and responsiveness and had a higher prognostic value for the development of asthma and rhinitis over a 12-year period.

Both allergic and nonallergic asthma are associated with increased FE(NO) levels, but only in never-smokers.

BACKGROUND: Allergic asthma is consistently associated with increased FE(NO) levels whereas divergence exists regarding the use of exhaled nitric oxide (NO) as marker of inflammation in nonallergic asthma and in asthmatic smokers. The aim of this study is to analyze the effect of having allergic or nonallergic asthma on exhaled nitric oxide levels, with special regard to smoking history. METHODS: Exhaled NO measurements were performed in 695 subjects from Turin (Italy), Gothenburg and Uppsala (both Sweden). Current asthma was defined as self-reported physician-diagnosed asthma with at least one asthma symptom or attack recorded during the last year. Allergic status was defined by using measurements of specific immunoglobulin E (IgE). Smoking history was questionnaire-assessed. RESULTS: Allergic asthma was associated with 91 (60, 128) % [mean (95% CI)] increase of FE(NO) while no significant association was found for nonallergic asthma [6 (-17, 35) %] in univariate analysis, when compared to nonatopic healthy subjects. In a multivariate analysis for never-smokers, subjects with allergic asthma had 77 (27, 145) % higher FE(NO) levels than atopic healthy subjects while subjects with nonallergic asthma had 97 (46, 166) % higher FE(NO) levels than nonatopic healthy subjects. No significant asthma-related FE(NO) increases were noted for ex- and current smokers in multivariate analysis. CONCLUSIONS: Both allergic and nonallergic asthma are related to increased FE(NO) levels, but only in never-smoking subjects. The limited value of FE(NO) to detect subjects with asthma among ex- and current smokers suggests the predominance of a noneosinophilic inflammatory phenotype of asthma among ever-smokers.

Effects of growth and aging on the reference values of pulmonary nitric oxide dynamics in healthy subjects.

The lung just like all other organs is affected by age. The lung matures by the age of 20 and age-related changes start around middle age, at 40-50 years. Exhaled nitric oxide (FENO) has been shown to be age, height and gender dependent. We hypothesize that the nitric oxide (NO) parameters alveolar NO (CANO), airway flux (JawNO), airway diffusing capacity (DawNO) and airway wall content (CawNO) will also demonstrate this dependence. Data from healthy subjects were gathered by the current authors from their earlier publications in which healthy individuals were included as control subjects. Healthy subjects (n = 433) ranged in age from 7 to 78 years. Age-stratified reference values of the NO parameters were significantly different. Gender differences were only observed in the 20-49 age group. The results from the multiple regression models in subjects older than 20 years revealed that age, height and gender interaction together explained 6% of variation in FENO at 50 ml s-1 (FENO50), 4% in JawNO, 16% in CawNO, 8% in DawNO and 12% in CANO. In conclusion, in this study we have generated reference values for NO parameters from an extended NO analysis of healthy subjects. This is important in order to be able to use these parameters in clinical practice.

Extended nitric oxide analysis may improve personalized anti-inflammatory treatment in asthmatic children with intermediate F(E)NO50.

