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1.  Exhaled Nitric Oxide is Associated with Allergic Inflammation in Children 
Journal of Korean Medical Science  2011;26(10):1265-1269.
Exhaled nitric oxide (eNO) has been proposed as a noninvasive marker of airway inflammation in asthma. In asthmatic patients, exhaled NO levels have been shown to relate with other markers of eosinophilic recruitment, which are detected in blood, sputum, bronchoalveolar lavage fluid and bronchial biopsy samples. The purpose of this study was to assess the possible relationship between eNO and allergic inflammation or sensitization in childhood asthma and allergic rhinitis. Subjects consisted of 118 asthmatic children, 79 patients with allergic rhinitis, and 74 controls. Their age ranged from 6 to 15 yr old. eNO level, peripheral blood eosinophil count, eosinophil cationic protein (ECP), serum total IgE level and specific IgE levels were measured. Methacholine challenge test and allergic skin prick test for common allergens were performed in all subjects. Atopic group (n = 206, 44.48 ± 30.45 ppb) had higher eNO values than non-atopic group (n = 65, 20.54 ± 16.57 ppb, P < 0.001). eNO level was significantly higher in patients with asthma (42.84 ± 31.92 ppb) and in those with allergic rhinitis (43.59 ± 29.84 ppb) than in healthy controls (27.01 ± 21.34 ppb, P < 0.001) but there was no difference between asthma and allergic rhinitis group. eNO also had significant positive correlations with Dermatophagoides pteronyssinus IgE level (r = 0.348, P < 0.001), Dermatophagoides farinae IgE level (r = 0.376, P < 0.001), and the number of positive allergens in skin prick test (r = 0.329, P = 0.001). eNO had significant positive correlations with peripheral blood eosinophil count (r = 0.356, P < 0.001), serum total IgE level (r = 0.221, P < 0.001), and ECP (r = 0.436, P < 0.001). This study reveals that eNO level is associated with allergic inflammation and the degree of allergic sensitization.
PMCID: PMC3192335  PMID: 22022176
Exhaled Nitric Oxide; Asthma; Allergic Rhinitis; Allergy; Sensitization
2.  Comparison of exhaled and nasal nitric oxide and exhaled carbon monoxide levels in bronchiectatic patients with and without primary ciliary dyskinesia 
Thorax  2003;58(1):68-72.
Methods: The levels of exhaled nitric oxide (eNO), carbon monoxide (eCO) and nasal NO (nNO) from bronchiectatic patients with PCD (n=14) were compared with those from patients with non-PCD bronchiectasis without (n=31) and with cystic fibrosis (CF) (n=20) and from normal subjects (n=37) to assess the clinical usefulness of these measurements in discriminating between PCD and other causes of bronchiectasis.
Results: Exhaled NO levels were lower in patients with PCD than in patients with non-PCD non-CF bronchiectasis or healthy subjects (median (range) 2.1 (1.3–3.5) ppb v 8.7 (4.5–26.0) ppb, p<0.001; 6.7 (2.6–11.9) ppb, p<0.001, respectively) but not lower than bronchiectatic patients with CF (3.0 (1.5–7.5) ppb, p>0.05). Nasal levels of nNO were significantly lower in PCD patients than in any other subjects (PCD: 54.5 (5.0–269) ppb, non-PCD bronchiectasis without CF: 680 (310–1000) ppb, non-PCD bronchiectasis with CF: 343 (30–997) ppb, control: 663 (322–1343) ppb). In contrast, eCO levels were higher in all patient groups than in control subjects (PCD: 4.5 (3.0–24.0) ppm, p<0.01, other bronchiectasis without CF: 5.0 (3.0–15.0) ppm, p<0.001; CF: 5.3 (2.0–23.0) ppm, p<0.001 v 3.0 (0.5–5.0) ppm). Low values in both eNO and nNO readings (<2.4 ppb and <187 ppb, respectively) identified PCD patients from other bronchiectatic patients with a specificity of 98% and a positive predictive value of 92%.
Conclusion: The simultaneous measurement of eNO and nNO is a useful screening tool for PCD.
PMCID: PMC1746449  PMID: 12511725
3.  Exhaled 8-isoprostane in childhood asthma 
Respiratory Research  2005;6(1):79.
Exhaled breath condensate (EBC) is a non-invasive method to assess airway inflammation and oxidative stress and may be useful in the assessment of childhood asthma.
Exhaled 8-isoprostane, a stable marker of oxidative stress, was measured in EBC, in children (5–17 years) with asthma (13 steroid-naïve and 12 inhaled steroid-treated) and 11 healthy control.
Mean exhaled 8-isoprostane concentration was significantly elevated in steroid-naïve asthmatic children compared to healthy children 9.3 (SEM 1.7) vs. 3.8 (0.6) pg/ml, p < 0.01. Children on inhaled steroids also had significantly higher 8-isoprostane levels than those of normal subjects 6.7 (0.7) vs. 3.8 (0.6) pg/ml, p < 0.01. Steroid-naïve asthmatics had higher exhaled nitric oxide (eNO) than those of controls 28.5 (4.7) vs. 12.6 (1.5) ppb, p < 0.01. eNO in steroid-treated asthmatics was similar to control subjects 27.5(8.8) vs. 12.6(1.5) ppb. Exhaled 8-isoprostane did not correlate with duration of asthma, dose of inhaled steroids or eNO.
We conclude that 8-isoprostane is elevated in asthmatic children, indicating increased oxidative stress, and that this does not appear to be normalized by inhaled steroid therapy. This suggests that 8-isoprostane is a useful non-invasive measurement of oxidative stress in children and that antioxidant therapy may be useful in the future.
