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Purpose: This study aimed to demonstrate the role of fractional concentration of exhaled nitric oxide (FeNO) in association with Global Initiative for Asthma (GINA) guidelines for treatment of adult patients with asthma., Methods: It was a prospective and randomized study. The symptomatic asthmatic patients were randomly divided into two groups: GINA group (followed GINA guidelines; N = 86) or GINA + FeNO group (followed GINA guidelines + FeNO for titration of inhaled corticosteroids - ICS; N = 90). They were followed-up for 9 months., Results: In GINA group, 37.2% patients had no treatment and 62.8% patients discontinued treatment vs. 40.0% and 60.0% in GINA + FeNO, respectively. After 3, 6 and 9 months of treatment, the percentage of mild, moderate and severe asthma showed no significant difference between the two groups. At 9th month, Δ moderate asthma (reduction) in GINA + FeNO group was significantly higher than in the GINA group (-22.0% vs. -11.6%; P = 0.018). The improvement of asthma control test (ACT) score was not different between the groups at 9th month (12 ± 6 vs. 10 ± 5; P > 0.05); the level of FeNO reduction in GINA + FeNO group was significantly higher than that in GINA group (-42 ± 11 vs. -35 ± 9; P = 0.022). The daily dose of ICS in GINA + FeNO group was significantly lower than that in GINA group (397 ± 171 vs. 482 ± 240 mcg and 375 ± 203 vs. 424 ± 221 mcg; respectively) at the end of 6 and 9 months., Conclusion: The use of FeNO in association with GINA guidelines has a beneficial role for accurate daily dose of ICS in adult patients with asthma., Competing Interests: Declaration of competing interest The authors declare no conflict of interests for this study., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: This study aimed to evaluate the role of nasal nitric oxide (NO) in the management of patients with persistent allergic rhinitis (PER)., Methods: It was a randomized and comparative study. The study subjects were classified as controls (healthy subjects) or patients with PER based on defined criteria. All clinical, functional and biological data were collected for analyzing. Nasal fractional exhaled nitric oxide (FENO) was measured by electroluminescence device. Patients with PER were randomized for treatment with antihistamine (ATH) combined with leukotriene receptor antagonists (LRA) or only with intranasal steroids (INS)., Results: During two years, 501 subjects were included: 234 control subjects and 267 patients with PER. The levels of nasal NO, total IgE, blood eosinophil counts, and apnea-hypopnea index (AHI) in patients with PER were higher than controls (P < 0.001; P < 0.05; P < 0.05; P < 0.01; respectively). There were statistically significant correlations between nasal NO, nasal peak flows, total IgE, and blood eosinophil counts in patients with PER (R = -0.687 and P = 0.0012; R = -0.643 and P = 0.0018; R = 0.432 and P = 0.0024; R = 0.445 and P = 0.002; respectively). After 6 months of treatment, patients treated with INS had greater improvement of clinical symptoms and reduction of nasal NO values than patients treated with ATH + LRA (985 ± 253 vs. 732 ± 298 ppb; P < 0.05)., Conclusion: Nasal NO measurement is a useful tool for the follow-up of patients with PER. It also helps clinicians to estimate the level of response to treatment in patients with PER., Competing Interests: Declaration of competing interest The authors declare no conflict of interests for this study., (Published by Elsevier B.V.)

Background and Objective: The concentration of exhaled nitric oxide (eNO), reflecting the activity of inducible NO synthase in airway epithelium, has been found to increase in patients with obstructive sleep apnea (OSA). This study aimed to measure eNO concentration in patients with suspected OSA and to correlate different eNO parameters with clinical and sleep apnea characteristics., Methods: In this cross-sectional study, all patients underwent in-lab overnight polysomnography (PSG) and eNO measurement using a method of multiple flow rates before and after PSG (pre- and post-PSG)., Results: According to the result of PSG, 82 persons were divided into two groups: control subjects (n = 30; 54 ± 14 years) and patients with OSA defined as apnea-hypopnea index (AHI) ≥ 5/hour (n = 52; 53 ± 12 years). Body mass index (BMI) and neck and abdomen circumferences of OSA patients were significantly higher than those from control subjects. In OSA group, post-PSG alveolar NO concentration (CANO) (5.3 ± 1.9 ppb) was significantly higher than pre-PSG CANO (4.0 ± 1.7 ppb; P < 0.001). Significant correlations have been found between CANO and AHI (P < 0.001) and between CANO and nadir SpO2 (P < 0.05). The daytime CANO value of more than 4.1 ppb can be used to screen symptomatic subjects for the presence of OSA with a high specificity of 93.3%., Conclusion: Our findings indicate CANO as a surrogate marker for OSA in persons with suggestive symptoms.