Exhaled nitric oxide (F(E)NO) is elevated in asthma, and a clinical practice guideline has been published with recommendations for anti-inflammatory treatment. It summarizes that a F(E)NO at an expiratory flow rate of 50 ml s(-1) (F(E)NO50) above 35 ppb in children indicates eosinophilic inflammation, and the most likely response is to use inhaled corticosteroids. Intermediate F(E)NO50 between 20-35 ppb should be interpreted cautiously. The aim of the study was to investigate this guideline in a small group of asthmatic children. Thirty-seven asthmatic children; 23 boys and 14 girls, visited the outpatient clinic, and provided exhaled breath samples for offline NO measurement. These samples were analysed with chemiluminescence techniques. Three flow rates, namely 16, 90 and 230 ml s(-1) were used for the extended NO analysis (Högman-Meriläinen algorithm, HMA) to estimate the alveolar concentration (C(A)NO), diffusion rate of the airway wall (D(aw)NO) and airway wall content (C(aw)NO). For accuracy of the HMA, the estimated value of F(E)NO at 50 ml s(-1) (F(E)NO50) was compared with measured F(E)NO50. In nine children the difference was more than 5 ppb and the data were therefore excluded. Five children with F(E)NO50 <20 ppb had no known allergy and their F(E)NO50 geometrical mean (25th; 75th percentile) was 11 (10;14) and CawNO was 32 (20;43) ppb. Ten children with F(E)NO50 > 35 ppb had an allergy and had F(E)NO50 of 56 (47;60) ppb and C(aw)NO of 140 (121;172) ppb. Thirteen children with allergies, with intermediate F(E)NO50, had F(E)NO50 of 27 (25;30) ppb with a wide range of C(aw)NO. In five of these children, values were comparable to healthy children, 44 (43;50) ppb while eight children had elevated C(aw)NO values of 108 (95;129) ppb. Our data indicate the clinical potential use of extended NO analysis to determine the personal target value of F(E)NO50 for monitoring the treatment outcome. Furthermore, for children with intermediate F(E)NO50 more than half of them could possibly benefit from an adjustment of inhaled corticosteroids if the C(aw)NO value was considered.

Hyperosmolarity reduces the relaxing potency of nitric oxide donors in guinea-pig trachea.

1. Non-responders to inhaled nitric oxide treatment have been observed in various patient groups. The bronchodilatory effect of inhaled nitric oxide was attenuated when the airway lumen was rendered hyperosmolar in an in vivo study on rabbits. We used a guinea-pig tracheal perfusion model to investigate the effects of increased osmolarity (450 mOsm, NaCl added) on the relaxing potency of the nitric oxide donors sodium nitroprusside (SNP) and (+/-)-S-nitroso-N-acetylpenicillamine (SNAP). 2. Under iso-osmolar conditions SNP relaxed the carbachol (CCh, 1 microM) contracted trachea by 83+/-3%. After pretreatment with intraluminal hyperosmolarity SNP relaxed the CCh-contracted trachea by only 31+/-7% (P<0.05). When the trachea was contracted to the same extent under untreated and hyperosmolar conditions, the untreated trachea was completely relaxed by SNP but, after hyperosmolar pretreatment, SNP could no longer relax the trachea. 3. SNAP relaxed the CCh contracted trachea by 27+/-5%. After pretreatment with intraluminal hyperosmolarity, SNAP relaxed the trachea by 11+/-4%, which was less than in the iso-osmolar control (P<0.05). 4. Extraluminal hyperosmolarity did not affect carbachol elicited contraction, and SNP administered externally during extraluminal hyperosmolarity was able to relax the trachea (P<0.05). 5. The cell permeable guanosine 3'5'-cyclic monophosphate analogue 8-Br-cGMP relaxed the CCh contracted trachea in both iso-osmolar (P<0.05) and hyperosmolar conditions (P<0.05). 6. The relaxant effect of nitric oxide donors on tracheal smooth muscle is markedly reduced when the airway epithelium is exposed to hyperosmolar solution.

Theoretical and experimental comparison of constant inspired concentration and pulsed delivery in NO therapy.

OBJECTIVE: Inhaled NO therapy of artificially ventilated patients has been established as being based on constant inspired concentration of NO. In this study a new volumetrically controlled pulsed NO delivery mode is compared with the established concentration-based concept. DESIGN: To evaluate the relationship between NO delivery parameters, alveolar NO fraction, and patient uptake, a mathematical lung model was created where NO delivery can be simulated in varying ventilator settings, delivery modes, and lung properties. This model and the efficacy of pulsed delivery in inducing pulmonary capillary vasodilatation were examined experimentally. SETTING: Animal laboratory, Department of Medical Sciences, Clinical Physiology. SUBJECTS: The experimental study was performed with nine pigs of mixed breed weighing 25-35 kg. INTERVENTIONS: The pigs were anaesthetised and artificially ventilated. Pulmonary vasoconstriction was induced by hypoxia. NO was delivered periodically in the various delivery modes. MEASUREMENTS AND RESULTS: In simulation, in all delivery modes the NO uptake was found to be dependent on the ventilator settings and the volume of the dead space. Measured from pulmonary artery pressure, the pulsed delivery was as effective in reducing the induced pulmonary vasoconstriction as the constant inspired concentration delivery. The amount of NO that could reduce the vasoconstriction back to baseline was 105 nmol x min(-1). By delivering in the early part of the inspiration, ambient contamination by the exhaust gas is avoided. The expired NO values obtained in the simulation and the experiments were equal. Based on the simulation, the alveolar NO fraction and the NO uptake depend on the ventilator settings and the dead space in both volumetric- and concentration-based delivery. CONCLUSIONS: With pulsed delivery, a therapeutic effect comparable to constant inspired concentration delivery is achieved, NO gas is used more effectively, and environmental exhausts are reduced. The theoretical model shows that the NO delivery does not predict alveolar NO fraction and the NO uptake. However, it still remains an open question if the online measurement of these parameters would provide useful information, having added value in predicting and controlling the efficacy of the NO treatment.

