Nitric Oxide In Asthma Research Articles

Exhaled nitric oxide in asthma: “Everything we have always wanted” or “Not quite ready for prime time?”

Exhaled nitric oxide in asthma: “Everything we have always wanted” or “Not quite ready for prime time?”

Airway nitric oxide release is reduced after PBS inhalation in asthma

Exhaled nitric oxide (NO) is elevated in asthma, but the underlying mechanisms remain poorly understood. Recent results in subjects with asthma have reported a decrease in exhaled breath pH and ammonia, as well as altered expression and activity of glutaminase in both alveolar and airway epithelial cells. This suggests that pH-dependent nitrite conversion to NO may be a source of exhaled NO in the asthmatic airway epithelium. However, the anatomic location (i.e., airway or alveolar region) of this pH-dependent NO release has not been investigated and could impact potential therapeutic strategies. We quantified airway (proximal) and alveolar (peripheral) contributions to exhaled NO at baseline and then after PBS inhalation in stable (mild-intermittent to severe) asthmatic subjects (20-44 yr old; n = 9) and healthy controls (22-41 yr old; n = 6). The mean (SD) maximum airway wall flux (pl/s) and alveolar concentration (ppb) at baseline in asthma subjects and healthy controls was 2,530 (2,572) and 5.42 (7.31) and 1,703 (1,567) and 1.88 (1.29), respectively. Compared with baseline, there is a significant decrease in the airway wall flux of NO in asthma as early as 15 min and continuing for up to 60 min (maximum -28% at 45 min) after PBS inhalation without alteration of alveolar concentration. Healthy control subjects did not display any changes in exhaled NO. We conclude that elevated airway NO at baseline in asthma is reduced by inhaled PBS. Thus airway NO may be, in part, due to nitrite conversion to NO and is consistent with airway pH dysregulation in asthma.

Buffering airway acid decreases exhaled nitric oxide in asthma

The human airway is believed to be acidified in asthma. In an acidic environment nitrite is converted to nitric oxide (NO). We hypothesized that buffering airway lining fluid acid would decrease the fraction of exhaled NO (F(ENO)). We treated 28 adult nonsmoking subjects (9 healthy control subjects, 11 subjects with mild intermittent asthma, and 8 subjects with persistent asthma) with 3 mL of 10 mmol/L phosphate buffered saline (PBS) through a nebulizer and then serially measured F(ENO) levels. Six subjects also received PBS mouthwash alone. F(ENO) levels decreased after buffer inhalation. The maximal decrease occurred between 15 and 30 minutes after treatment; F(ENO) levels returned to pretreatment levels by 60 minutes. The decrease was greatest in subjects with persistent asthma (-7.1 +/- 1.0 ppb); this was more than in those with either mild asthma (-2.9 +/- 0.3 ppb) or healthy control subjects (-1.7 +/- 0.3 ppb, P < .001). Levels did not decrease in subjects who used PBS mouthwash. Neutralizing airway acid decreases F(ENO) levels. The magnitude of this change is greatest in persistent asthma. These data suggest that airway pH is a determinant of F(ENO) levels downstream from NO synthase activation. Airway biochemistry modulates F(ENO) levels. For example, nitrite is converted to NO in the airway, particularly the inflamed airway, by means of acid-based chemistry. Thus airway pH should be considered in interpreting clinical F(ENO) values. In fact, PBS challenge testing integrates airway pH and F(ENO) analysis, potentially improving the utility of F(ENO) as a noninvasive test for the type and severity of asthmatic airway inflammation.

Research Progress of Leukotrienes and Nitric Oxide in Asthma

一氧化氮(NO)是近年来研究较多的一种生物活性物质,在哮喘发病机制中具重要作用.而目前认为呼出气中NO(eNO)测定是反映哮喘气道炎症的新型无创伤性、极敏感的生物指标.eNO浓度在哮喘早期即增加,在哮喘恶化时进一步升高.白三烯是哮喘发病机制中又一重要的内源性炎性介质,与NO存在复杂的相互作用,而白三烯受体拮抗剂可降低哮喘患者的eNO浓度,其机制尚有待阐明.