Exhaled nitric oxide (NO) is increased as a result of lung inflammation, which in turn causes subsequent interstitial lung disease in patients with systemic sclerosis (SSc). However, the exact time course of inflammatory and fibrotic changes in the SSc lung has not yet been described. Our objective was to assess the chronological evolution of lung inflammatory and fibrotic processes in mice pre-treated with hypochlorous acid (HOCl) or bleomycin. C57BL/6 mice were randomized into three groups receiving subcutaneous injections of HOCl, bleomycin, or PBS for 2, 4 or 6 weeks. Exhaled NO (eNO) was measured at the end of each injection period and after 2 resting weeks without injection (8 week group). Mice were then sacrificed to obtain skin and lung tissues to measure fibrotic changes and NO synthases (NOS) expression. Increased eNO, inducible NOS and nitrotyrosine expression in bronchial epithelium, lung neutrophils and macrophages were observed at early phases in both HOCl- and bleomycin-treated mice. Conversely, lung vascular endothelial NOS expression decreased significantly at 6th and 8th weeks. Skin fibrosis was significantly increased from the 4th week and lung fibrosis from 6th week. We conclude that lung inflammation occurs early after injury as reflected by increased exhaled NO and inducible NOS expression, and precedes fibrotic changes in skin and lungs of mice pre-treated with bleomycin and HOCl. Early detection and treatment of pulmonary inflammation might be useful in preventing subsequent occurrence of lung fibrosis in SSc patients.

Purpose: To assess distal/alveolar inflammation in patients with suggestive symptoms of obstructive sleep apnoea (OSA) using exhaled nitric oxide (NO) measured by two-compartment model (2-CM) after correction for axial NO back-diffusion (trumpet model)., Methods: Ninety five patients suspected for OSA prospectively underwent pulmonary function test, overnight polysomnography (PSG), and exhaled NO measurement. Patients with apnoea-hypopnoea index (AHI) < 5/hour were included in non-OSA group. Exhaled NO was repeatedly measured after PSG in 21 OSA patients and 8 non-OSA subjects., Results: Alveolar NO concentration (C(ANO)) was significantly higher in OSA patients (n = 71; 4.07 ± 1.7 ppb) as compared with non-OSA subjects (n = 24; 2.24 ± 1.06 ppb; p < 0.0001) whilst maximal bronchial NO flux (J'awNO) and fractional exhaled NO (F(ENO)) did not differ between the two groups. C(ANO) was strongly associated to AHI (r = 0.701; p < 0.0001) and to recording time with SaO2 < 90% (ST-90%; r = 0.659; p < 0.0001) in OSA patients but not in non-OSA persons. The area under ROC curve for screening patients with OSA and significant nocturnal oxygen desaturation (ST-90% > 1%) was 0.865 ± 0.036 (95% IC, 0.793-0.937; p < 0.0001). C(ANO) at 4.5 ppb could detect these patients with specificity of 94% and sensitivity of 46%. Increase of C(ANO) measured after PSG was significantly related to oxygen desaturation index (ST-90%) in OSA patients., Conclusions: Increased alveolar NO concentration was related to the severity of nocturnal oxygen desaturation in patients with OSA, linking the distal airway inflammation to intermittent hypoxia. (250 words)., (Copyright © 2015 Elsevier Inc. All rights reserved.)

White matter damage (WMD) and bronchopulmonary dysplasia (BPD) are the two main complications occurring in very preterm infants. Inhaled nitric oxide (iNO) has been proposed to promote alveolarization in the developing lung, and we have reported that iNO promotes myelination and induces neuroprotection in neonatal rats with excitotoxic brain damage. Our hypothesis is that, in addition to its pulmonary effects, iNO may be neuroprotective in rat pups exposed to hyperoxia. To test this hypothesis, we exposed rat pups to hyperoxia, and we assessed the impact of iNO on WMD and BPD. Rat pups were exposed to either hyperoxia (80% FiO2) or to normoxia for 8 days. Both groups received iNO (5 ppm) or air. We assessed the neurological and pulmonary effects of iNO in hyperoxia-injured rat pups using histological, molecular and behavioral approaches. iNO significantly attenuated the severity of hyperoxia-induced WMD induced in neonatal rats. Specifically, iNO decreased white matter inflammation, cell death, and enhanced the density of proliferating oligodendrocytes and oligodendroglial maturation. Furthermore, iNO triggered an early upregulation of P27kip1 and brain-derived growth factor (BDNF). Whereas hyperoxia disrupted early associative abilities, iNO treatment maintained learning scores to a level similar to that of control pups. In contrast to its marked neuroprotective effects, iNO induced only small and transient improvements of BPD. These findings suggest that iNO exposure at low doses is specifically neuroprotective in an animal model combining injuries of the developing lung and brain that mimicked BPD and WMD in preterm infants., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Animal models such as rats and mice are useful for studying the multiple roles of nitric oxide (NO) in various respiratory disorders. The production of NO is catalyzed by the three isoforms of the enzymes (NO synthases; NOS). Indirect assessment of NOS gene or protein expression only provides partial information on the role of NO in health and lung disease. NO can also be measured in exhaled air by invasive or non-invasive approaches as a direct and quantitative marker of NO production in animal models. Whilst addressing the different methods of exhaled NO analysis in small animals (rats and mice), this review also focuses on the possible clinical implications, and discusses the advantages and limitations of these methods.