Assessment of respiratory system mechanics by artificial neural networks: an exploratory study.

We evaluated 1) the performance of an artificial neural network (ANN)-based technology in assessing the respiratory system resistance (Rrs) and compliance (Crs) in a porcine model of acute lung injury and 2) the possibility of using, for ANN training, signals coming from an electrical analog (EA) of the lung. Two differently experienced ANNs were compared. One ANN (ANN(BIO)) was trained on tracings recorded at different time points after the administration of oleic acid in 10 anesthetized and paralyzed pigs during constant-flow mechanical ventilation. A second ANN (ANN(MOD)) was trained on EA simulations. Both ANNs were evaluated prospectively on data coming from four different pigs. Linear regression between ANN output and manually computed mechanics showed a regression coefficient (R) of 0.98 for both ANNs in assessing Crs. On Rrs, ANN(BIO) showed a performance expressed by R = 0.40 and ANN(MOD) by R = 0.61. These results suggest that ANNs can learn to assess the respiratory system mechanics during mechanical ventilation but that the assessment of resistance and compliance by ANNs may require different approaches.

Hyperosmolarity-induced relaxation and prostaglandin release in guinea pig trachea in vitro.

In this study, a tracheal perfusion apparatus was used to investigate the nature of the relaxing factor released by hyperosmolarity on the epithelial side of guinea pig trachea. NaCl induced concentration-dependent relaxation. This relaxation was not affected when the trachea was preincubated with a vasoactive intestinal peptide (VIP) receptor antagonist or with the nitric oxide synthesis inhibitor N(G)-monomethyl-L-arginine (L-NMMA). When the prostaglandin synthesis was prevented by preincubation with the phospholipase A(2)-inhibitor quinacrine, or the cyclooxygenase inhibitor indomethacin, the maximal relaxation induced by NaCl was suppressed by 50% (P<0.05). Moreover, the prostaglandin E(2) concentration was four times higher (P<0.05) in the organ bath during the relaxations, whereas the nitric oxide concentration remained unchanged. In conclusion, increased osmolarity on the airway surface leads to the release of prostaglandins, which are involved in part in the hyperosmolarity-induced relaxation of airway smooth muscle. This might be relevant for asthmatic patients since prostaglandin may modulate the bronchoconstrictive response to hyperosmolar stimuli and exercise.

Exhaled nitric oxide partitioned into alveolar, lower airways and nasal contributions.

During the last year exhaled nitric oxide (NO) has been proposed as a marker of airway inflammation. More knowledge of the production and transfer of this molecule are needed in order for NO analysis to become a clinical tool. This was the aim of the study. Exhaled NO values from multiple flow rates were used to model alveolar NO, transfer rate and tissue concentration of NO in the airways. Three flows rates, 0.005, 0.1 and 0.51 sec(-1) were found to be optimal. The NO transfer rate of the airways was 9 +/- 2 ml sec(-1), the tissue source was 75 +/- 28 ppb and the alveolar fraction of NO was 2 +/- 1 ppb in 10 healthy subjects (mean +/- CI95%). In conclusion, we have shown that it is possible to get more information about the distribution of NO in the lungs and the airways than only a single value from one expiratory flow rate can give. Further studies will reveal if this airway modelling can be useful in disease of the respiratory system.

