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Exhaled nitric oxide and clinical phenotypes of childhood asthma
Bruno Mahut, Séverine Peyrard, Christophe Delclaux
Respiratory Research , 2011, DOI: 10.1186/1465-9921-12-65
Abstract: We performed multivariate (exhaled NO as dependent variable) and k-means cluster analyses in a population of 169 asthmatic children (age ± SD: 10.5 ± 2.6 years) recruited in a monocenter cohort that was characterized in a cross-sectional design using 28 parameters describing potentially different asthma domains: atopy, environment (tobacco), control, exacerbations, treatment (inhaled corticosteroid and long-acting bronchodilator agonist), and lung function (airway architecture and tone).Two subject-related characteristics (height and atopy) and two disease-related characteristics (bronchodilator response and ICS dose > 200 μg/d) explained 36% of exhaled NO variance. Nine domains were isolated using principal component analysis. Four clusters were further identified: cluster 1 (47%): boys, unexposed to tobacco, with well-controlled asthma; cluster 2 (26%): girls, unexposed to tobacco, with well-controlled asthma; cluster 3 (6%): girls or boys, unexposed to tobacco, with uncontrolled asthma associated with increased airway tone, and cluster 4 (21%): girls or boys, exposed to parental smoking, with small airway to lung size ratio and uncontrolled asthma. FENO0.05 was not different in these four clusters.In conclusion, FENO0.05 is independently linked to two pathophysiological characteristics of asthma (ICS-dependant inflammation and bronchomotor tone) but does not help to identify a clinically relevant phenotype of asthmatic children.Numerous studies have evaluated exhaled nitric oxide (NO) correlates in asthma. For instance, exhaled NO fraction (FENO) has been linked to atopy rather than to asthma per se which could be due to the underlying relationship between FENO and eosinophilic inflammation of airways[1]. We and others have emphasized that FENO is also linked to other intrinsic dimensions of asthma such as airway reactivity/tone [2,3] and remodeling of airways[1,4]. All these relationships may explain the complex and still debated relationship between exhaled NO
Arginine and Nitric Oxide Pathways in Obesity-Associated Asthma  [PDF]
Fernando Holguin
Journal of Allergy , 2013, DOI: 10.1155/2013/714595
Abstract: Obesity is a comorbidity that adversely affects asthma severity and control by mechanisms that are not fully understood. This review will discuss evidence supporting a role for nitric oxide (NO) as a potential mechanistic link between obesity and late-onset asthma (>12 years). Several studies have shown that there is an inverse association between increasing body mass index (BMI) and reduced exhaled NO. Newer evidence suggests that a potential explanation for this paradoxical relationship is related to nitric oxide synthase (NOS) uncoupling, which occurs due to an imbalance between L-arginine (NOS substrate) and its endogenous inhibitor, asymmetric di-methyl arginine (ADMA). The review will propose a theoretical framework to understand the relevance of this pathway and how it may differ between early and late-onset obese asthmatics. Finally, the paper will discuss potential new therapeutic approaches, based on these paradigms, for improving the respiratory health of obese subjects with asthma. 1. Introduction Although obesity is associated with less asthma control, greater risk of asthma exacerbations, and reduced inhaled corticosteroid efficacy, whether in fact these conditions are causally related remains uncertain [1]. However, by defining the phenotypical aspects of this relationship, some potential new mechanistic links have been uncovered. Using cluster analyses, obesity has been shown to be an important factor among female patients whose asthma occurs after childhood and have less atopy [2, 3]. This cluster has also been associated with lower airway eosinophils and exhaled nitric oxide (eNO) [3, 4]. The inverse association between body mass index (BMI) and eNO [5] may be explained by an imbalance between L-arginine and one of its methylated products known as asymmetric dimethyl arginine (ADMA) [6, 7]. L-arginine is the substrate that nitric oxide synthase (NOS) uses to generate NO. However, L-arginine is methylated to ADMA, which is an endogenous inhibitor of all NOS isoforms [8]. In addition, ADMA can uncouple NOS and preferentially generate anion superoxide instead of NO [9]. Therefore, conditions favoring a lower L-arginine/ADMA balance would in theory contribute to reducing NO airway bioavailability and increasing airway oxidative stress. This phenomenon has been more extensively studied in the vasculature, as a mechanism leading to endothelial dysfunction or impaired NO-mediated vasodilatation [10]. However, in the lung, the L-arginine/ADMA balance is just beginning to surface as a potential explanation to understand metabolic diseases such
