Nitric Oxide In Asthma Research Articles

FMRI BOLD responses to film stimuli and their association with exhaled nitric oxide in asthma and health.

Little is known about central nervous system (CNS) responses to emotional stimuli in asthma. Nitric oxide in exhaled breath (FENO) is elevated in asthma due to allergic immune processes, but endogenous nitric oxide is also known to modulate CNS activity. We measured fMRI blood oxygen-dependent (BOLD) brain activation to negative (blood-injection-injury themes) and neutral films in 31 participants (15 with asthma). Regions-of-interest analysis was performed on key areas relevant to central adaptive control, threat processing, or salience networks, with dorsolateral prefrontal cortex (PFC), anterior insula, dorsal anterior cingulate cortex (dACC), amygdala, ventral striatum, ventral tegmentum, and periaqueductal gray, as well as top-down modulation of emotion, with ventrolateral and ventromedial PFC. Both groups showed less BOLD deactivation from fixation cross-baseline in the left anterior insula and bilateral ventromedial PFC for negative than neutral films, and for an additional number of areas, including the fusiform gyrus, for film versus recovery phases. Less deactivation during films followed by less recovery from deactivation was found in asthma compared to healthy controls. Changes in PCO2 did not explain these findings. FENO was positively related to BOLD activation in general, but more pronounced in healthy controls and more likely in neutral film processing. Thus, asthma is associated with altered processing of film stimuli across brain regions not limited to central adaptive control, threat processing, or salience networks. Higher levels of NO appear to facilitate CNS activity, but only in healthy controls, possibly due to allergy's masking effects on FENO.

Comparison of fractional exhaled nitric oxide in asthmatics with and without allergic rhinitis

Purpose of the study The aim of this study was to measure the concentration of FeNO in asthmatics with and without allergic rhinitis (AR) and to determine usefulness of the test in the assessment of asthma control in the Polish population. The next objective of this study was to estimate the cut-off point of FeNO which might be a good indicator of uncontrolled asthma. Materials and methods The measurements were taken using the Hyp’Air FeNO in 303 adult patients with asthma, AR, comorbid AR and asthma, and non-diseased volunteers. Results FeNO level in healthy adults was similar to the FeNO concentration in AR as well as controlled asthmatic patients without and with AR. Patients with partly controlled and uncontrolled asthma with and without AR had higher FeNO (>60 ppb) levels when compared to adults with controlled disease. The optimal cut-off point of FeNO > 46 ppb and FeNO > 33 ppb was estimated for identification of uncontrolled asthmatics without and with AR, respectively. Conclusion In conclusion, we found a significant correlation between the FeNO concentration and the level of asthma symptom control in asthmatic patients with and without AR.

Inflammatory patterns in fixed airflow obstruction are dependent on the presence of asthma.

Fixed airflow obstruction (FAO) can complicate asthma. Inflammation is a proposed underlying mechanism. Our aim in this cross-sectional investigation was to evaluate the blood leucocyte pattern and level of exhaled nitric oxide in asthmatics and non-asthmatics with or without FAO. A total of 11,579 individuals aged ≥20 years from the US National Health and Nutrition Examination Survey were included. They were grouped as: controls without asthma and FAO (n = 9,935), asthmatics without FAO (n = 674), asthmatics with FAO (n = 180) and non-asthmatics with FAO (n = 790). FAO was defined as post-bronchodilator FEV1/FVC < lower limit of normal. Exhaled nitric oxide ≥ 25ppb, blood eosinophil levels ≥300 cells/μL, and blood neutrophil levels ≥5100 cells/μL were defined as elevated. Stratified analyses for smoking and smoking history were performed. Elevated blood eosinophil levels were more common in all groups compared to the controls, with the highest prevalence in the group with asthma and fixed airflow obstruction (p<0.01). In a multiple logistic regression model adjusted for potential confounders including smoking, the asthma groups had significantly higher odds ratios for elevated B-Eos levels compared to the control group (odds ratio 1.4, (confidence interval: 1.1-1.7) for the asthma group without fixed airflow obstruction and 2.5 (1.4-4.2) for the asthma group with fixed airflow obstruction). The group with fixed airflow obstruction without asthma had higher odds ratio for elevated blood neutrophil levels compared to the controls: 1.4 (1.1-1.8). Smoking and a history of smoking were associated to elevated B-Neu levels. Fixed airflow obstruction in asthma was associated with elevated blood eosinophil levels, whereas fixed airflow obstruction without asthma was associated with elevated blood neutrophil levels.