PMCID: PMC1188076  PMID: 16042771
oxidative stress; 8-isoprostane; exhaled breath condensate; childhood asthma
4.  Overexpression of endothelial nitric oxide synthase suppresses features of allergic asthma in mice 
Respiratory Research  2006;7(1):58.
Asthma is associated with airway hyperresponsiveness and enhanced T-cell number/activity on one hand and increased levels of exhaled nitric oxide (NO) with expression of inducible NO synthase (iNOS) on the other hand. These findings are in paradox, as NO also relaxes airway smooth muscle and has immunosuppressive properties. The exact role of the endothelial NOS (eNOS) isoform in asthma is still unknown. We hypothezised that a delicate regulation in the production of NO and its bioactive forms by eNOS might be the key to the pathogenesis of asthma.
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.
PMCID: PMC1456969  PMID: 16597326
5.  Controlled low flow off line sampling of exhaled nitric oxide in children 
Thorax  2001;56(4):285-289.
BACKGROUND—The aim of this study was to validate exhaled nitric oxide (eNO) values obtained with an alternative off line, single breath, low flow balloon sampling method against on line sampling according to ERS and ATS guidelines in children who could perform both methods.
METHODS—One hundred and twenty seven white children of median age 14.1 years, all pupils of a secondary school, participated in the study. They performed the two different sampling techniques at three different flows of 50, 100, 150 ml/s. Additional measurements were done in random subgroups to determine the influence of the dead space air on eNO values obtained off line by excluding the first 220 ml of exhaled air. All children completed a questionnaire on respiratory and allergic disorders and underwent spirometric tests.
RESULTS—The off line eNO values were significantly higher than the on line values at all flows. At 50 ml/s the geometric mean (SE) off line eNO was 18.7 (1.1) ppb and the on line eNO was 15.1 (1.1) ppb (p<0.0001). However, when dead space air was discarded, off line and on line values were similar: at 50 ml/s off line eNO was 17.7 (1.0) ppb and on line eNO 16.0 (1.2) ppb. There was a good agreement between off line eNO values without dead space air and on line eNO: for 50 ml/s the mean on/off line ratio was 0.95 (95% agreement limits 0.63 to 1.27). The off line eNO level at 50 ml/s in 80 children with negative questionnaires for asthma, rhinitis, and eczema was 13.6 (1.0) ppb compared with 33.3 (1.1) ppb in the remaining children with positive questionnaires on asthma and allergy and/or recent symptoms of cold (p<0.0001).
CONCLUSIONS—In children, off line assessment of eNO using constant low flow sampling and excluding dead space air is feasible and produces similar results as on line assessment with the same exhalation flow rate. Both sampling methods are sufficiently sensitive to differentiate between groups of otherwise healthy school children with and without self-reported asthma, allergy, and/or colds. We propose that, for off line sampling, similar low flow rates should be used as are recommended for on line measurements.

PMCID: PMC1746033  PMID: 11254819
6.  Effect of intubation and mechanical ventilation on exhaled nitric oxide in preterm infants with and without bronchopulmonary dysplasia measured at a median postmenstrual age of 49 weeks 
BMC Research Notes  2014;7:389.
Exhaled nitric oxide (eNO) is a marker of established airway inflammation in adults and children, but conflicting results have been reported in preterm infants when postnatal eNO is measured during tidal breathing. This study investigated the extent to which intubation and mechanical ventilation (MV) affect eNO and NO production (V’NO) in preterm infants with and without bronchopulmonary dysplasia (BPD).
Patients and methods
A total of 176 very low birth weight (VLBW) infants (birth weight <1500 g), including 74 (42%) with and 102 (58%) without BPD, were examined at a median postmenstrual age of 49 weeks. Of the 176 infants, 84 (48%) did not require MV, 47 (27%) required MV for <7 days and 45 (26%) required MV for ≥7 days. Exhaled NO and tidal breathing parameters were measured in sleeping infants during tidal breathing, respiratory mechanics were assessed by occlusion tests, and arterialized capillary blood gas was analyzed.
eNO was significantly correlated with tidal breathing parameters, while V’NO was correlated with growth parameters, including age and body length (p < 0.001 each). Infants who were intubated and received MV for <7 days had significantly lower eNO (p < 0.01) and V’NO (p < 0.01) than non-ventilated infants. In contrast, eNO and V’NO did not differ significantly in non-ventilated infants and those receiving MV for ≥7 days. Multivariate analysis showed that independent on the duration of MV eNO (p = 0.003) and V’NO (p = 0.018) were significantly increased in BPD infants comparable with the effects of intubation and MV on eNO (p = 0.002) and V’NO (p = 0.017).
Preterm infants with BPD show only weak postnatal increases in eNO and V’NO, but these changes may be obscured by the distinct influences of breathing pattern and invasive respiratory support. This limits the diagnostic value of postnatal eNO measurements in the follow-up of BPD infants.
PMCID: PMC4102333  PMID: 24957096
Prematurity; Exhaled nitric oxide; Mechanical ventilation; Bronchopulmonary dysplasia; Lung function test; Neonate
7.  Expired nitric oxide and airway reactivity in infants at risk for asthma 
Family histories of atopy, as well as histories of atopic dermatitis and food allergy, are important risk factors for an infant to have asthma. Although atopic sensitization appears to contribute to the development of asthma, it is unclear when the airways become involved with the atopic process and whether airway function relates to the atopic characteristics of the infant.
We sought to evaluate whether atopic infants without prior episodes of wheezing have increased expired nitric oxide (eNO) levels and heightened airway reactivity.
Infants with eczema were recruited, and atopic status was defined by specific IgE levels to foods or aeroallergens and total IgE levels. eNO, forced expiratory flow at 75% exhaled volume (FEF75), and airway reactivity to inhaled methacholine were measured in sedated infants. Airway reactivity was quantified by using the provocative concentration to decrease FEF75 by 30%.