Elevated Exhaled Nitric Oxide in Allergen-Provoked Asthma Is Associated with Airway Epithelial iNOS  [PDF]
Abraham B. Roos, Michiko Mori, Reidar Gr?nneberg, Christina ?sterlund, Hans-Erik Claesson, Jan Wahlstr?m, Johan Grunewald, Anders Eklund, Jonas S. Erjef?lt, Jon O. Lundberg, Magnus Nord
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0090018
Abstract: Background Fractional exhaled nitric oxide is elevated in allergen-provoked asthma. The cellular and molecular source of the elevated fractional exhaled nitric oxide is, however, uncertain. Objective To investigate whether fractional exhaled nitric oxide is associated with increased airway epithelial inducible nitric oxide synthase (iNOS) in allergen-provoked asthma. Methods Fractional exhaled nitric oxide was measured in healthy controls (n = 14) and allergic asthmatics (n = 12), before and after bronchial provocation to birch pollen out of season. Bronchoscopy was performed before and 24 hours after allergen provocation. Bronchial biopsies and brush biopsies were processed for nitric oxide synthase activity staining with nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d), iNOS immunostaining, or gene expression analysis of iNOS by real-time PCR. NADPH-d and iNOS staining were quantified using automated morphometric analysis. Results Fractional exhaled nitric oxide and expression of iNOS mRNA were significantly higher in un-provoked asthmatics, compared to healthy controls. Allergic asthmatics exhibited a significant elevation of fractional exhaled nitric oxide after allergen provocation, as well as an accumulation of airway eosinophils. Moreover, nitric oxide synthase activity and expression of iNOS was significantly increased in the bronchial epithelium of asthmatics following allergen provocation. Fractional exhaled nitric oxide correlated with eosinophils and iNOS expression. Conclusion Higher fractional exhaled nitric oxide concentration among asthmatics is associated with elevated iNOS mRNA in the bronchial epithelium. Furthermore, our data demonstrates for the first time increased expression and activity of iNOS in the bronchial epithelium after allergen provocation, and thus provide a mechanistic explanation for elevated fractional exhaled nitric oxide in allergen-provoked asthma.
Exhaled nitric oxide in childhood asthma: methodological issues and clinical applications
Mari?lle Pijnenburg
European Respiratory Review , 2006,
Abstract: The work described herein was presented as an oral, invited presentation at the European Respiratory Society (ERS) Congress 2006 and was awarded the European Respiratory Society Annual Award for Paediatric Respiratory Research in Europe; the work consists of two parts. The first part is on methodological issues of measuring exhaled nitric oxide fraction (Fe,NO) in children. The second part includes four studies on clinical applications of Fe,NO measurements in asthmatic children.
Exhaled Nitric Oxide Fraction as an Add-On to ACQ-7 for Not Well Controlled Asthma Detection  [PDF]
Vicente Plaza, David Ramos-Barbón, Ana María Mu?oz, Ana María Fortuna, Astrid Crespo, Cristina Murio, Rosa Palomino, on behalf of the EOLO Study Investigators
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0077085
Abstract: Background The measurement of fractional nitric oxide concentration in exhaled breath (FeNO), a noninvasive indicator of airway inflammation, remains controversial as a tool to assess asthma control. Guidelines currently limit asthma control assessment to symptom and spirometry based appraisals such as the Asthma Control Questionnaire-7 (ACQ-7). We aimed at determining whether adding FeNO to ACQ-7 improves current asthma clinical control assessment, through enhanced detection of not well controlled asthma. Methods Asthmatic subjects, classified as not well controlled as per ACQ-7 on regular clinical practice, were included in a prospective, multicenter fashion, and had their maintenance treatment adjusted on visit 1. On follow-up (visit 2) four weeks later, the subjects were reevaluated as controlled or not well controlled using ACQ-7 versus a combination of FeNO and ACQ-7. Results Out of 381 subjects enrolled, 225 (59.1%) had not well controlled asthma on visit 2 as determined by ACQ-7, and 264 (69.3%) as per combined FeNO and ACQ-7. The combination of FeNO to ACQ-7 increased by 14.8% the detection of not well controlled asthma following maintenance therapy adjustment. Conclusions The addition of FeNO to ACQ-7 increased the detectability of not well controlled asthma upon adjustment of maintenance therapy. Adding a measure of airway inflammation to usual symptom and spirometry based scores increases the efficacy of current asthma clinical control assessment.