A suitable protocol for measuring alveolar nitric oxide in asthma with differing severity to assess peripheral airways inflammation

Objective: Extended nitric oxide (NO) analysis offers the partitioned monitoring of inflammation in central and peripheral airways. Different mathematical models are used to estimate pulmonary NO dynamics in asthma with variable results and limitations. We aimed to establish a protocol for extended NO analysis in patients with differing asthma severity. Methods: Forty patients with stable asthma and 25 matched control subjects were recruited. Exhaled NO was measured at constant flow rates between 10 and 300 mL/s. Twelve controls performed NO measurements weekly for 4 weeks. Results: The proportions of patients with technically acceptable measurements at 10–30–50–100–150–200–250–300 mL/s exhalation flow rates were 8–58–100–98–98–95–90–80%, respectively. Alveolar NO (CANO) and total flux of NO in the conducting airways (JawNO) were calculated with the linear method from NO values measured at 100–150–200–250 mL/s exhalation flows. The mean intrasubject bias for JawNO and CANO in controls was 0.16 nL/s and 0.85 ppb, respectively. Both JawNO (1.31/0.83–2.97/vs. 0.70/0.54–0.87/nL/s, p < 0.001) and CANO (4.08/2.63–7.16/vs. 2.42/1.83–2.89/ppb, p < 0.001) were increased in patients with asthma compared to controls. In patients, CANO correlated with RV/TLC (r = 0.58, p < 0.001), FEF25-75% (p = 0.02, r = –0.36) and DL,CO (r = –0.46, p = 0.004). JawNO was not related to lung function parameters. Conclusions: Calculation of alveolar NO concentration with the linear method from values obtained at medium flow rates (100–250 mL/s) is feasible even in asthmatic patients with severe airflow limitation and may provide information on small airways dysfunction in asthma.

Pharmacological modulation of reactive oxygen species (ROS) improves the airway hyperresponsiveness by shifting the Th1 response in allergic inflammation induced by ovalbumin

Asthma is an allergic inflammation driven by the Th2 immune response with release of cytokines such as IL-4 and IL-13, which contribute to the airflow limitations and airway hyperresponsiveness (AHR). The involvement of oxidative stress in this process is well-established, but the specific role of the superoxide anion and nitric oxide in asthma are poorly understood. Thus, the aim of this study was to investigate the mechanisms underlying the superoxide anion/nitric oxide production and detoxification in a murine asthma model. BALB/c male mice were sensitised and challenged with ovalbumin (OVA). Pretreatments with either apocynin (14 mg/kg) or allopurinol (25 mg/kg) (superoxide anion synthesis inhibitors), aminoguanidine (50 mg/kg) (nitric oxide synthesis inhibitor) or diethyldithiocarbamate (100 mg/kg) (superoxide dismutase inhibitor) were performed 1 h before the challenge. Our data showed that apocynin and allopurinol ameliorated AHR and reduced eosinophil peroxidase, as well as IL-4 and IL-13 levels. Apocynin also abrogated leukocyte peribronchiolar infiltrate and increased IL-1β secretion. Aminoguanidine preserved lung function and shifted the Th2 to the Th1 response with a reduction of IL-4 and IL-13 and increase in IL-1β production. Diethyldithiocarbamate prevented neither allergen-induced AHR nor eosinophil peroxidase (EPO) generation. All treatments protected against oxidative damage observed by a reduction in TBARS levels. Taken together, these results suggest that AHR in an asthma model can be avoided by the down-regulation of superoxide anion and nitric oxide synthesis in a mechanism that is independent of a redox response. This down-regulation is also associated with a transition in the typical immunological Th2 response toward the Th1 profile.