Median age for the 114 infants evaluated was 10.7 months (range, 2.6–19.1 months). Infants sensitized to egg or milk compared with infants sensitized to neither egg nor milk had lower flows (FEF75: 336 vs 285 mL/s, P < .003) and lower lnPC30 (mg/mL) provocative concentrations to decrease FEF75 by 30% (−0.6 vs −1.2, P < .02) but no difference in eNO levels. Infants with total serum IgE levels of greater than 20 IU/mL had higher eNO levels compared with infants with IgE levels of 20 IU/mL or less (14.6 vs 11.2 ppb, P < .023) but no difference in forced flows or airway reactivity.
Our findings suggest that atopic characteristics of the infant might be important determinants of the airway physiology of forced expiratory flows, airway reactivity, and eNO.
PMCID: PMC4308034  PMID: 18760452
Atopy; eczema; airway reactivity
8.  Effects of nitrogen dioxide exposure and ascorbic acid supplementation on exhaled nitric oxide in healthy human subjects 
Thorax  2001;56(10):774-778.
BACKGROUND—Nitric oxide (NO) is detectable in the exhaled breath, is involved in airway defence and inflammation, and probably modulates bronchial smooth muscle tone. Given the sensitivity of nitrogen oxides to local redox conditions, we postulated that exposure to oxidant or antioxidant compounds could alter concentrations of NO in the exhaled breath (eNO). We assessed the effect of nitrogen dioxide (NO2) and ascorbic acid exposure on eNO in healthy human subjects.
METHODS—Ten healthy subjects were randomised to undergo a 20 minute single blind exposure to NO2 (1.5 parts per million) or medical air in a crossover fashion. Exhaled NO and pulmonary function were measured before and for 3 hours after exposure. In a separate double blind crossover study 20 healthy subjects received ascorbic acid 500 mg twice daily or placebo for 2 weeks with a 6 week interim washout. Serum ascorbic acid levels and eNO were measured before and after each supplementation phase.
RESULTS—NO2 induced a decrease of 0.62 (95% CI 0.32 to 0.92) ppb in the mean post-exposure eNO (p<0.01) with no change in forced expiratory volume in 1 second (FEV1). Oral supplementation with ascorbic acid increased the mean serum ascorbic acid concentration by 7.4(95% CI 5.1 to 9.7) µg/ml (63%) but did not alter eNO.
CONCLUSIONS—NO2 exposure causes a decrease in eNO, an effect which may be mediated through changes in epithelial lining fluid redox state or through a direct effect on epithelial cells. In contrast, ascorbic acid does not appear to play a significant role in the metabolism of NO in the epithelial lining fluid.

PMCID: PMC1745935  PMID: 11562516
9.  Microbial content of household dust associated with exhaled NO in asthmatic children 
Environment international  2013;0:141-147.
Exhaled nitric oxide (eNO) is increasingly used as a non-invasive measure of airway inflammation. Despite this, little information exists regarding the potential effects of indoor microbial components on eNO. We determined the influence of microbial contaminants in house dust and other indoor environmental characteristics on eNO levels in seven-year-olds with and without a physician- diagnosis of asthma. The study included 158 children recruited from a birth cohort study, and 32 were physician-diagnosed as asthmatic. The relationship between eNO levels and exposures to home dust streptomycetes, endotoxin, and molds was investigated. Streptomycetes and endotoxin were analyzed both as loads and concentrations in separate models. Dog, cat, and dust mite allergens also were evaluated. In the multivariate exposure models high streptomycetes loads and concentrations were significantly associated with a decrease in eNO levels in asthmatic (p <0.001) but not in healthy children. The presence of dog allergen, however, was associated with increased levels of eNO (p = 0.001). Dust endotoxin was not significant. The relationship between eNO and indoor exposure to common outdoor molds was u-shaped. In non-asthmatic children, none of the exposure variables were significantly associated with eNO levels. To our knowledge, this is the first study demonstrating a significant association between microbial components in the indoor environment and eNO levels in asthmatic children. This study demonstrates the importance of simultaneously assessing multiple home exposures of asthmatic children to better understand opposing effects. Common components of the indoor Streptomyces community may beneficially influence airway inflammation.
PMCID: PMC3759577  PMID: 23807177
streptomycetes; mold; allergens; asthma; exhaled nitric oxide; children
10.  Exhaled nitric oxide in neonates with or without hypoxemic respiratory failure 
Exhaled nitric oxide (eNO) is one of the airway condensate derived markers, reflecting mainly airway inflammation in asthma and other lung diseases. The changes of eNO levels as pathophysiology of neonatal hypoxemic respiratory failure (HRF) in early postnatal life have not been thoroughly studied. The present study was to establish a method for measuring eNO concentrations in neonates with or without HRF.
Twenty-two newborn infants with HRF and 26 non-NRF controls were included within the first 24 hours of postnatal life. Their eNO levels were detected with a rapid-response chemiluminescence analyzer daily during the first week of their postnatal life, and lung mechanics and gas exchange efficiency were monitored at the same time, such as pulse oxygen saturation (SpO2), inspired fraction of oxygen (FiO2) and other parameters.
During the first two days of postnatal life, eNO values of HRF neonates were significantly higher than those of the control neonates (day 1, 7.9±3.2 vs. 5.8±1.8 parts per billion [ppb], P<0.05; day 2, 8.8±3.2 vs. 6.0±2.4 ppb, P<0.05), but there were no significant differences in the following days. With SpO2/FiO2 increasing, difference of eNO values between the HRF and non-HRF neonates became narrowed, but there was still a two-fold difference of eNO/[SpO2/(FiO2×100)] on days 5-7.
We established a method for measuring eNO and found difference in neonates with or without HRF, which diminished with prolonged postnatal days, reflecting pathophysiological characteristics of HRF.