Clinical patterns in asthma based on proximal and distal airway nitric oxide categories
James L Puckett, Richard WE Taylor, Szu-Yun Leu, Olga L Guijon, Anna S Aledia, Stanley P Galant, Steven C George
Respiratory Research , 2010, DOI: 10.1186/1465-9921-11-47
Abstract: In 200 consecutive children with asthma, and 21 non-asthmatic, non-atopic controls, we measured baseline spirometry, bronchodilator response, asthma control and morbidity, atopic status, use of inhaled corticosteroids, and eNO at multiple flows (50, 100, and 200 ml/s) in a cross-sectional study design. A trumpet-shaped axial diffusion model of NO exchange was used to characterize J'awNO and CANO.J'awNO was not correlated with CANO, and thus asthmatic subjects were grouped into four eNO categories based on upper limit thresholds of non-asthmatics for J'awNO (≥ 1.5 nl/s) and CANO (≥ 2.3 ppb): Type I (normal J'awNO and CANO), Type II (elevated J'awNO and normal CANO), Type III (elevated J'awNO and CANO) and Type IV (normal J'awNO and elevated CANO). The rate of inhaled corticosteroid use (lowest in Type III) and atopy (highest in Type II) varied significantly amongst the categories influencing J'awNO, but was not related to CANO, asthma control or morbidity. All categories demonstrated normal to near-normal baseline spirometry; however, only eNO categories with increased CANO (III and IV) had significantly worse asthma control and morbidity when compared to categories I and II.J'awNO and CANO reveal inflammatory categories in children with asthma that have distinct clinical features including sensitivity to inhaled corticosteroids and atopy. Only categories with increase CANO were related to poor asthma control and morbidity independent of baseline spirometry, bronchodilator response, atopic status, or use of inhaled corticosteroids.Asthma is a complex disease characterized by inflammation throughout the respiratory tract from the large airways to the alveoli [1-3]. Moreover, there is mounting evidence that asthma control is correlated with the extent of inflammation, such that symptoms are worse when the inflammation reaches the more peripheral lung compartments [2-6]. One of the great challenges in asthma research is to develop minimally invasive approaches, particul
Overexpression of endothelial nitric oxide synthase suppresses features of allergic asthma in mice
Robert Broeke, Rini De Crom, Rien Van Haperen, Vivienne Verweij, Thea Leusink-Muis, Ingrid Van Ark, Fred De Clerck, Frans P Nijkamp, Gert Folkerts
Respiratory Research , 2006, DOI: 10.1186/1465-9921-7-58
Abstract: The contribution of eNOS on the development of asthmatic features was examined. We used transgenic mice that overexpress eNOS and measured characteristic features of allergic asthma after sensitisation and challenge of these mice with the allergen ovalbumin.eNOS overexpression resulted in both increased eNOS activity and NO production in the lungs. Isolated thoracic lymph nodes cells from eNOS overexpressing mice that have been sensitized and challenged with ovalbumin produced significantly less of the cytokines IFN-γ, IL-5 and IL-10. No difference in serum IgE levels could be found. Further, there was a 50% reduction in the number of lymphocytes and eosinophils in the lung lavage fluid of these animals. Finally, airway hyperresponsiveness to methacholine was abolished in eNOS overexpressing mice.These findings demonstrate that eNOS