Relationship between serum arginase I and l-arginine or exhaled nitric oxide in asthma

The relationship between serum arginase I and serum l-arginine or fractional exhaled nitric oxide (FENO) was evaluated cross-sectionally in asthmatic patients. No sex difference was observed in the serum mean levels of arginase I and l-arginine or FENO. Arginase I and FENO were higher in patients 60 or younger years than in those over 60 years. Asthmatic patients were divided into three groups: no steroid therapy, inhalation steroid therapy, and oral steroid therapy. Arginase I, FENO and high-sensitivity-C-reactive protein (hs-CRP) were significantly lower in the inhalation steroid therapy group than in the no steroid therapy group. Correlations were observed between arginase I and FENO, l-arginine, hs-CRP, WBC, and age, and also between FENO and IgE, WBC, and age. A logistic regression analysis revealed the positive association of arginase I with FENO, and the negative association of l-arginine. FENO was positively associated with arginase I and IgE. These results indicated that serum arginase I might influence serum levels of l-arginine and FENO, and that IgE might influence FENO in asthmatic patients.

Daily life negative mood and exhaled nitric oxide in asthma

BackgroundPsychosocial stress and negative affect have been linked to asthma exacerbations, but longitudinal studies demonstrating a daily life association between negative affect and airway nitric oxide are missing. ObjectiveThe longitudinal association between negative mood fluctuations, exhaled nitric oxide, and lung function in asthma was examined. MethodsSelf-assessments of the fraction of exhaled nitric oxide (FeNO), spirometry (forced expiratory volume in the first second, FEV1), negative mood, and daily activities were obtained from 20 patients with asthma for 2 months, resulting in 1108 assessments for the analyses (approximately 55 per patient). Concurrent and prospective associations between FeNO, FEV1, and negative mood were analyzed using mixed effects regression models for longitudinal data. ResultsNegative mood was positively associated with changes in FeNO during the same day, and to a stronger extent when prior day negative mood was included in the prediction. FeNO and negative mood were positively associated with same-day FEV1, with the latter relation being partially mediated by changes in FeNO. Associations between FeNO and FEV1 were stronger in younger patients, with earlier onset of asthma, or with lower asthma control. Findings were not changed when controlling for physical activity, medication, cold symptoms, air pollution, and hours spent outside. ConclusionDaily life changes of negative mood in asthma are positively associated with FeNO changes and FeNO increases are associated with a mild bronchodilation. These findings indicate that psychological influences need to be considered when using FeNO as indicator of airway inflammation and guide for treatment decisions.

Revisiting the role of exhaled nitric oxide in asthma

This review focuses on the most recent studies investigating fractional nitric oxide concentration in exhaled breath (FeNO) as a useful biomarker for identifying specific phenotypes in asthma and as a tool for asthma diagnosis, monitoring and clinical decision-making. On the basis of the current literature, it has been highlighted that FeNO is a clinically relevant marker in various clinical aspects of asthma: FeNO is a predictor for developing asthma in persistent rhinitis or in infants with respiratory symptoms; FeNO contributes to identification of asthma phenotypes in both children and adults, also in relation to severity; FeNO is useful in monitoring the effectiveness of inhaled corticosteroids (including compliance) and biologic treatments like omalizumab; FeNO, in conjunction with symptom registration and lung function measurements, contributes to asthma diagnosis and optimizes asthma management. FeNO provides further information in distinguishing different phenotypes in asthma, allowing a much more appropriate control of the disease, especially in patients with difficult/severe asthma. In the future, it would be interesting to shed light on the hidden biological mechanisms responsible for low or normal FeNO values in symptomatic asthmatic patients.

Measurement of fraction of exhaled nitric oxide in asthma

Measurement of fraction of exhaled nitric oxide in asthma

Effect of nursing intervention on airway inflammatory reaction evaluation by testing fractional concentration of exhaled nitric oxide in asthma patients

Objective To investigate the effect of standardized nursing intervention on airway inflammatory reaction evaluation by testing fractional concentration of exhaled nitric oxide in asthma patients.Methods 62 asthma patients were randomly divided into the intervention group(32 cases)and the control group (30 cases).Two groups were performed FENO determination before and after the treatment.The control group was given routine method for determination,the intervention group was given nursing intervention on the basis of conventional methods.The comfortable situation,satisfaction degree,treatment efficacy were determined between the two groups.Results The comfortable situation,satisfaction degree,treatment efficacy of the intervention group were better than those of the control group.Conclusions Standardized nursing intervention can eliminate the adverse interference in the FENO determination and improve the accuracy of the determination.It can also improve the clinical symptoms of patients with asthma and relieve airway inflammation.This method deserves to be recommended. Key words: Nursing intervention; FENO determination; Asthma

Exhaled Nitric Oxide in Asthma in Adults: The End is the Beginning?