PMCID: PMC4129703  PMID: 25215009
Neonates; Respiratory failure; Respiratory therapy; Nitric oxide; Respiratory physiology; Nitric oxide synthase
11.  Liquid chromatography/mass spectrometry analysis of exhaled leukotriene B4 in asthmatic children 
Respiratory Research  2005;6(1):119.
The role of leukotriene (LT) B4, a potent inflammatory mediator, in atopic asthmatic and atopic nonasthmatic children is largely unknown. The lack of a gold standard technique for measuring LTB4 in exhaled breath condensate (EBC) has hampered its quantitative assessment in this biological fluid. We sought to measure LTB4 in EBC in atopic asthmatic children and atopic nonasthmatic children. Exhaled nitric oxide (NO) was measured as an independent marker of airway inflammation.
Fifteen healthy children, 20 atopic nonasthmatic children, 25 steroid-naïve atopic asthmatic children, and 22 atopic asthmatic children receiving inhaled corticosteroids were studied. The study design was of cross-sectional type. Exhaled LTB4 concentrations were measured using liquid chromatography/mass spectrometry-mass spectrometry (LC/MS/MS) with a triple quadrupole mass spectrometer. Exhaled NO was measured by chemiluminescence with a single breath on-line method. LTB4 values were expressed as the total amount (in pg) of eicosanoid expired in the 15-minute breath test. Kruskal-Wallis test was used to compare groups.
Compared with healthy children [87.5 (82.5–102.5) pg, median and interquartile range], exhaled LTB4 was increased in steroid-naïve atopic asthmatic [255.1 (175.0–314.7) pg, p < 0.001], but not in atopic nonasthmatic children [96.5 (87.3–102.5) pg, p = 0.59)]. Asthmatic children who were receiving inhaled corticosteroids had lower concentrations of exhaled LTB4 than steroid-naïve asthmatics [125.0 (25.0–245.0) pg vs 255.1 (175.0–314.7) pg, p < 0.01, respectively]. Exhaled NO was higher in atopic nonasthmatic children [16.2 (13.5–22.4) ppb, p < 0.05] and, to a greater extent, in atopic steroid-naïve asthmatic children [37.0 (31.7–57.6) ppb, p < 0.001] than in healthy children [8.3 (6.1–9.9) ppb]. Compared with steroid-naïve asthmatic children, exhaled NO levels were reduced in asthmatic children who were receiving inhaled corticosteroids [15.9 (11.5–31.7) ppb, p < 0.01].
In contrast to exhaled NO concentrations, exhaled LTB4 values are selectively elevated in steroid-naïve atopic asthmatic children, but not in atopic nonasthmatic children. Although placebo control studies are warranted, inhaled corticosteroids seem to reduce exhaled LTB4 in asthmatic children. LC/MS/MS analysis of exhaled LTB4 might provide a non-invasive, sensitive, and quantitative method for airway inflammation assessment in asthmatic children.
PMCID: PMC1283153  PMID: 16236169
12.  Exhaled Nitric Oxide is Decreased by Exposure to the Hyperbaric Oxygen Therapy Environment 
Mediators of Inflammation  2006;2006(5):72620.
Exhaled nitric oxide (eNO) detects airway inflammation. Hyperbaric oxygen therapy (HBOT) is used for tissue hypoxia, but can cause lung damage. We measured eNO following inhalation of oxygen at different tensions and pressures. Methods. Part 1, eNO was measured before and after HBOT. Part 2, normal subjects breathed 40% oxygen. Results. Baseline eNO levels in patients prior to HBOT exposure were significantly higher than in normal subjects (P < .05). After HBOT, eNO significantly decreased in patients (15.4 ± 2.0 versus 4.4 ± 0.5 ppb, P < .001), but not in normal subjects, after either 100% O2 at increased pressure or 40% oxygen, 1 ATA. In an in vitro study, nitrate/nitrite release decreased after 90 minutes HBOT in airway epithelial (A549) cells. Conclusion. HBO exposure causes a fall in eNO. Inducible nitric oxide synthase (iNOS) may cause elevated eNO in patients secondary to inflammation, and inhibition of iNOS may be the mechanism of the reduction of eNO seen with HBOT.
PMCID: PMC1657071  PMID: 17392577
13.  Tooth loss and obstructive sleep apnoea 
Respiratory Research  2006;7(1):8.
Complete tooth loss (edentulism) produces anatomical changes that may impair upper airway size and function. The aim of this study was to evaluate whether edentulism favours the occurrence of obstructive sleep apnoea (OSA).
Polysomnography was performed in 48 edentulous subjects on two consecutive nights, one slept with and the other without dentures. Upper airway size was assessed by cephalometry and by recording forced mid-inspiratory airflow rate (FIF50). Exhaled nitric oxide (eNO) and oral NO (oNO), were measured as markers of airway and oropharyngeal inflammation.
The apnoea/hypopnoea index (AHI) without dentures was significantly higher than with dentures (17·4 ± 3·6 versus 11·0 ± 2·3. p = 0·002), and was inversely related to FIF50 (p = 0·017) and directly related to eNO (p = 0·042). Sleeping with dentures, 23 subjects (48%) had an AHI over 5, consistent with OSA, but sleeping without dentures the number of subjects with abnormal AHI rose to 34 (71%). At cephalometry, removing dentures produced a significant decrease in retropharyngeal space (from 1·522 ± 0·33 cm to 1·27 ± 0·42 cm, p = 0·006). Both morning eNO and oNO were higher after the night slept without dentures (eNO 46·1 ± 8·2 ppb versus 33·7 ± 6·3 ppb, p = 0·035, oNO 84·6 ± 13·7 ppb versus 59·2 ± 17·4 ppb, p = 0·001).