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

Exhaled nitric oxide has been used as a means of indirectly measuring the underlying inflammation in asthma. The objectives of the study were to measure exhaled nitric oxide levels in asthma patients and healthy volunteers, to study peripheral blood lymphocyte cytokine expression, and to study the relationship between exhaled nitric oxide and intracellular cytokine expression. Exhaled nitric oxide was elevated in patients with moderate to severe asthma and with treatment decreased in the first week reaching to a near normal level by 4 weeks. Elevated exhaled nitric oxide was associated with decreased IL-4 and IL-13 cytokine expression by CD8 lymphocytes.

Nitric oxide paradox in asthma

Asthma results from allergen-driven intrapulmonary Th2 response, and is characterized by intermittent airway obstruction, airway hyperreactivity (AHR), and airway inflammation. Accumulating evidence indicates that inflammatory diseases of the respiratory tract are commonly associated with elevated production of nitric oxide (NO). It has been shown that exhaled NO may be derived from constitutive NO synthase (NOS) such as endothelial (NOS 3) and neural (NOS 1) in normal airways, while increased levels of NO in asthma appear to be derived from inducible NOS2 expressed in the inflamed airways. Nevertheless, the functional role of NO and NOS isoforms in the regulation of AHR and airway inflammation in human or experimental models of asthma is still highly controversial. In the present commentary we will discuss the role of lipopolysaccharides contamination of allergens as key element in the controversy related to the regulation of NOS2 activity in experimental asthma.

Effect of Fluticasone/Salmeterol and Monteleukast on Total Exhaled, Bronchial, and Alveolar Nitric Oxide in Asthmatics

There is a paucity of lung function data in patients, both before and after episodes of near-fatal asthma (NFA), requiring transient endotracheal intubation and mechanical ventilation. Lung function was initially measured in 43 asthmatic patients (age range, 16 to 49 years), who were observed and treated in a tertiary referral asthma clinic and were clinically stable at the time of study. Subsequently, clinical and physiologic follow-up studies were obtained over > 5 years. The primary outcomes were to determine (1) the integrity of lung elastic recoil and (2) the severity of expiratory airflow limitation, and (3) to correlate these outcomes with adverse clinical complications. Fourteen of 26 asthmatic patients (54%) [age range, 30 to 49 years] had significantly reduced lung elastic recoil pressures at all lung volumes compared to 3 of 17 asthmatic patients (18%); p = 0.02 [chi(2) test and Fisher exact test] [age range, 16 to 26 years]. In asthmatic patients between the ages of 30 and 49 years, significant loss of lung elastic recoil was noted in 4 of 10 patients with mild reduction in FEV(1) (FEV(1), > 79% predicted), 6 of 12 patients with moderate reduction in FEV(1) (FEV(1), 61 to 79% predicted), and all 4 patients with severe reduction in FEV(1) (FEV(1), < 61% predicted). In asthmatic patients between the ages of 16 and 26 years, significant loss of lung elastic recoil was noted in 0 of 11 patients with mild reduction in FEV(1), 2 of 5 patients with moderate reduction in FEV(1), and 1 of 1 patient with severe reduction in FEV(1). A subgroup of 10 asthmatic patients (7 men) [mean (+/- SD) age, 37 +/- 11 years] were studied when clinically stable, both before and after an episode of NFA in 8 cases and only after an episode of NFA in 2 additional cases. In 1 of 10 cases, the FEV(1) was mildly reduced, in 4 cases it was moderately reduced, and in 5 cases it was severely reduced, both before and after an episode of NFA. The sensitivity was 90%, the specificity was 61%, the positive predictive value was 41%, and the negative predictive value was 95% for NFA with an FEV(1) < or = 79% predicted or FEV(1)/FVC ratio of < 75%. Prior to an episode of NFA, all 8 asthmatic patients had significant loss of lung elastic recoil pressure, and afterward all 10 had significant loss of lung elastic recoil pressure (ie, less than the predicted normal mean minus 1.64 SD at a total lung capacity [TLC] of 100 to 70% predicted). The sensitivity was 100%, the specificity was 79%, the positive predictive value was 59%, and the negative predictive value was 100% for NFA with the loss of lung elastic recoil. The mean TLC measured with a plethysmograph in 10 patients with NFA was 7.2 +/- 1.41 (124 +/- 16% predicted). The sensitivity for TLC of > 115% predicted was 70%, the specificity was 70%, the positive predictive value was 88%, and the negative predictive value was 41% for NFA. A persistent reduction in FEV(1) of < or = 79% predicted or an FEV(1)/FVC ratio of < 75%, and, especially, the loss of lung elastic recoil and hyperinflation at TLC are risk factors for NFA. The loss of lung elastic recoil in asthmatic patients was associated with increased age, duration of disease, and progressive expiratory airflow limitation.