overexpression attenuates both airway inflammation and airway hyperresponsiveness in a model of allergic asthma. We suggest that a delicate balance in the production of bioactive forms of NO derived from eNOS might be essential in the pathophysiology of asthma.Asthma is a chronic inflammatory disease of the airways characterized by airway obstruction, epithelial damage and airway hyperresponsiveness [1,2]. The increased airway responsiveness is believed to be the result of airway inflammation as well as epithelial damage [3-5]. There is increasing evidence that activated T lymphocytes modulate the pathogenesis of asthma [6,7]. Specifically, increased numbers of CD4+ T cells (Th2) have been found in the bronchial mucosa of asthmatic patients, with the consequent elevated levels of interleukin-5 (IL-5) and IL-10 [8-10]. Moreover, interferon-γ (IFN-γ) secreting T cells (Th1) were increased in bronchoalveolar lavage (BAL) fluid of asthmatic patients [11,12] and it has been reported that these T cells can induce airway inflammation with neutrophilic inflammation [13,14]. Therefore, both Th1 and Th2 cells are important in airway inflammation a
Associations between Nitric Oxide Synthase Genes and Exhaled NO-Related Phenotypes according to Asthma Status  [PDF]
Emmanuelle Bouzigon, Florent Monier, Mekki Boussaha, Nicole Le Moual, Hélène Huyvaert, Régis Matran, Sébastien Letort, Jean Bousquet, Isabelle Pin, Mark Lathrop, Francine Kauffmann, Florence Demenais, Rachel Nadif, on behalf of the EGEA Cooperative Group
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0036672
Abstract: Background The nitric oxide (NO) pathway is involved in asthma, and eosinophils participate in the regulation of the NO pool in pulmonary tissues. We investigated associations between single nucleotide polymorphisms (SNPs) of NO synthase genes (NOS) and biological NO-related phenotypes measured in two compartments (exhaled breath condensate and plasma) and blood eosinophil counts. Methodology SNPs (N = 121) belonging to NOS1, NOS2 and NOS3 genes were genotyped in 1277 adults from the French Epidemiological study on the Genetics and Environment of Asthma (EGEA). Association analyses were conducted on four quantitative phenotypes: the exhaled fraction of NO (FeNO), plasma and exhaled breath condensate (EBC) nitrite-nitrate levels (NO2–NO3) and blood eosinophils in asthmatics and non-asthmatics separately. Genetic heterogeneity of these phenotypes between asthmatics and non-asthmatics was also investigated. Principal Findings In non-asthmatics, after correction for multiple comparisons, we found significant associations of FeNO levels with three SNPs in NOS3 and NOS2 (P≤0.002), and of EBC NO2–NO3 level with NOS2 (P = 0.002). In asthmatics, a single significant association was detected between FeNO levels and one SNP in NOS3 (P = 0.004). Moreover, there was significant heterogeneity of NOS3 SNP effect on FeNO between asthmatics and non-asthmatics (P = 0.0002 to 0.005). No significant association was found between any SNP and NO2–NO3 plasma levels or blood eosinophil counts. Conclusions Variants in NO synthase genes influence FeNO and EBC NO2–NO3 levels in adults. These genetic determinants differ according to asthma status. Significant associations were only detected for exhaled phenotypes, highlighting the critical relevance to have access to specific phenotypes measured in relevant biological fluid.