These findings suggest that complete tooth loss favours upper airway obstruction during sleep. This untoward effect seems to be due to decrease in retropharyngeal space and is associated with increased oral and exhaled NO concentration.
PMCID: PMC1368974  PMID: 16417639
14.  Clinical patterns in asthma based on proximal and distal airway nitric oxide categories 
Respiratory Research  2010;11(1):47.
The exhaled nitric oxide (eNO) signal is a marker of inflammation, and can be partitioned into proximal [J'awNO (nl/s), maximum airway flux] and distal contributions [CANO (ppb), distal airway/alveolar NO concentration]. We hypothesized that J'awNO and CANO are selectively elevated in asthmatics, permitting identification of four inflammatory categories with distinct clinical features.
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.
PMCID: PMC2876084  PMID: 20426813
15.  Bidirectional link between upper and lower airways in patients with allergic rhinitis 
European Journal of Medical Research  2009;14(Suppl 4):18-20.
Exhaled nitric oxide has been proposed as a noninvasive marker of eosinophilic airway inflammation in lower airways. The aim of the study was to investigate the impact of atopy, pollen exposure, and pharmacological treatment on NO production in lower airways of patients with allergic rhinitis.
Subjects and methods
Measurements of exhaled NO were performed in 79 non-asthmatic subjects with seasonal allergic rhinitis outside and in pollen season, before and after pharmacological treatment, and in 54 healthy controls.
Patients with allergic rhinitis had significantly higher levels of exhaled NO (18.3 ± 11.0 ppb) than healthy controls (13.0 ± 7.2 ppb) measured outside the pollen season (P = 0.0024). Increased exhaled NO levels were also found in patients with allergic rhinitis in the pollen season (27.0 ± 20.0 ppb) compared with the levels outside pollen season (P = 0.0001), before pharmacological treatment. In rhinitic patients treated by nasal corticosteroids and antihistamines in the pollen season, the levels of exhaled NO were significantly lower (17.0 ± 16.4 ppb; P = 0.045) than those before treatment. No difference was found in NO levels in rhinitic patients outside and in pollen season after pharmacological treatment.
This study has shown the presence of eosinophilic airway inflammation in the lower airways in allergic rhinitis patients. A significant increase of exhaled NO after pollen exposure in rhinitic patients underlies the impact of inflammation on the upper respiratory tract. A bidirectional link between upper and lower airways is confirmed by a decrease in exhaled NO in the pollen season, almost to the starting levels, after application of topic corticosteroids and antihistamines.
PMCID: PMC3521381  PMID: 20156718
exhaled nitric oxide; allergic rhinitis
16.  Increased carbon monoxide in exhaled air of patients with cystic fibrosis 
Thorax  1999;54(10):917-920.
BACKGROUND—Inflammation, oxidative stress, and recurrent pulmonary infections are major aggravating factors in cystic fibrosis. Nitric oxide (NO), a marker of inflammation, is not increased, however, probably because it is metabolised to peroxynitrite. Exhaled carbon monoxide (CO), a product of heme degradation by heme oxygenase 1 (HO-1) which is induced by inflammatory cytokines and oxidants, was therefore tested as a non-invasive marker of airway inflammation and oxidative stress.
METHODS—Exhaled CO and NO concentrations were measured in 29 patients (15 men) with cystic fibrosis of mean (SD) age 25 (1) years, forced expiratory volume in one second (FEV1) 43 (6)%, 14 of whom were receiving steroid treatment.
RESULTS—The concentration of exhaled CO was higher in patients with cystic fibrosis (6.7 (0.6) ppm) than in 15 healthy subjects (eight men) aged 31 (3) years (2.4 (0.4) ppm, mean difference 4.3 (95% CI 2.3 to 6.1), p<0.001). Patients not receiving steroid treatment had higher CO levels (8.4 (1.0) ppm) than treated patients (5.1(0.5) ppm, mean difference 3.3 (95% CI -5.7 to -0.9), p<0.01). Normal subjects had higher NO levels (6.8 (0.4) ppb) than patients with cystic fibrosis (3.2 (0.2) ppb, mean difference 3.8 (95% CI 2.6 to 4.9), p<0.05) and were not influenced by steroid treatment (3.8 (0.4) ppb and 2.7 (0.3) ppb for treated and untreated patients, respectively, mean difference 0.8 (95% CI -0.6 to 2.3), p>0.05). Patients homozygous for the ΔF508 CFTR mutation had higher CO and NO concentrations than heterozygous patients (CO: 7.7 (1.8) ppm and 4.0 (0.6) ppm, respectively, mean difference 3.7 (95% CI -7.1 to -0.3), p<0.05; NO: 4.1 (0.5) ppb and 1.9 (0.7) ppb, respectively, mean difference 2.2 (95% CI -3.7 to -0.6), p<0.05).
CONCLUSIONS—High exhaled CO concentrations in patients with cystic fibrosis may reflect induction of HO-1. Measurement of exhaled CO concentrations may be clinically useful in the management and monitoring of oxidation and inflammatory mediated lung injury.

PMCID: PMC1745371  PMID: 10491455
17.  Effect of allergen-specific immunotherapy with purified Alt a1 on AMP responsiveness, exhaled nitric oxide and exhaled breath condensate pH: a randomized double blind study 
Little information is available on the effect of allergen-specific immunotherapy on airway responsiveness and markers in exhaled air. The aims of this study were to assess the safety of immunotherapy with purified natural Alt a1 and its effect on airway responsiveness to direct and indirect bronchoconstrictor agents and markers in exhaled air.