Nitric oxide synthase inhibition: therapeutic potential in asthma.

Nitric oxide (NO) is synthesized from L-arginine in the human respiratory tract by enzymes of the NO synthase (NOS) family. Levels of NO in exhaled air are increased in asthma, and measurement of exhaled NO has been advocated as a noninvasive tool to monitor the underlying inflammatory process. However, the relation of NO to disease pathophysiology is uncertain, and in particular the fundamental question of whether it should be viewed primarily as beneficial or harmful remains unanswered. Exogenously administered NO has both bronchodilator and bronchoprotective properties. Although it is unlikely that NO is an important regulator of basal airway tone, there is good evidence that endogenous NO release exerts a protective effect against various bronchoconstrictor stimuli. This response is thought to involve one or both of the constitutive NOS isoforms, endothelial NOS (eNOS) and neuronal NOS (nNOS). Therefore, inhibition of these enzymes is unlikely to be therapeutically useful in asthma and indeed may worsen disease control. On the other hand, the high concentrations of NO in asthma, which are believed to reflect upregulation of inducible NOS (iNOS) by proinflammatory cytokines, may produce various deleterious effects. These include increased vascular permeability, damage to the airway epithelium, and promotion of inflammatory cell infiltration. However, the possible effects of iNOS inhibition on allergic inflammation in asthma have not yet been described and studies in animal models have yielded inconsistent findings. Thus, the evidence to suggest that inhibition of iNOS would be a useful therapeutic strategy in asthma is limited at present. More definitive information will require studies combining agents that potently and specifically target individual NOS isoforms with direct measurement of inflammatory markers.

Oxidative and nitrosative events in asthma.

Asthma affects over 15 million individuals in the United States, with over 1.5 million emergency room visits, 500,000 hospitalizations, and 5500 deaths each year, many of which are children. Airway inflammation is the proximate cause of the recurrent episodes of airflow limitation in asthma. Research applying molecular biology, chemistry, and cell biology to human asthma and model systems of asthma over the last decade has revealed that numerous biologically active proinflammatory mediators lead to increased production of reactive oxygen species (ROS) and the gaseous molecule nitric oxide (NO). Persistently increased ROS and NO in asthma lead to reactive nitrogen species (RNS) formation and subsequent oxidation and nitration of proteins, which may cause alterations in protein function that are biologically relevant to airway injury/inflammation. Eosinophil peroxidase and myeloperoxidase, leukocyte-derived enzymes, amplify oxidative events and are another enzymatic source of NO-derived oxidants and nitrotyrosine formation in asthma. Concomitant with increased generation of oxidative and nitrosative molecules in asthma, loss of protective antioxidant defense, specifically superoxide dismutase (SOD), contributes to the overall toxic environment of the asthmatic airway. This review discusses the rapidly accruing data linking oxidative and nitrosative events as critical participants in the acute and chronic inflammation of asthmatic airways.

Exhaled nitric oxide in asthma: From bench to bedside

With more than 600 publications, exhaled nitric oxide (NO) has been extensively investigated as a noninvasive marker of airway inflammation in a research setting. This clinical rostrum presents a synopsis of the latest research about this novel marker in asthma and suggests how it might move from bench to bedside. Specifically, we review the evidence citing the applicability of exhaled NO in diagnosing asthma, monitoring the response to therapy, evaluating current symptom control, and predicting exacerbations of asthma. These studies support a role for exhaled NO in the evaluation and treatment of asthma in the clinical arena. (J Allergy Clin Immunol 2003;111:256-62.)