Approximately 20 years after the initial report of the measurement of exhaled nitric oxide (NO) in the exhaled air of humans, numerous publications have evaluated the possible applications of the fraction of exhaled NO (FeNO) in patients with asthma. The aim of the present review is to evaluate the technical issues and confounding factors related to FeNO measurements, as well as the role of FeNO in the diagnosis of asthma, the evaluation of asthmatic patients and the guidance of treatment. Several other issues, including the pursuit for "normal" and best personal values, the prediction of clinically relevant asthma outcomes and the identification of asthma phenotypes and future directions are discussed. FeNO represents the only exhaled biomarker that has reached clinical practice even in primary care settings and this review provides a critical view of the possible applications of this biomarker, both for the basic researcher and the clinician.

Acute Stress–induced Increases in Exhaled Nitric Oxide in Asthma and Their Association with Endogenous Cortisol

psychosocial stress is known to influence the pathophysiology of asthma. Although stress has been linked to serum markers of inflammatory activity and exaggerated response to allergen challenge in asthma, few studies have examined inflammatory activity in the airways linked to psychosocial stress alone. Furthermore, although studies have demonstrated lower levels or reactivity of endogenous cortisol in asthma, the association with airway inflammatory activity in stress remains unexplored. we therefore studied airway inflammation and cortisol response to a standardized laboratory task inducing acute psychosocial stress. airway inflammation by the fraction of exhaled nitric oxide (FeNO) and saliva cortisol were sampled before and up to 45 minutes after experimental challenge with the Trier Social Stress Test in 20 adult patients with asthma and 19 healthy control subjects. Respiratory inductive plethysmography was used to control for changes in ventilatory activity that impact FeNO levels. FeNO levels were generally higher in patients with asthma than healthy control subjects and salivary cortisol levels were lower. Increases in cortisol levels were observed after the stress protocol in both groups (P < 0.001). FeNO levels at the time of peak cortisol increase after stress were significantly higher than before stress in both groups (P < 0.05). FeNO increases were independent of changes in ventilation. In patients with asthma, higher cortisol levels and stronger increases in cortisol after stress were significantly associated with smaller increases in FeNO (P < 0.05). acute psychosocial stress alone increases airway inflammatory markers and this increase is attenuated by stronger stress-related activity of the hypothalamic-pituitary-adrenal axis in asthma.

Quantifying proximal and distal sources of NO in asthma using a multicompartment model

Nitric oxide (NO) is detectable in exhaled breath and is thought to be a marker of lung inflammation. The multicompartment model of NO exchange in the lungs, which was previously introduced by our laboratory, considers parallel and serial heterogeneity in the proximal and distal regions and can simulate dynamic features of the NO exhalation profile, such as a sloping phase III region. Here, we present a detailed sensitivity analysis of the multicompartment model and then apply the model to a population of children with mild asthma. Latin hypercube sampling demonstrated that ventilation and structural parameters were not significant relative to NO production terms in determining the NO profile, thus reducing the number of free parameters from nine to five. Analysis of exhaled NO profiles at three flows (50, 100, and 200 ml/s) from 20 children (age 7-17 yr) with mild asthma representing a wide range of exhaled NO (4.9 ppb < fractional exhaled NO at 50 ml/s < 120 ppb) demonstrated that 90% of the children had a negative phase III slope. The multicompartment model could simulate the negative phase III slope by increasing the large airway NO flux and/or distal airway/alveolar concentration in the well-ventilated regions. In all subjects, the multicompartment model analysis improved the least-squares fit to the data relative to a single-path two-compartment model. We conclude that features of the NO exhalation profile that are commonly observed in mild asthma are more accurately simulated with the multicompartment model than with the two-compartment model. The negative phase III slope may be due to increased NO production in well-ventilated regions of the lungs.

