Epithelial alarmin levels in exhaled breath condensate in patients with idiopathic pulmonary fibrosis: A pilot study.

INTRODUCTION: Interleukin (IL)-25, IL-33 and thymic stromal lymphopoietin (TSLP) are epithelial alarmins involved in innate immune responses and have been shown to play an important role in chronic lung diseases. No data are available regarding their levels in exhaled breath condensate (EBC) in idiopathic pulmonary fibrosis (IPF). OBJECTIVES: To examine IL-25, IL-33 and TSLP levels in the EBC obtained from patients with IPF and compare them to those in healthy controls, patients with asthma and chronic obstructive pulmonary disease (COPD). METHODS: Twenty-three patients with asthma, 25 patients with COPD, 15 patients with IPF and 16 healthy controls were studied. Concentrations of alarmins in the EBC were evaluated by means of ELISA. RESULTS: IL-25 EBC levels were numerically lowest in IPF (25.33 ± 8.84 pg/ml). However, they did not differ significantly from healthy subjects (43.18 ± 5.53 pg/ml), but were significantly lower compared to asthma (72.07 ± 6.03 pg/ml; P < .001). IL-33 EBC levels were significantly increased in IPF (3.41 ± 0.55 pg/ml) compared to healthy controls (1.20 ± 0.60 pg/ml; P < .01) but did not differ from asthma (3.68 pg/ml) and COPD levels (2.47 ± 0.34 pg/ml). There were significant correlations between IL-33 EBC levels and lung diffusion capacity of carbon monoxide (DLco ) absolute (r = .63; P < .05) and % of predicted values (r = .67; P < .01) as well as with time since diagnosis (r = -.59; P < .05) in IPF subjects. TSLP was undetectable in examined samples. CONCLUSION: IL-25 and IL-33 are detectable in the EBC obtained from IPF subjects. Increased levels of IL-33 compared to healthy controls indicate its possible role in the pathobiology of IPF.

HFA-BDP Metered-Dose Inhaler Exhaled Through the Nose Improves Eosinophilic Chronic Rhinosinusitis With Bronchial Asthma: A Blinded, Placebo-Controlled Study.

Background: Eosinophilic chronic rhinosinusitis (ECRS) is a subtype of chronic rhinosinusitis with nasal polyps in Japanese. ECRS highly associated with asthma is a refractory eosinophilic airway inflammation and requires comprehensive care as part of the united airway concept. We recently reported a series of ECRS patients with asthma treated with fine-particle inhaled corticosteroid (ICS) exhalation through the nose (ETN). Objective: To evaluate fine-particle ICS ETN treatment as a potential therapeutic option in ECRS with asthma. Methods: Twenty-three patients with severe ECRS under refractory to intranasal corticosteroid treatment were randomized in a double-blind fashion to receive either HFA-134a-beclomethasone dipropionate (HFA-BDP) metered-dose inhaler (MDI) ETN (n = 11) or placebo MDI ETN (n = 12) for 4 weeks. Changes in nasal polyp score, computed tomographic (CT) score, smell test, and quality of life (QOL) score from baseline were assessed. Fractionated exhaled nitric oxide (FENO) was measured as a marker of eosinophilic airway inflammation. Response to corticosteroids was evaluated before and after treatment. Additionally, deposition of fine-particles was visualized using a particle deposition model. To examine the role of eosinophils on airway inflammation, BEAS-2B human bronchial epithelial cells were co-incubated with purified eosinophils to determine corticosteroid sensitivity. Results: HFA-BDP MDI ETN treatment improved all assessed clinical endpoints and corticosteroid sensitivity without any deterioration in pulmonary function. FENO and blood eosinophil number were reduced by HFA-BDP MDI ETN treatment. The visualization study suggested that ETN at expiratory flow rates of 10-30 L/min led to fine particle deposition in the middle meatus, including the sinus ostia. Co-incubation of eosinophils with BEAS-2B cells induced corticosteroid resistance. Conclusions: Additional HFA-BDP MDI ETN treatment was beneficial in patients with ECRS and should be considered as a potential therapeutic option for eosinophilic airway inflammation such as ECRS with asthma. (UMIN-CTR: R000019325) (http://www.umin.ac.jp/ctr/index.htm).

Maternal allergy as a potential source of variability of exhaled nitric oxide in children non-sensitized to common domestic allergens.