Inhaled ultrasonically nebulized distilled water decreases exhaled nitric oxide in asthma.

Exhaled nitric oxide (eNO) is increasingly used as a marker of disease activity in asthma. Inhaled hypertonic saline has been shown to induce bronchoconstriction and to decrease eNO in asthmatic subjects, whereas the effects of hypotonic solutions on eNO in these patients have not been studied. To evaluate the effect of ultrasonically nebulized distilled water (UNDW), an indirect hypotonic stimulus, on eNO, 17 asthmatic patients were enrolled and eNO from lower airways was measured by chemiluminescence. UNDW significantly reduced FEV(1) >or= 20% in 9 subjects (UNDW+), but had no effect in eight patients (UNDW-). Baseline eNO concentration were found to be 51.3 +/- 11.1 ppb in UNDW+ and 32.9 +/- 7.5 ppb in UNDW- patients, respectively ( p = 0.199, NS). UNDW inhalation significantly decreased eNO (from 51.3 +/- 11.1 ppb to 31.0 +/- 7.1 ppb in UNDW+ ( p < 0.020, n = 9) and from 32.9 +/- 7.5 ppb to 26.2 +/- 7.3 ppb in UNDW- subjects ( p < 0.024, n = 8), respectively). eNO percentage reduction in UNDW+ patients was significantly higher compared with UNDW- subjects (-37 +/- 4% vs -23 +/- 3%, p = 0.021). There was no correlation between FEV(1) changes and eNO percentage decreases in both UNDW+ and UNDW- subjects. In UNDW+ patients, acute bronchodilation induced by salbutamol caused a recovery in both FEV(1) and eNO, though eNO levels remained lower than baseline values. We concluded that UNDW inhalation can significantly decrease eNO in asthmatic patients, either responders or nonresponders to this indirect osmotic challenge; the reduction in eNO levels was only partly dependent on acute changes in airway caliber.

Molecular mechanisms of corticosteroids in allergic diseases.

Molecular mechanisms of corticosteroids in allergic diseases.

Nitric Oxide and Airway Reactivity

Nitric oxide (NO) has long been known as an atmospheric pollutant present in vehicle exhaust emissions and cigarette smoke. Its clinical importance as a biologic mediator in animals and humans has been recognized over the past decade. NO is present in virtually all mammalian organ systems and is present in the exhaled breath of humans. Patients with asthma have high levels of NO in their exhaled breath and high levels of nitric oxide synthase (NOS) II enzyme expression in the epithelial cells of their airways. Although these findings suggest a role for NO in asthma pathogenesis, the role of NO in asthma and airway reactivity remains elusive despite intense research. Whether NO is beneficial through its bronchodilator and antioxidant effects or harmful by inducing inflammation remains unclear. The use of exhaled NO in monitoring asthma is promising, but its clinical use awaits further developments in the field.

Role of exhaled nitric oxide in asthma.

Nitric oxide (NO), an evanescent atmospheric gas, has recently been discovered to be an important biological mediator in animals and humans. Nitric oxide plays a key role within the lung in the modulation of a wide variety of functions including pulmonary vascular tone, nonadrenergic non-cholinergic (NANC) transmission and modification of the inflammatory response. Asthma is characterized by chronic airway inflammation and increased synthesis of NO and other highly reactive and toxic substances (reactive oxygen species). Pro- inflammatory cytokines such as TNFalpha and IL-1beta are secreted in asthma and result in inflammatory cell recruitment, but also induce calcium- and calmodulin-independent nitric oxide synthases (iNOS) and perpetuate the inflammatory response within the airways. Nitric oxide is released by several pulmonary cells including epithelial cells, eosinophils and macrophages, and NO has been shown to be increased in conditions associated with airway inflammation, such as asthma and viral infections. Nitric oxide can be measured in the expired air of several species, and exhaled NO can now be rapidly and easily measured by the use of chemiluminescence analysers in humans. Exhaled NO is increased in steroid-naive asthmatic subjects and during an asthma exacerbation, although it returns to baseline levels with appropriate anti-inflammatory treatment, and such measurements have been proposed as a simple non-invasive method of measuring airway inflammation in asthma. Here the chemical and biological properties of NO are briefly discussed, followed by a summary of the methodological considerations relevant to the measurement of exhaled NO and its role in lung diseases including asthma. The origin of exhaled NO is considered, and brief mention made of other potential markers of airway inflammation or oxidant stress in exhaled breath.