Background: Respiratory failure is a life-threatening and unpredictable complication of systemic sclerosis (SSc). A study was undertaken to assess the value of alveolar nitric oxide (NO) in predicting the risk of lung function deterioration leading to respiratory failure or death in patients with SSc., Methods: 105 patients with SSc were enrolled in this prospective cohort and were followed longitudinally over a 3-year period during which the risk of occurrence of deleterious events was analysed according to alveolar concentration (C(A)NO), conducting airway output (J'(aw)NO) and fractional concentration (F(E)NO(0.05)) of exhaled NO measured at inclusion. Comparison was made between each NO parameter to predict the occurrence of deleterious events, defined as a 10% decrease in total lung capacity or forced vital capacity from baseline, or death., Results: The area under the receiver operating characteristic curve of C(A)NO to predict the occurrence of the combined events was 0.84 (95% CI 0.76 to 0.92; p<0.001), which was significantly higher than those of J'(aw)NO and F(E)NO(0.05) (p<0.001). A cut-off of C(A)NO of 5.3 ppb had a sensitivity of 88% and a specificity of 62% for the prediction of the occurrence of combined events during follow-up, and was validated in an independent cohort of patients with SSc. Combined events occurred more frequently in patients whose C(A)NO was >5.3 ppb. The adjusted HR for patients with C(A)NO >5.3 ppb was 6.06 (95% CI 2.36 to 15.53; p<0.001). C(A)NO accurately predicted the occurrence of combined events irrespective of forced vital capacity values or the presence of interstitial lung disease at baseline., Conclusions: Increased C(A)NO accurately identifies patients with SSc with a high risk of developing lung function deterioration and may help to initiate early appropriate treatment.

Objective: Lung inflammation is present in patients with systemic sclerosis (SSc) and interstitial lung disease (ILD), but the mechanisms linking inflammatory and fibrotic processes in ILD are unknown. Our aim was to investigate whether alveolar inflammation, reflected by increased alveolar concentration of exhaled nitric oxide (C(A)NO), is related to the ability of serum from patients with SSc to induce pulmonary fibroblast proliferation (PFP) and myofibroblast conversion., Methods: C(A)NO was measured in all subjects (37 patients with SSc and 10 healthy controls) whose sera were used to stimulate PFP (assessed by BrdU labeling index) and myofibroblast conversion (detected by alpha-smooth muscle actin expression). The PFP index in patients with SSc was compared to control values, and between patients with SSc who had elevated (> 4.3 ppb) and normal ( 4.3 ppb; n = 25, median 1.1, range 0.98-1.23) than in patients with SSc who had normal C(A)NO ( 4.3 ppb than in patients whose C(A)NO was

Nitric oxide metabolites (NOx) in serum, and alveolar concentration of NO (CA(NO)), are markers of inflammation and alveolitis, respectively, in systemic sclerosis (SSc). We prospectively evaluated the usefulness of both NOx and CA(NO) to assess lung involvement and skin fibrosis in SSc. Serum NOx, and CA(NO) measured by two different methods, namely the two-compartment (2CM) and the "trumpet" models (TM), were concomitantly assessed in 65 patients with SSc and 17 healthy controls. Whilst serum NOx remained comparable between groups, CA(NO) were significantly higher in SSc patients (n=65, 6.7ppb; 4.8-9.7 and 5.9ppb; 3.9-8.9) as compared with controls (n=17, 3.0ppb; 2.0-3.8 and 1.8ppb; 1.1-2.9, p<0.001, p<0.001) using the 2CM and the TM, respectively). CA(NO) from SSc patients with interstitial lung disease (ILD) (n=26, 8.6ppb; 6.5-10.9 and 8.5ppb; 5.9-10.7) or pulmonary arterial hypertension (n=12, 7.3ppb; 6.5-10.4 and 6.9ppb; 5.4-9.9) were significantly higher as compared with patients without ILD (n=27, 4.9ppb; 3.8-6.5 and 4.7ppb; 2.8-5.7; p<0.001 and p<0.001) using the 2CM and the TM, respectively). CA(NO) assessed either by the 2CM or the trumpet model were directly related to the extent of ILD and inversely related to DLCO. There was no correlation between NOx and ILD, or DLCO. Neither CA(NO) nor NOx was correlated with skin fibrosis and no relationship was found between CA(NO) and NOx. Alveolar concentration of NO, but not serum NOx, closely correlates with the extent of ILD in patients with systemic sclerosis. Neither parameter, however, is related to skin fibrosis.