This was a randomized double-blind trial. Subjects with allergic rhinitis with or without mild/moderate asthma sensitized to A alternata and who also had a positive skin prick test to Alt a1 were randomized to treatment with placebo (n = 18) or purified natural Alt a1 (n = 22) subcutaneously for 12 months. Bronchial responsiveness to adenosine 5'-monophosphate (AMP) and methacholine, exhaled nitric oxide (ENO), exhaled breath condensate (EBC) pH, and serum Alt a1-specific IgG4 antibodies were measured at baseline and after 6 and 12 months of treatment. Local and systemic adverse events were also registered.
The mean (95% CI) allergen-specific IgG4 value for the active treatment group increased from 0.07 μg/mL (0.03-0.11) at baseline to 1.21 μg/mL (0.69-1.73, P < 0.001) at 6 months and to 1.62 μg/mL (1.02-2.22, P < 0.001) at 12 months of treatment. In the placebo group, IgG4 value increased nonsignificantly from 0.09 μg/mL (0.06-0.12) at baseline to 0.13 μg/mL (0.07-0.18) at 6 months and to 0.11 μg/mL (0.07-0.15) at 12 months of treatment. Changes in the active treatment group were significantly higher than in the placebo group both at 6 months (P < 0.001) and at 12 months of treatment (P < 0.0001). However, changes in AMP and methacholine responsiveness, ENO and EBC pH levels were not significantly different between treatment groups. The overall incidence of adverse events was comparable between the treatment groups.
Although allergen-specific immunotherapy with purified natural Alt a1 is well tolerated and induces an allergen-specific IgG4 response, treatment is not associated with changes in AMP or methacholine responsiveness or with significant improvements in markers of inflammation in exhaled air. These findings suggest dissociation between the immunotherapy-induced increase in IgG4 levels and its effect on airway responsiveness and inflammation.
PMCID: PMC2949816  PMID: 20846390
18.  Protection from Lipopolysaccharide-induced Lung Injury by Augmentation of Airway S-Nitrosothiols 
Rationale: S-Nitrosothiols (SNO) inhibit immune activation of the respiratory epithelium and airway SNO levels are decreased in inflammatory lung disease. Ethyl nitrite (ENO) is a gas with chemical properties favoring SNO formation. Augmentation of airway SNO by inhaled ENO treatment may decrease lung inflammation and subsequent injury by inhibiting activation of the airway epithelium.
Objectives: To determine the effect of inhaled ENO on airway SNO levels and LPS-induced lung inflammation/injury.
Methods: Mice were treated overnight with inhaled ENO (10 ppm) or air, followed immediately by exposure to aerosolized LPS or saline. Parameters of inflammation and lung injury were quantified 1 hour after completion of the aerosol exposure and correlated to lung airway and tissue SNO levels.
Measurements and Main Results: Aerosolized LPS induced a decrease in airway and lung tissue SNO levels including S-nitrosylated NF-κB. The decrease in lung SNO was associated with an increase in lung NF-κB activity, cytokine/chemokine expression (keratinocyte-derived chemokine, tumor necrosis factor-α, and IL-6), airway neutrophil influx, and worsened lung compliance. Pretreatment with inhaled ENO restored airway SNO levels and reduced LPS-mediated NF-κB activation thereby inhibiting the downstream inflammatory response and preserving lung compliance.
Conclusions: Airway SNO serves an antiinflammatory role in the lung. Inhaled ENO can be used to augment airway SNO and protect from LPS-induced acute lung injury.
PMCID: PMC2701501  PMID: 19324975
ethyl nitrite; NF-κB; nitric oxide; S-nitrosylation
19.  Exhaled nitric oxide - circadian variations in healthy subjects 
European Journal of Medical Research  2009;14(Suppl 4):6-8.
Exhaled nitric oxide (eNO) has been suggested as a marker of airway inflammatory diseases. The level of eNO is influenced by many various factor including age, sex, menstrual cycle, exercise, food, drugs, etc. The aim of our study was to investigate a potential influence of circadian variation on eNO level in healthy subjects.
Measurements were performed in 44 women and 10 men, non-smokers, without respiratory tract infection in last 2 weeks. The eNO was detected at 4-hour intervals from 6 a.m. to 10 p.m. using an NIOX analyzer. We followed the ATS/ERS guidelines for eNO measurement and analysis.
Peak of eNO levels were observed at 10 a.m. (11.1 ± 7.2 ppb), the lowest value was detected at 10 p.m. (10.0 ± 5.8 ppb). The difference was statistically significant (paired t-test, P < 0.001).
The daily variations in eNO, with the peak in the morning hours, could be of importance in clinical practice regarding the choice of optimal time for monitoring eNO in patients with respiratory disease.
PMCID: PMC3521365  PMID: 20156715
exhaled nitric oxide; circadian variation
20.  Comparison of orally exhaled nitric oxide in allergic versus nonallergic rhinitis 
Fractional exhaled nitric oxide (FeNO), a well-known marker of airway inflammation, is rarely evaluated in rhinitis of different etiology. We aimed to compare the eNO levels in allergic rhinitis (AR) and nonallergic rhinitis (NAR) with/without asthma, as well as the contributing factors that interfere with elevated FeNO.
Patients were enrolled based on chronic nasal symptoms. Orally exhaled NO was measured with the single exhalation method at 50 mL/s. All subjects underwent a panel of tests: skin-prick tests, asthma control test, blood sampling, spirometry, and health-related quality-of-life questionnaires.