Fractional exhaled nitric oxide in asthma: an update

In asthma, clinical symptoms and lung function are insensitive in reflecting the underlying airway inflammation, and monitoring of this process has only recently become available. Fractional exhaled nitric oxide (Fe(NO)) is now recognized as a reliable surrogate marker of eosinophilic airway inflammation and offers the advantage of being completely non-invasive and very easy to obtain. This review summarizes the clinical use of Fe(NO) in asthma. It covers the relationship between Fe(NO) and the underlying eosinophilic inflammation, the pathophysiology and production of Fe(NO), technical aspects of Fe(NO) measurement and potential confounding factors in interpreting levels. Fe(NO) reference values and the role of Fe(NO) in asthma assessment, diagnosis and management are also discussed.

Say NO to Exhaled Nitric Oxide for Asthma: Pulmonary Trends

Say NO to Exhaled Nitric Oxide for Asthma: Pulmonary Trends

Airway biomarkers of the oxidant burden in asthma and chronic obstructive pulmonary disease: current and future perspectives.

The pathogenesis of asthma and chronic obstructive pulmonary disease (COPD) has been claimed to be attributable to increased systemic and local oxidative stress. Detection of the oxidant burden and evaluation of their progression and phenotypes by oxidant biomarkers have proved challenging and difficult. A large number of asthmatics are cigarette smokers and smoke itself contains oxidants complicating further the use of oxidant biomarkers. One of the most widely used oxidant markers in asthma is exhaled nitric oxide (NO), which plays an important role in the pathogenesis of asthma and disease monitoring. Another oxidant marker that has been widely investigated in COPD is 8-isoprostane, but it is probably not capable of differentiating asthma from COPD, or even sensitive in the early assessment of these diseases. None of the current biomarkers have been shown to be better than exhaled NO in asthma. There is a need to identify new biomarkers for obstructive airway diseases, especially their differential diagnosis. A comprehensive evaluation of oxidant markers and their combinations will be presented in this review. In brief, it seems that additional analyses utilizing powerful tools such as genomics, metabolomics, lipidomics, and proteomics will be required to improve the specificity and sensitivity of the next generation of biomarkers.

Exhaled nitric oxide in asthma: progress since the introduction of standardized methodology

The measurement of nitric oxide (NO) in exhaled breath has given us the ability to learn about and monitor the inflammatory status of the airway through a non-invasive method that is easy to perform and repeat. This has been most useful in the diagnosis and management of asthma and has promised a seemingly unlimited potential for evaluating the airways and how clinical decisions are made (Grob N M and Dweik R A 2008 Chest 133 837–9). The exhaled NO field was initially limited, however, due to the absence of standardized methodology. The ATS and ERS jointly released recommendations for standardized methods of measuring and reporting exhaled NO in 1999 that were revised in 2005 (1999 Am. J. Respir. Crit. Care. Med. 160 2104–17; 2005 Am. J. Respir. Crit. Care. Med. 171 912–30). In this paper, we summarize the literature that followed this standardization. We searched the literature for all papers that included the term ‘exhaled nitric oxide’ and selected those that followed ATS guidelines for online measurement for further review. We also reviewed cut-off values suggested by groups studying exhaled nitric oxide. We found a wide range of NO values reported for normal and asthma populations. The geometric mean for FENO ranged from 10 ppb to 33 ppb in healthy adult control populations. For asthma, the FENO geometric mean ranged from 6 ppb to 98 ppb. This considerable variation likely reflects the different clinical settings and purposes of measurement. Exhaled NO has been used for a multitude of reasons that range from screening, to diagnosis, to monitoring the effect of therapy. The field of exhaled NO has made undeniable progress since the standardization of the measurement methods. Our challenge now is to have guidelines to interpret exhaled NO levels in the appropriate context. As the utility of exhaled NO continues to evolve, it can serve as a good example of the crucial role of the standardization of collection and measurement methods to propel any new test in the right direction as it makes its way from a research tool to a clinically useful test.