Clinical aspects of exhaled nitric oxide.

There has been intense research into the role nitric oxide (NO) plays in physiological and pathological mechanisms and its clinical significance in respiratory medicine. Elevated levels of exhaled levels of exhaled NO in asthma and other inflammatory lung diseases lead to many studies examining NO as potential markers of airway inflammation, enabling repeated noninvasive and standardized monitoring of airway inflammation. In airway inflammation, NO is not merely a marker but may have anti-inflammatory and pro-inflammatory effects. Significant correlation has been found between exhaled NO and skin test scores in steroid naive asthmatic patients, allowing to discriminate patients with and without airway responsiveness. Exhaled NO is significantly elevated in acute asthma, or steroid-resistant severe asthma, or when the maintenance dose of inhaled steroids is reduced, and quickly reduced down to the levels in patients with stable asthma after steroid treatment. Exhaled NO has been successfully used to monitor anti-inflammatory treatment with inhaled corticosteroids in asthma. Exhaled NO is extremely sensitive and rapid marker of the dose-dependent effect of steroid treatment, or asthma deterioration, which is increased to any changes in lung function, provocative concentration causing a 20% fall in forced expiratory volume, sputum eosinophilia or asthma symptoms. Exhaled NO is not increased in stable chronic obstructive pulmonary disease (COPD), but patients with unstable COPD, or bronchiectasis have high NO levels. Exhaled and nasal NO are diagnostically low in cystic fibrosis and primary pulmonary dyskinesia. Analysis of exhaled air, including nitric oxide, is feasible and could provide a noninvasive method for use in monitoring and management of lung diseases.

Role of endogenous nitric oxide in asthma.

Endogenous nitric oxide (NO) is an ubiquitous signaling molecule with important regulatory functions such as regulation of blood pressure, neurotransmission, and host and immune defense. In the respiratory tract, NO is formed and released by various sources including endothelial and epithelial cells, nerves, airway smooth muscle, and inflammatory cells. Recent evidence suggests that endogenous NO is the neurotransmitter of the nonadrenergic noncholinergic inhibitory (iNANC) system, the only bronchorelaxant neural pathway of human airways. A number of studies also suggest that in some species epithelium-derived NO accounts for the functional bronchoprotective role of the so-called epithelium-derived relaxing factor. In human airways, endogenous NO counteracts the bronchoconstriction induced by pharmacologic stimuli such as bradykinin, histamine, and methacholine. On the basis of these and other observations, it is suggested that a reduced synthesis and/or activity of endogenous NO may contribute to the pathogenesis of airway hyperresponsiveness that characterizes asthma and other respiratory disorders. This short paper summarizes the activities of endogenous NO in the airways of experimental animals and man, and discusses the evidence supporting the view that NO confers bronchoprotection.

No role for NO in asthma?

Nitric oxide (NO) is formed in the airways by constitutive nitric-oxide synthase (cNOS), of which there are two isoforms, in vascular endothelial cells and neurons, and by an inducible form of nitric-oxide synthase (iNOS) in epithelial cells and various inflammatory cells.1 Upregulation of iNOS in inflamed airways is thought to increase the concentration of exhaled NO in patients with untreated asthma.2 NO is involved in mast-cell activation, cell chemotaxis, lymphocyte differentiation and may be an endogenous suppressor of inflammation.