The study group consisted of mainly women (130 women/41 men), with a mean age of 32.6 ± 13.2 years. AR was diagnosed in 122 (78.2%), NAR in 34 (21.8%), and 15 subjects were healthy controls. FeNO was insignificantly higher in patients with AR compared with patients with NAR and controls (32.2 parts per billion [ppb] versus 27 and 19.4 ppb), with no difference between genders. NAR + asthma had higher FeNO than those without asthma (40.5 ppb versus 14.9 ppb; p < 0.03), whereas accompanying asthma did not affect FeNO levels in the AR group. AR ± asthma had significantly higher FeNO levels than the NAR-only group (p < 0.01). Among AR + asthma, perennial sensitization caused higher FeNO levels than did seasonal allergens (48.5 ± 33.9 and 19.5 ± 13.6′ p = 0.003), whereas FeNO was significantly higher during the allergen season. Nasally inhaled corticosteroids insignificantly reduced FeNO levels in all groups. Severity and seasonality of rhinitis, asthma, and ocular symptoms, but not gender, age, body mass index, Total IgE, forced expiratory volume in 1 second, and smoking, were associated with FeNO.
Rhinitis and comorbid asthma are responsible for increased FeNO, irrespective of atopy. However, NAR without asthma may not be considered as a strong risk factor for airway inflammation.
PMCID: PMC3906508  PMID: 22487277
Airway inflammation; allergic rhinitis; asthma; atopy; exhaled nitric oxide; inhaled corticosteroids; nonallergic rhinitis
21.  Inhaled Ethyl Nitrite Prevents Hyperoxia-impaired Postnatal Alveolar Development in Newborn Rats 
Rationale: Inhaled nitric oxide (NO) has been used to prevent bronchopulmonary dysplasia, but with variable results. Ethyl nitrite (ENO) forms S-nitrosothiols more readily than does NO, and resists higher-order nitrogen oxide formation. Because S-nitrosylation is a key pathway mediating many NO biological effects, treatment with inhaled ENO may better protect postnatal lung development from oxidative stress than NO.
Objectives: To compare inhaled NO and ENO on hyperoxia-impaired postnatal lung development.
Methods: We treated newborn rats beginning at birth to air or 95% O2 ± 0.2–20.0 ppm ENO for 8 days, or to 10 ppm NO for 8 days. Pups treated with the optimum ENO dose, 10 ppm, and pups treated with 10 ppm NO were recovered in room air for 6 more days.
Measurements and Main Results: ENO and NO partly prevented 95% O2–induced airway neutrophil influx in lavage, but ENO had a greater effect than did NO in prevention of lung myeloperoxidase accumulation, and in expression of cytokine-induced neutrophil chemoattractant-1. Treatment with 10 ppm ENO, but not NO, for 8 days followed by recovery in air for 6 days prevented 95% O2–induced impairments of body weight, lung compliance, and alveolar development.
Conclusions: Inhaled ENO conferred protection superior to inhaled NO against hyperoxia-induced inflammation. ENO prevented hyperoxia impairments of lung compliance and postnatal alveolar development in newborn rats.
PMCID: PMC1994219  PMID: 17478622
bronchopulmonary dysplasia; O-nitrosoethanol; S-nitrosylation
22.  Regulation of inflammatory arthritis by the upstream kinase mitogen activated protein kinase kinase 7 in the c-Jun N-Terminal kinase pathway 
The c-Jun N-terminal kinase (JNK) is a key regulator of matrix metalloproteinase (MMP) and cytokine production in rheumatoid arthritis (RA) and JNK deficiency markedly protects mice in animal models of arthritis. Cytokine-induced JNK activation is strictly dependent on the mitogen-activated protein kinase kinase 7 (MKK7) in fibroblast-like synoviocytes (FLS). Therefore, we evaluated whether targeting MKK7 using anti-sense oligonucleotides (ASO) would decrease JNK activation and severity in K/BxN serum transfer arthritis.
Three 2'-O-methoxyethyl chimeric ASOs for MKK7 and control ASO were injected intravenously in normal C57BL/6 mice. PBS, control ASO or MKK7 ASO was injected from Day -8 to Day 10 in the passive K/BxN model. Ankle histology was evaluated using a semi-quantitative scoring system. Expression of MKK7 and JNK pathways was evaluated by quantitative PCR and Western blot analysis.
MKK7 ASO decreased MKK7 mRNA and protein levels in ankles by about 40% in normal mice within three days. There was no effect of control ASO on MKK7 expression and MKK7 ASO did not affect MKK3, MKK4 or MKK6. Mice injected with MKK7 ASO had significantly less severe arthritis compared with control ASO (P < 0.01). Histologic evidence of synovial inflammation, bone erosion and cartilage damage was reduced in MKK7 ASO-treated mice (P < 0.01). MKK7 deficiency decreased phospho-JNK and phospho-c-Jun in ankle extracts (P < 0.05), but not phospho-MKK4. Interleukin-1beta (IL-1β), MMP3 and MMP13 gene expression in ankle joints were decreased by MKK7 ASO (P < 0.01).
MKK7 plays a critical regulatory role in the JNK pathway in a murine model of arthritis. Targeting MKK7 rather than JNK could provide site and event specificity when treating synovitis.
PMCID: PMC3392838  PMID: 22353730
C-Jun N-terminal kinase; Mitogen-activated protein kinase kinase 7; Rheumatoid arthritis; Anti-sense oligonucleotide
23.  Exhaled nitric oxide in the diagnosis of asthma: comparison with bronchial provocation tests 
Thorax  2005;60(5):383-388.
Background: Bronchial provocation tests such as exercise, methacholine (MCH), and adenosine-5'-monophosphate (AMP) challenges are used extensively in the diagnosis of asthma. A study was undertaken to determine whether exhaled nitric oxide (eNO) can be used to diagnose asthma in patients with non-specific respiratory symptoms and to compare this test with conventional provocation tests.
Methods: Patients with non-specific respiratory symptoms and normal spirometric parameters were included in the study. eNO was measured and exercise, MCH and AMP challenges performed in all subjects. Patients were defined as asthmatic based on clinical follow up 24 months after testing.