The goal of the study is to evaluate the importance of maternal atopy as a potential biological source of variability of exhaled FeNO values in healthy children who were non-asthmatic and non-sensitized to common domestic allergens. The study sample consisted of 61 seven-year old children. Fractional exhaled nitric oxide (FeNO) has been measured by NObreath (Bedfont portable device). Children with reported maternal atopy had significantly higher mean FeNO values (geometric mean =10.7 ppb; 95%CI: 6.7-17.1 ppb) than those who denied it (geometric mean =5.2 ppb 95%CI: 3.9-6.9 ppb) (p=0.010). Neither the correlation between FeNO values and gender, respiratory and eczema symptoms, nor ETS exposure in the prenatal and postnatal period or body mass of children were significant. We also found no significant association of FeNO values with the amount of common domestic allergens measured in the households. The results of the ROC analysis suggested 11 ppb as the cut-off point for FeNO to distinguish groups of healthy children with and without maternal atopy. In conclusion, our study provided some evidence suggesting that maternal atopy may affect FeNO level in children independently of asthma and sensitization status to common domestic allergens. The data should be considered in the interpretation of FeNO levels in clinical practice and setting up FeNO screening criteria for identification of eosinophilic airway inflammation.

Extended exhaled nitric oxide analysis in field surveys of schoolchildren: a pilot test.

Extended exhaled nitric oxide (eNO) analysis can distinguish proximal and distal airway contributions to FeNO. Thus, it has the potential to detect effects of different environmental influences, allergic phenotypes, and genetic variants on proximal and distal airways. However, its feasibility in field surveys has not been demonstrated, and models for estimating compartmental NO contributions have not been standardized. In this study we verified that extended NO tests can be performed by children in schools, and assessed different analytical models to estimate bronchial flux and alveolar NO concentration. We tested students at a middle school, using EcoMedics NO analyzers with ambient NO scrubbers, at flows of 50 (conventional), 30, 100, and 300 ml/sec, with 2-3 trials at each flow. Data from 65 children were analyzed by two linear and four nonlinear published models, plus a new empirical nonlinear model. Bronchial NO flux estimates from different models differed in magnitude but were strongly correlated (r >or= 0.95), and increased in subjects with allergic asthma. Alveolar concentration estimates differed among models and did not consistently show the same effects of allergy or asthma. A novel index of nonlinear behavior of NO output versus flow was significantly related to asthma status, and not strongly correlated with bronchial flux or alveolar concentration. Field-based extended NO testing of children can yield useful information about NO in different regions of the respiratory tract that is not obtainable from conventional FeNO. Extended NO analysis holds promise for investigating environmental and genetic determinants of regional airway inflammatory states.

Decreased exhaled nitric oxide as a marker of postinsult immune paralysis.

Nitric oxide (NO) regulates neutrophil migration and alveolar macrophage functions such as cytokine synthesis and bacterial killing, both of which are impaired in immune paralysis associated with critical illness. The aim of this study was to determine whether NO is involved in immune paralysis and whether exhaled NO measurement could help to monitor pulmonary defenses. NO production (protein expression, enzyme activity, end products, and exhaled NO measurements) was assessed in rats after cecal ligation and puncture to induce a mild peritonitis (leading to approximately 20% mortality rate). An early and sustained decrease in exhaled NO was found after peritonitis (from 1 to 72 h) compared with healthy rats [median (25th-75th percentile), 1.5 parts per billion (ppb) (1.2-1.7) vs. 4.0 ppb (3.6-4.3), P < 0.05], despite increased NO synthase-2 and unchanged NO synthase-3 protein expression in lung tissue. NO synthase-2 activity was decreased in lung tissue. Nitrites and nitrates in supernatants of isolated alveolar macrophages decreased after peritonitis compared with healthy rats, and an inhibitory experiment suggested arginase overactivity in alveolar macrophages bypassing the NO substrate. Administration of the NO synthase-2 inhibitor aminoguanidine to healthy animals reproduced the decreased neutrophil migration toward alveolar spaces that was observed after peritonitis, but L-arginine administration after peritonitis failed to correct the defect of neutrophil emigration despite increasing exhaled NO compared with D-arginine administration [4.8 (3.9-5.7) vs. 1.6 (1.3-1.7) ppb, respectively, P < 0.05]. In conclusion, the decrease in exhaled NO observed after mild peritonitis could serve as a marker for lung immunodepression.