Single constant flow exhaled nitric oxide (eNO) cannot distinguish between the sources of NO. The present study measured eNO at multiple expired flows (MEFeNO) to partition NO into alveolar (Calv,NO) and bronchial (Jaw,NO) fractions to investigate peripheral lung contribution to eNO in chronic obstructive lung disease (COPD).MEFeNO were made in 81 subjects including 18 nonsmokers, 16 smokers and 47 COPD patients of different severity by the classification of the Global Initiative for Chronic Obstructive Lung Disease (GOLD): 0 (n514), 1 (n57), 2 (n511), 3 (n58) and 4 (n57).COPD severity was correlated with an increased Calv,NO regardless of the patient's smoking habit or current treatment. The levels of Calv,NO (in ppb) were 1.4¡0.09 in nonsmokers, 2.1¡0.1 in smokers categorised as GOLD stage 0 (smokers-GOLD0), 3.3¡0.18 in GOLD1-2 and 3.4¡0.1 in GOLD3-4. Jaw,NO levels (pL?s -1 ) were higher in nonsmokers than smokers-GOLD0 (716.2¡33.3versus 464.7¡41.8), GOLD3-4 (609.4¡71). Diffusion of NO in the airways (Daw,NO pL?ppb -1 s -1 ) was higher (p,0.05) in GOLD3-4 than in nonsmokers (15¡1.2 versus 11¡0.5) and smokers-GOLD0 (11.6¡0.5). MEFeNO measurements were reproducible, free from day-to-day and diurnal variation and were not affected by bronchodilators.In conclusion, chronic obstructive pulmonary disease is associated with elevated alveolar nitric oxide. Measurements of nitric oxide at multiple expired flows may be useful in monitoring inflammation and progression of chronic obstructive pulmonary disease, and the response to anti-inflammatory treatment.KEYWORDS: Chronic obstructive pulmonary disease, exhaled nitric oxide, multiple expiratory flow, small airway inflammation S ingle expiratory flow exhaled nitric oxide (eNO) measurements are simple, highly reproducible [1], have been used to monitor larger airway inflammation in asthma research [2], and are now moving into clinical practice [3]. However, small airways and lung parenchyma are the predominant sites of inflammation in patients with chronic obstructive pulmonary disease (COPD) [4]. Progression of COPD is associated with the accumulation of inflammatory mucous exudates in the lumen and infiltration of the small airway wall by inflammatory cells [4]. There is a high level of expression of inducible NO synthase (iNOS) presence in sputum macrophages [5], alveolar walls, small airway epithelium and vascular smooth muscle of COPD patients [5,6]. In patients with COPD this may result in an increased production of NO and NO-related species in the lung periphery, which through the function of peroxynitrite may amplify the inflammation and lead to inhaled corticosteroid (ICS) resistance, particularly as the disease becomes more severe [7].The current single expiratory technique measures predominantly larger airway-derived NO and may only partially reflect peripheral inflammation [8,9]. eNO is often in the normal range or even reduced in moderate COPD [10], probably due to down-regulation of endothelial NO synthase (eNOS) [11] and iNOS [12] by cigarette ...

Measurement of J(NO) and C(alv) is feasible in 70% of school-age children. FeNO(50) and J(NO) give the same information (r = 0.97, p < 0.0001), C(alv) is higher in asthmatic children than in normal children and is affected by asthma control, but not by atopy. C(alv) may possibly reflect alveolar inflammation in asthma.

Rationale: Nitric oxide (NO) is increased in the lung periphery of patients with chronic obstructive pulmonary disease (COPD). However, expression of the NO synthase(s) responsible for elevated NO has not been identified in the peripheral lung tissue of patients with COPD of varying severity. Objectives:Methods: Protein and mRNA expression of nitric oxide synthase type I (neuronal NOS [nNOS]), type II (inducible NOS [iNOS]), and type III (endothelial NOS [eNOS]) were quantified by Western blotting and reverse transcription-polymerase chain reaction, respectively, in specimens of surgically resected lung tissue from nonsmoker control subjects, patients with COPD of varying severity, and smokers without COPD, and in a lung epithelial cell line (A549). The effects of nitrative/oxidative stress on NOS expression and activity were also evaluated in vitro in A549 cells. nNOS nitration was quantified by immunoprecipitation and dimerization of nNOS was detected by low-temperature SDS-PAGE/Western blot in the presence of the peroxynitrite generator, 3-morpholinosydnonimine-N-ethylcarbamide (SIN1), in vitro and in vivo. Measurements and Main Results:Lung tissue from patients with severe and very severe COPD had graded increases in nNOS (mRNA and protein) compared with nonsmokers and normal smokers. Hydrogen peroxide (H 2 O 2 ) and SIN1 as well as the cytokine mixture (IFN-γ, IL-1β, and tumor necrosis factor-α) increased mRNA expression and activity of nNOS in A549 cells in a concentration-dependent manner compared with nontreated cells. Tyrosine nitration resulted in an increase in nNOS activity in vitro, but did not affect its dimerization. Conclusions:Patients with COPD have a significant increase in nNOS expression and activity that reflects the severity of the disease and may be secondary to oxidative stress.

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