Reproducibility and intraindividual variation over days in buccal cell DNA methylation of two asthma genes, interferon γ (IFNγ) and inducible nitric oxide synthase (iNOS)
DZ Torrone, JS Kuriakose, K Moors, H Jiang, MM Niedzwiecki, FF Perera, RL Miller
Clinical Epigenetics , 2012, DOI: 10.1186/1868-7083-4-3
Abstract: The biological mechanisms responsible for the development of asthma symptoms in children following acute exposure to air pollution and other triggers are complex. These include the induction of oxidative stress pathways and formation of excessive reactive oxygen species in the airways [1-5]. Also, exposure to diesel and other combustion products may upregulate proallergic T helper (Th) 2 immune mechanisms [1,6-9]. Epigenetic regulation of gene expression associated with airway inflammation and allergic immune responses following exposure to air pollutants has been proposed as a key molecular step linking environmental exposures with altered asthma gene expression and asthma symptoms [10-14].To date, clinical research on epigenetic changes in asthma and other complex diseases has been limited, especially in children [11,12]. One cross-sectional study by White and colleagues observed promoter demethylation of the allergy counter-regulatory and Th1 cytokine interferon γ (IFNγ) gene in association with in vitro differentiation of CD4+ neonatal T cells [15]. Another study by Kwon and colleagues found phytohemagglutinin (PHA) and dust mite allergen stimulation of CD4+ T lymphocytes induced small increases in the degree of demethylation in several CpG loci of the Th2 interleukin (IL)-4 promoter (CpG-80, CpG+5) in adult asthmatic subjects, when compared to the control group [16]. The changes in DNA methylation at the IFNγ promoter were less consistent. Recently, Breton and colleagues sampled children living in Southern California in one of the first large cohort studies analyzing DNA methylation of asthma genes in buccal cells [17]. They hypothesized that buccal cell DNA methylation levels in two genes important to the production of proinflammatory nitric oxide, namely arginase (ARG) and inducible nitric oxide synthases (iNOS), would be associated inversely with fractional exhaled nitric oxide (FeNO) levels measured concurrently at one timepoint. They found that methylation
Usefulness of Fractional Exhaled Nitric Oxide-Guided Treatment in Patients with Asthma-Chronic Obstructive Pulmonary Disease Overlap  [PDF]
Taisuke Akamatsu, Toshihiro Shirai, Yuko Tanaka, Hirofumi Watanabe, Yoshinari Endo, Yukiko Shimoda, Takahito Suzuki, Rie Noguchi, Mika Saigusa, Akito Yamamoto, Yuichiro Shishido, Takefumi Akita, Satoru Morita, Kazuhiro Asada
Open Journal of Respiratory Diseases (OJRD) , 2018, DOI: 10.4236/ojrd.2018.81001
Background: Some patients present clinical features of both asthma and chronic obstructive pulmonary disease (COPD), which has led to the recent proposal of asthma-COPD overlap (ACO) as a diagnosis. Fractional exhaled nitric oxide (FeNO) is a candidate biomarker to diagnose ACO. We assessed the effect of an add-on treatment with budesonide/formoterol (BUD/FM) combination in patients with ACO, which was diagnosed by FeNO. Methods: This was a prospective, single-arm, open-label, before and after comparison study. Subjects included 83 patients with COPD who attended outpatient clinics for routine checkups at Shizuoka General Hospital between June and November 2016. All patients fulfilled the GOLD definition of COPD and were receiving long-acting muscarinic antagonist (LAMA) or LAMA/long-acting β2 agonist (LABA) combinations. After an 8-week run-in period, BUD/FM was added to the patients with FeNO levels of ≥35 ppb, defined as having ACO. For patients receiving LAMA/LABA, BUD/FM was added after the discontinuation of LABA. The modified British Medical Research Council (mMRC) score, COPD assessment test (CAT) score, spirometric indices, forced oscillation parameters, and FeNO were assessed before and after 8 weeks of BUD/ FM add-on treatment. Results: Twenty-four patients (28.9%) had FeNO levels ≥ 35 ppb, and 17 patients completed the study (mean age: 73 years and GOLD I/II/III/IV, 5/10/1/1). The mean CAT scores significantly improved (9.2 to 5.4, p = 0.015) and 10 patients (58.8%) showed ≥2 points improvement, a minimal clinically important difference. The mean FeNO levels significantly decreased from 63.0 to 34.3 ppb (p < 0.006). However, there were no changes in mMRC scores, spirometric indices, or forced oscillation parameters. Conclusions: FeNO-guided treatment with BUD/FM improves symptoms in patients with ACO.
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