The clinical utility of biomarkers in asthma and COPD

Biomarkers with potential utility in the diagnosis and prognosis of asthma and chronic obstructive pulmonary disease (COPD), and in monitoring the natural history of these diseases and the effect of therapeutic interventions, are being widely researched. This review critically describes the methodologies used for obtaining and analysing appropriate biofluid, tissue and exhaled breath samples for biomarker analysis. Currently measurements of sputum eosinophils and exhaled nitric oxide in asthmatics are the best established markers for disease activity and response to anti-inflammatory therapy. Circulating C-reactive protein (CRP) levels have been shown to predict risk of hospitalisation and death from COPD. Biomarker measurements in exhaled breath condensate are the least well-validated techniques. Other assessments in both conditions have potential value in clinical use but require further research and validation.

The Clinical Significance of Exhaled Nitric Oxide in Asthma

Asthma is an inflammatory disease of the airways, for which many therapeutic options are available. Guidelines for the management of asthma suggest a stepwise approach to pharmacotherapy based on assessment of asthma severity and control. However, the assessment of asthma control presently relies on surrogate measures, such as the frequency of symptoms or the frequency of use of short-acting beta2-adrenergic agonists. There is no simple, noninvasive technique for the assessment of severity of actual airway inflammation in asthma. The collection and analysis of nitric oxide (NO) levels in exhaled breath has recently become feasible in humans. Based on increased exhaled NO (eNO) levels in patients with asthma, eNO analysis has been proposed as a novel, noninvasive approach to the assessment and monitoring of airway inflammation, and as a basis for adjustments in asthma therapy. In the present paper, the relationship of elevated eNO levels in asthma with inflammatory, physiological and clinical markers of asthma in adults was reviewed. Use of eNO is a promising tool for diagnosing asthma, for monitoring asthma control and for guiding optimal anti-inflammatory asthma therapy. However, because of many unresolved questions, eNO cannot be recommended at present for routine clinical management of adults with asthma.

Exhaled Nitric Oxide in Asthma: Variability, Relation to Asthma Severity, and Peripheral Blood Lymphocyte Cytokine Expression

Shome GP, Starnes JD 3rd, Shearer M, et al. J Asthma. 2006;43:95–99 PURPOSE OF THE STUDY. To measure and compare exhaled nitric oxide (eNO) levels in patients with asthma and healthy volunteers, to study peripheral blood lymphocyte cytokine expression, and to study the relationship between eNO and intracellular cytokine expression. STUDY POPULATION. A total of 36 subjects were enrolled onto the study, with 19 asthmatic patients and 17 healthy control subjects. METHODS. At least once per week for 4 weeks, patients with asthma visited the clinic and underwent a detailed history, physical examination, spirometry, and eNO-level measurement. These patients were maintained on established pharmacologic therapy regimens. A blood sample was taken and analyzed by flow cytometry. eNO was measured by using an NO analyzer. Univariate linear regression analysis was used to determine correlations between continuous variables and eNO concentrations. RESULTS. eNO levels were significantly elevated in patients with moderate-to-severe asthma compared with those in healthy subjects (18.53 ± 2.00 vs 5.90 ± 0.90 ppb). With treatment, eNO levels in patients with moderate-to-severe asthma decreased to levels near those of the healthy subjects by 4 weeks. Interferon γ expression was decreased in patients with moderate-to-severe asthma. An elevated eNO level was also associated with decreased interleukin 4 and interleukin 13 cytokine expression in CD8 lymphocytes. CONCLUSIONS. eNO levels were elevated in patients with moderate-to-severe asthma. With 4 weeks of treatment, eNO levels in patients with moderate-to-severe asthma were no different from those in the control subjects. There was decreased interferon γ expression by the CD4- and CD8-positive peripheral blood lymphocytes of patients with moderate-to-severe asthma. Elevated eNO levels were associated with suppression of both T-helper 1 and 2 cytokine expression by the peripheral blood lymphocyte, suggesting a systemic immunomodulatory effect. REVIEWER COMMENTS. This study adds to the growing information on the utility of eNO levels to monitor asthma-treatment response. It demonstrates how eNO can be used to measure the reduction in airway inflammation as a response to treatment primarily in patients with moderate-to-severe asthma. At this point, it is not clear what the implications are of the association between elevated eNO levels and cytokine suppression.