Nitric oxide regulation of asthmatic airway inflammation with segmental allergen challenge

Background: Despite evidence of increased nitric oxide (NO) in asthmatic compared with healthy individuals, the role of NO in airway inflammation is unclear. Objective: The purpose of the study was to determine the in vivo effects of localized allergen challenge on airway NO levels and transcription factor activation. Methods: In this study localized allergen challenge was used as a model of asthmatic exacerbation to determine the relationship of NO to airway inflammation. Results: With allergen challenge, asthmatic patients had a rise in airway NO levels, whereas NO levels in healthy controls did not change. The increased NO in asthma with allergen challenge compared with healthy control subjects was associated with an increase in inflammatory cytokines (GM-CSF and macrophage inflammatory protein-1) in epithelial lining fluid and eosinophilic infiltrate in bronchoalveolar lavage fluid (BAL) and biopsy specimens. To investigate the mechanisms of cytokine gene expression, activation of the transcription factors activator protein-1 and nuclear factor-κB (NF-κB) in cells from BAL were evaluated. Activator protein-1 was not activated before or after local allergen challenge. In contrast, NF-κB activation was less in BAL cells from asthmatic patients with increased NO in comparison with controls. Conclusion: Our studies are the first to suggest an inverse correlation between NF-κB and airway NO in a localized segmental allergen challenge model in allergic asthmatic patients. The current study demonstrates that activation of the inflammatory response (eg, cytokines, cellular infiltrate) in allergic asthmatic patients is temporally associated with increased airway NO. We propose that NO that is up-regulated by cytokines is part of an autoregulatory feedback loop (ie, allergen challenge stimulates inflammatory cytokine production, which in turn stimulates NO production, and NO down-regulates cytokine production). (J Allergy Clin Immunol 1999;104:1174-82.)

Nitrotyrosine formation in the airways and lung parenchyma of patients with asthma

Background: Recent evidence has shown that nitric oxide (NO) levels are increased in asthmatic airways. Although the role of NO in asthma is unknown, reactive metabolites of NO may lead to nitrotyrosine formation and promote airway dysfunction. Objective: The aim of this study was to determine whether nitrotyrosine, as a marker of nitrating species, could be found in the airways and lung parenchyma of subjects with asthma who died of status asthmaticus or other nonrespiratory causes. Methods: Lung tissue specimens were obtained from 5 patients who died of status asthmaticus, 2 asthmatic patients who died of nonrespiratory causes, and 6 nonasthmatic control subjects who died of nonrespiratory causes. Lung sections were stained for immunofluorescence with use of an antinitrotyrosine antibody, followed by a indiocarbocyanine (Cy5, Jackson Immunochemicals, Westgrove, Pa)–conjugated secondary antibody. Results: Nonasthmatic lungs showed little or no nitrotyrosine staining, whereas asthmatic lungs demonstrated significantly more staining of nitrotyrosine residues distributed in both the airways and lung parenchyma. Conclusion: This study demonstrates the presence of nitrotyrosine, and hence evidence of formation of nitrating species, in the airways and lung parenchyma of patients with asthma who died of status asthmaticus or other nonrespiratory causes. This finding supports the concept that widespread airway and parenchymal inflammation occurs in asthma, and, more specifically, that NO and its reactive metabolites may play a pathophysiologic role in asthma. (J Allergy Clin Immunol 1999;104:747-54.)

Nitric oxide in asthma. Pathogenic, therapeutic, or diagnostic?

Nitrogen monoxide, more commonly called nitric oxide or simply NO, is a fascinating free radical molecule, which participates in a broad range of important physiologic processes, including vasodilation, neurotransmission, and host defense. NO is generated from L -arginine by the enzyme nitric oxide synthase (NOS), of which there are three known isoforms. Types I and III NOS, found predominantly in neurons and endothelium, respectively, are constitutively expressed and are dependent upon calcium for activity. The third isoform, NOS II, can be expressed by a wide range of cells primarily after it has been induced by certain cytokines, microbes, or microbial products (1, 2). All three isoforms are dimeric, with each subunit containing iron protoporpyrin IX, tetrahydrobiopterin, flavin adenine dinucleotide, flavin mononucleotide, and binding sites for