Exhaled nitric oxide and its relationship to airway responsiveness and atopy in asthma. BHR-Study Group.

Exhaled nitric oxide (NO) has attracted increasing interest as a non-invasive marker of airway inflammation. The purpose of this study was to determine whether exhaled nitric oxide in subjects with asthma varied according to their atopic status and to examine its correlation with airway hyperresponsiveness and lung function measurements. Forty patients with asthma and 13 controls participated in the study. Nitric oxide was measured on three occasions with intervals of at least 3 days, using a chemiluminescence method. Airway responsiveness was assessed with methacholine challenge and lung function measurements were made. All subjects recorded peak expiratory flow and kept a symptom diary during a 17-day period. There was no significant difference in lung function measurements, peak expiratory flow or symptom score between the two asthma groups. Atopic patients with asthma had a significantly higher mean amount of exhaled NO than non-atopic subjects with asthma (162 +/- 68 vs. 113 +/- 55 nl min-1; P = 0.03) and the control group (88 +/- 52 nl min-1; P = 0.004). No significant difference was found in the amount of exhaled NO between non-atopic patients with asthma and the controls. In atopic subjects with asthma the mean exhaled NO was significantly correlated to the dose-response slope for methacholine (r = -0.52; P = 0.02), while no such correlation was found in the non-atopic group. In conclusion; in this study, atopic subjects with asthma had higher levels of exhaled NO than non-atopic subjects. Atopic status should be taken into account when measuring levels of exhaled NO in subjects with asthma.

Extended NO analysis applied to patients with COPD, allergic asthma and allergic rhinitis.

The recommended method to measure exhaled nitric oxide (NO) cannot reveal the source of NO production. We applied a model based on the classical Fick's first law of diffusion to partition NO in the lungs. The aim was to develop a simple and robust solution algorithm with a data quality control feature, and apply it to patients with known alterations in exhaled NO. Subjects with allergic rhinitis, allergic asthma, chronic obstructive pulmonary disease (COPD) smokers and controls were investigated. NO was measured at three expiratory flow rates. An iteration method was developed to partition NO. The airway tissue content of NO was increased in asthma, 144 +/- 80 ppb (P = 0.04) and decreased in smokers, 56 +/- 36 ppb (P = 0.02). There was no difference between subjects with rhinitis, 98 +/- 40 ppb and controls, 98 +/- 44 ppb. The airway transfer rate was increased in allergic asthma and allergic rhinitis, 12 +/- 4 vs. 12 +/- 5 ml sec(-1), compared to controls, 8 +/- 2 ml sec(-1) (P < 0.001). The alveolar levels were no different from controls, 2 +/- 1 ppb. In COPD the alveolar levels were increased, 4 +/- 2 ppb (P < 0.001). Extended NO analysis reveals from where in the respiratory system NO is generated. Hence, this new test can be added to the tools the physician has for the diagnosis and treatment of patients with respiratory disorders.

Nebulisation of hypertonic saline causes oedema of the airway wall.

The effect of aerosol challenge with distilled water, and with isotonic and hypertonic saline on the respiratory system of the anaesthetized rabbit was investigated. Nebulisation of hypertonic (3.6%) saline caused an increase in the extravascular lung water without altering the total body weight. Morphometrical investigations revealed an increase of the subepithelial tissue compartment (connective tissue and smooth muscle) of the airway wall. X-ray microanalysis showed higher content of Na, K, and Cl in this compartment already 10 min after nebulisation of hypertonic saline. The formation of oedema was associated with a significant decrease in both compliance and gas exchange.

A practical approach to the theoretical models to calculate NO parameters of the respiratory system.