Results: Forty patients were considered asthmatic and 45 were not. The area under receiver operating characteristic curves gave values of 0.896 for eNO, 0.781 for exercise, 0.924 for MCH, and 0.939 for AMP (p = 0.033, 0.575 and 0.085 for eNO v exercise, MCH and AMP respectively). From our data, a cut off value of NO >7 ppb at a flow rate of 250 ml/s best differentiates between asthmatics and non-asthmatics (sensitivity 82.5%, specificity 88.9%). Optimal cut off values for other tests were exercise: ΔFEV1 ⩾10% (sensitivity 57.9%, specificity 100%); PC20-MCH: ⩽3 mg/ml (sensitivity 87.5%, specificity 86.7%); and PC20-AMP: ⩽150 mg/ml (sensitivity 89.5%, specificity 95.6%).
Conclusions: Measurement of eNO can be used as a safe, simple and rapid test for the diagnosis of asthma and is as good as bronchial provocation tests.
PMCID: PMC1758892  PMID: 15860713
24.  Differential regulation of anti-inflammatory genes by p38 MAP kinase and MAP kinase kinase 6 
Conventional p38α inhibitors have limited efficacy in rheumatoid arthritis, possibly because p38 blockade suppresses the counter-regulatory mechanisms that limit inflammation. In contrast, targeting the upstream MAP kinase kinases, MKK3 and MKK6, partially maintains p38-mediated anti-inflammatory responses in bone marrow-derived macrophages (BMDM). In this study, we explored the mechanisms that preserve anti-inflammatory gene expression by evaluating differential regulation of IL-10 and p38-dependent anti-inflammatory genes in MKK3−/−, MKK6−/−, and p38 inhibitor-treated wildtype cells.
BMDM from wild type (WT), MKK3−/−, and MKK6−/− mice were pre-treated with p38 inhibitor SB203580 (SB), JNK inhibitor SP600125 (SP), and/or ERK inhibitor PD98059 (PD) and stimulated with LPS. Supernatant protein levels were measured by multiplex bead immunoassay. mRNA expression was determined by qPCR and protein expression by Western blot analysis. De novo IL-10 mRNA synthesis was quantified in cells treated with ethynyl-uridine and LPS followed by reverse transcription and qPCR. mRNA half-life was measured in LPS-treated cells that were then incubated with actinomycin D ± SB203580.
Pre-treatment of WT BMDM with p38 inhibitor significantly reduced IL-10 production in the three groups, while ERK and JNK inhibitors had minimal effects. IL-10 production was significantly decreased in MKK3−/− BMDM compared with either WT or MKK6−/− cells. IL-10 mRNA expression was modestly reduced in MKK3−/− BMDM but was preserved in MKK6−/− cells compared with WT. De novo IL-10 mRNA synthesis was inhibited in MKK3−/− and p38 inhibitor pre-treated cells, but not MKK6−/− cells compared with WT. IL-10 mRNA half-life was markedly reduced in p38 inhibitor-treated WT cells while MKK-deficiency had minimal effect. DUSP1 mRNA levels were preserved in MKK-deficient cells but not in p38 inhibitor-treated WT cells. Tristetraprolin mRNA and protein levels were reduced in p38 inhibitor-treated WT cells compared with MKK6−/− cells.
Unlike p38-inhibition, the absence of MKK6 mostly preserves IL-10 and TTP protein expression in BMDM. MKK6-deficiency also spares DUSP1 and IL-1RA, which are key negative regulators of the inflammatory response. Together, these data suggest that MKK6 is a potential therapeutic target in RA.
PMCID: PMC4030013  PMID: 24855454
p38 inhibitor; Rheumatoid arthritis; IL-10; MKK6; Tristetraprolin; Anti-inflammatory response
25.  531 Comparison of Exhaled Nitric Oxide and Spirometry in Hispanic/Latino Children Living in Miami to Those Living in Latin America 
The World Allergy Organization Journal  2012;5(Suppl 2):S185-S186.
Differences in atopic markers of inflammation has been shown to be due to varying environmental exposures between individuals. There is sparse information in the literature to compare the levels of atopic inflammatory markers in Hispanics/Latinos from distinctly different environments. Our aim was to study the levels of these clinical inflammatory markers in this population with similar levels of allergy/asthma control but from differing environments.
A retrospective review was limited to Hispanic/Latino children referred to our Allergy clinic over 6 months. These children were referred by their pediatrician for diagnosis of asthma and/or reactive airways disease. Respiratory tests of spirometry with Koko (nSpire Health, Colorado) and exhaled NO with MINO (Aerocrine, Sweden) was performed in all children by ATS guidelines. Collection of laboratory results of serum eosinophils and total IgE was also done. Two groupings were made based on the location of family residence, either locally in Miami, Florida (MF) or Latin America (LA). All patients in the MF group were of Hispanic/Latino ancestry, either first or second generation. The country of ancestry represented in the MF group were Colombia, Costa Rica, Cuba, Ecuador, El Salvador, Mexico, Nicaragua, Venezuela. The patients in the LA group were coming from Costa Rica, Dominican Republic, Ecuador, El Salvador, Guatemala, Honduras, and Venezuela.
Thirty-five children fromMF group and 29 children from the LA group were found. The mean age in the MF group was 8+3 years of age and in the LA group was 9+4 years of age. There was statistical significance between eNO in both groups. The mean eNO was 23ppb in the MF group and 41ppb in the LA group. Normal eNO based on age and height for both groups is less than 15 to 20 ppb. There was no statistical significance between FEV1% in spirometry between both groups. The mean FEV1% in the MF group was 95 + 13%, and the mean FEV1% in the LA group was 92 + 9%. No differences were found between groups with either laboratory measures of serum eosinophils or total IgE.
Our analysis confirmed that despite similar levels of allergy/asthma control, there was a difference found in eNO in Hispanics/Latinos. This may be attributable to differences in environmental exposures between MF and LA.
PMCID: PMC3513138

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