Expired nitric oxide (NO) is used as a biomarker in different respiratory diseases. The recommended flow rate of 50 mL s⁻¹ (F(E)NO0.05) does not reveal from where in the lung NO production originated. Theoretical models of NO transfer from the respiratory system, linear or nonlinear approaches, have therefore been developed and applied. These models can estimate NO from distal lung (alveolar NO) and airways (bronchial flux). The aim of this study was to show the limitation in exhaled flow rate for the theoretical models of NO production in the respiratory system, linear and nonlinear models. Subjects (n = 32) exhaled at eight different flow rates between 10-350 mL s⁻¹ for the theoretical protocols. Additional subjects (n = 32) exhaled at tree flow rates (20, 100 and 350 mL s⁻¹) for the clinical protocol. When alveolar NO is calculated using high flow rates with the linear model, correction for axial back diffusion becomes negligible, -0.04 ppb and bronchial flux enhanced by 1.27. With Högman and Meriläinen algorithm (nonlinear model) the corrections factors can be understood to be embedded, and the flow rates to be used are ≤20, 100 and ≥350 mL s⁻¹. Applying these flow rates in a clinical setting any F(E)NO can be calculated necessitating fewer exhalations. Hence, measured F(E)NO0.05 12.9 (7.2-18.7) ppb and calculated 12.9 (6.8-18.7) ppb. In conclusion, the only possibility to avoid inconsistencies between research groups is to use the measured NO values as such in modelling, and apply tight quality control to accuracies in both NO concentration and exhaled flow measurements.

Methods of NO detection in exhaled breath.

There is still an unexplored potential for exhaled nitric oxide (NO) in many clinical applications. This study presents an overview of the currently available methods for monitoring NO in exhaled breath and the use of the modelling of NO production and transport in the lung in clinical practice. Three technologies are described, namely chemiluminescence, electrochemical sensing and laser-based detection with their advantages and limitations. Comparisons are made in terms of sensitivity, time response, size, costs and suitability for clinical purposes. The importance of the flow rate for NO sampling is discussed from the perspective of the recent recommendations for standardized procedures for online and offline NO measurement. The measurement of NO at one flow rate, such as 50 ml s(-1), can neither determine the alveolar site/peripheral contribution nor quantify the difference in NO diffusion from the airways walls. The use of NO modelling (linear or non-linear approach) can solve this problem and provide useful information about the source of NO. This is of great value in diagnostic procedures of respiratory diseases and in treatment with anti-inflammatory drugs.

Suffering from meticillin-resistant Staphylococcus aureus: experiences and understandings of colonisation.

The objective was to explore individuals' experiences and understandings of meticillin-resistant Staphylococcus aureus (MRSA) colonisation. Thirteen interviews were performed and processed using content analysis, resulting in the theme 'Invaded, insecure and alone'. The participants experienced fears and limitations in everyday life and expressed a need to protect others from contagion. Moreover, they experienced encounters with, and information from, healthcare workers differently: some were content, whereas others were discontent. The described fears, limitations and inadequate professional-patient relationship generated unacceptable distress for MRSA-colonised persons. Thus, the healthcare sector should assume responsibility for managing MRSA, and healthcare workers must improve their professionalism and information skills, so as to better meet MRSA-colonised persons' needs.

Extended NO analysis in asthma.

The discovery of the flow dependence of exhaled NO made it possible to model NO production in the lung. The linear model provides information about the maximal flux of NO from the airways and the alveolar concentrations of NO. Nonlinear models give additional flow-independent parameters such as airway diffusing capacity and airway wall concentrations of NO. When these models are applied to patients with asthma, a clear-cut increase in NO flux is found, and this is caused by an increase in both airway diffusing capacity and airway wall concentrations of NO. There is no difference in alveolar concentrations of NO compared to healthy subjects, except in severe asthma where an increase has been found. Inhaled corticosteroids are able to reduce the airway wall concentrations but not diffusing capacity or alveolar concentrations. Oral prednisone affects the alveolar concentration, suggesting that in severe asthma there is a systemic component. Steroids distributed by any route do not affect the airway diffusing capacity. Therefore, the airway diffusing capacity should be in focus in testing new drugs or in combination treatment for asthma. Exhaled NO analysis is a promising tool in characterizing asthma in both adults and children. However, there is a strong need to agree on the models and to standardize the flow rates to be used for the modelling in order to perform a systematic and robust analysis of NO production in the lung.

Effect of smoking on exhaled nitric oxide and flow-independent nitric oxide exchange parameters.

It is a well-known fact that smoking is associated with a reduction in exhaled nitric oxide (NO) levels. There is, however, limited knowledge relating to the smoking-induced changes in production or exchange of NO in different compartments of the airways. This study comprised 221 adult subjects from the European Community Respiratory Health Survey II, who were investigated in terms of their exhaled NO, lung function, immunoglobulin E sensitisation and smoking habits. The following parameters were determined using extended NO analysis: airway tissue nitric oxide concentration (Caw,NO), airway transfer factor (or diffusing capacity) for nitric oxide (Daw,NO), alveolar nitric oxide concentration (CA,NO) and fractional exhaled nitric oxide concentration at a flow rate of 50 mL x s(-1) (FeNO,0.05). Maximum total airway nitric oxide flux (J'aw,NO) was calculated from Daw,NO(Caw,NO-CA,NO). Current smokers (n = 35) exhibited lower (geometric mean) FeNO,0.05 (14.0 versus 22.8 ppb), Caw,NO (79.0 ;versus 126 ppb) and J'aw,NO (688 versus 1,153 pL x s(-1)) than never-smokers (n = 111). Ex-smokers (n = 75) were characterised by lower FeNO,0.05 (17.7 versus 22.8 ppb) and Jaw,NO (858 versus 1,153 pL x s(-1)) than never-smokers. These relationships were maintained after adjusting for potential confounders (sex, age, height, immunoglobulin E sensitisation and forced expiratory volume in one second), and, in this analysis, a negative association was found between current smoking and CA,NO. Snus (oral moist snuff) consumption (n = 21) in ex-smokers was associated with an increase in Daw,NO and a reduction in Caw,NO, after adjusting for potential confounders. Passive smoking was associated with a higher CA,NO. Using extended nitric oxide analysis, it was possible to attribute the reduction in exhaled nitric oxide levels seen in ex- and current smokers to a lower total airway nitric oxide flux in ex-smokers and reduced airway and alveolar nitric oxide concentrations in current smokers. The association between snus (oral tobacco) use and reduced nitric oxide concentrations in the airways and increased nitric oxide transfer from the airways warrants further studies.

Gut mucosal granulocyte activation precedes nitric oxide production: studies in coeliac patients challenged with gluten and corn.

BACKGROUND AND AIMS: To elucidate the dynamics of nitric oxide (NO) production induced by rectal gluten challenge and the relation between NO production and mucosal granulocyte activation. SUBJECTS AND METHODS: Release of rectal NO was measured in 13 patients with coeliac disease and in 18 controls before and after rectal wheat gluten challenge. Rectal gas was collected with a rectal balloon using a newly developed instrument/technique, the "mucosal patch technique". The instrument allows simultaneous measurements of concentrations of granulocyte mediators in the rectal mucosa. We measured myeloperoxidase (MPO), eosinophil cationic protein (ECP), and histamine. For comparison, we made similar measurements after corn (maize) gluten challenge. RESULTS: In all coeliac patients rectal NO concentration increased after gluten challenge and reached a peak after 15 hours (mean 9464 (SEM 2393) parts per billion (ppb); range 250-24982). The maximum MPO and ECP increase occurred five hours after challenge. A correlation was found between mucosal MPO and NO production at 15 hours. Six of the patients showed an increase in NO production 15 hours after rectal corn gluten challenge but this was much smaller than after gluten challenge. No increases were seen in the control group after either challenge. CONCLUSION: Mucosal activation of neutrophils and eosinophils precedes pronounced enhancement of mucosal NO production after rectal wheat gluten challenge in patients with coeliac disease. Some of our coeliac patients displayed signs of an inflammatory reaction, as measured by NO and granulocyte markers, after rectal corn gluten challenge.

Pathophysiology of asthma.

Further insight into the inflammatory process of asthma has accumulated during the past few years. New inhalational anaesthetics seem to have a better bronchorelaxant effect, and prophylactic treatment with beta2-agonists and local anaesthetics may also be an alternative. Bronchospasm during anaesthesia appears to be less common now, but persons with asthma should still be considered to be at an increased risk of severe morbidity.