Decreased concentration of exhaled nitric oxide (NO) in patients with cystic fibrosis

Grasemann, Hartmut; Michler, Enrico; Wallot, M.; Ratjen, Félix

doi:10.1002/(sici)1099-0496(199709)24:3<173::aid-ppul2>3.0.co;2-o

Cited by 191 publications

(154 citation statements)

References 37 publications

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“…− released by activated PMNs can thus decrease NO [46], and we suggest that NO consumption by the reaction with O2 − contributes to the decreased levels of exhaled NO seen in CF patients [47]. In addition, nitrosative lesions in the lung tissue of CF patients can occur as a consequence of ONOO − reacting with tyrosine residues, leading to the increased content of 3-nitrotyrosine in CF lungs [48].…”

Section: Discussionmentioning

confidence: 79%

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Nitric oxide production by polymorphonuclear leucocytes in infected cystic fibrosis sputum consumes oxygen

Kolpen

Bjarnsholt

Moser

et al. 2014

Clinical and Experimental Immunology

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SummaryChronic Pseudomonas aeruginosa lung infection in cystic fibrosis (CF) patients is characterized by persisting mucoid biofilms in hypoxic endobronchial mucus. These biofilms are surrounded by numerous polymorphonuclear leucocytes (PMNs), which consume a major part of present molecular oxygen (O2) due to production of superoxide (O2 − ). In this study, we show that the PMNs also consume O2 for production of nitric oxide (NO) by the nitric oxide synthases (NOS) in the infected endobronchial mucus. Fresh expectorated sputum samples (n = 28) from chronically infected CF patients (n = 22) were analysed by quantifying and visualizing the NO production. NO production was detected by optode measurements combined with fluorescence microscopy, flow cytometry and spectrophotometry. Inhibition of nitric oxide synthases (NOS) with N G -monomethyl-L-arginine (L-NMMA) resulted in reduced O2 consumption (P < 0·0008, n = 8) and a lower fraction of cells with fluorescence from the NO-indicator 4-amino-5-methylamino-2′,7′-difluorofluorescein diacetate (DAF-FM) (P < 0·002, n = 8). PMNs stained with DAF-FM and the superoxide indicator hydroethidine (HE) and host cells with inducible NOS (iNOS) were identified in the sputum. In addition, the production of the stable end-products of NO in CF sputum was correlated with the concentration of PMNs; NO3 − (P < 0·04, r = 0·66, n = 10) and NO2 − (P< 0·006, r = 0·78, n = 11). The present study suggests that besides consumption of O2 for production of reactive oxygen species, the PMNs in CF sputum also consume O2 for production of NO.

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Section: Discussionmentioning

confidence: 79%

“…We therefore suggest that activated PMNs are involved in the accumulation of the NO3 − and NO2 − in CF sputum [47,54,55] due to the combined action of iNOS and NOX-2. Furthermore, the finding of elevated NO3…”

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confidence: 82%

Nitric oxide production by polymorphonuclear leucocytes in infected cystic fibrosis sputum consumes oxygen

Kolpen

Bjarnsholt

Moser

et al. 2014

Clinical and Experimental Immunology

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“…This regulatory pathway balancing inflammation and NO production is relevant to pulmonary disorders such as diffuse panbronchiolitis, CF, and ciliary dyskinesia, which are thought to involve NO dysregulation in the presence of excessive inflammation (7,13,21,22,24). It has been previously reported that exhaled NO is depressed in patients with these disorders, in contrast to other inflammatory lung disorders such as asthma, bronchiectasis, and chronic bronchitis (3,7,14,15,21,24), which may be partially due to reduced NOS2 expression in CF airway epithelial cells (13,22). Because NO also acts as an anti-inflammatory, it is suggested that this lack of NO in CF airways contributes to the hyperinflammatory response to chronic bacterial infection characteristic of this disease (13,22).…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of NOS2 regulation by Rho GTPase signaling in airway epithelial cells

Kraynack

Corey

Elmer

et al. 2002

American Journal of Physiology-Lung Cellular and Molecular Phys

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The aberrant dysregulation of the inducible form of nitric oxide synthase (NOS2) is thought to play a role in many inflammatory disorders including cystic fibrosis (CF). The complex regulation of NOS2 expression is the subject of intense investigation, and one intriguing regulatory pathway known to influence NOS2 expression is the Rho GTPase cascade. We examined NOS2 regulation in response to inflammatory cytokines in a human alveolar epithelial cell line treated with inhibitors of different upstream and downstream components of the Rho GTPase pathway to better define potential signaling mechanisms. Statin-mediated 3-hydroxy-3-methylglutaryl-CoA reductase inhibition increased cytokine-dependent activation of the NOS2 promoter, reversible by the addition of geranylgeranyl pyrphosphate. However, inhibition of Rho-associated kinase (ROCK) with Y-27632 resulted in a decrease in NOS2 promoter activity, yet an increase in NOS2 mRNA and protein levels. Our results suggest that prenylation events influence NOS2 promoter activity independently of the Rho GTPase pathway and that Rho GTPase signaling mediated through ROCK suppresses NOS2 production downstream of promoter function at the message and protein level.

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“…It would be desirable therefore to identify a measure of pulmonary inflammation (single or combined), that is more sensitive than pulmonary function testing, noninvasive, repeatable and applicable to young children. The assessment of exhaled breath in CF has not been fruitful: nitric oxide levels are normal [2], or reduced [3] in CF when compared with control subjects, and exhaled pentane is raised in CF, but prone to gastrointestinal contamination [4].The measurement of inflammatory mediators in breath condensate (exhaled aerosolized bronchoalveolar lining fluid), might provide a noninvasive, direct assessment of pulmonary inflammation. Condensate is capable of carrying molecules <65 kDa [5]: that could include the majority of pro-inflammatory pulmonary cytokines that are increased in CF.…”

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confidence: 99%

mentioning

confidence: 99%

Measurement of inflammatory markers in the breath condensate of children with cystic fibrosis

Cunningham

McColm

et al. 2000

Eur Respir J

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Identifying noninvasive markers of pulmonary inflammation would be useful in assessing new therapies in children. Breath condensate is a simple and potentially acceptable sample medium even in small children. The technique has previously been used in adults, but not children with cystic fibrosis.The technique was assessed in 36 children with cystic fibrosis (mean age 10.4 yrs) and 17 control subjects, analysing samples for nitrite, interleukin(IL)-8 and salivary and nasal contamination. Correlations were made between levels of the inflammatory markers and forced expiratory volume in one second/forced vital capacity, chest radiograph score and use of inhaled steroids.On samples without significant contamination (<10 u . L -1 amylase) nitrite was detected in 93% of samples at a median concentration of 3.0 mM compared with 50% of control samples at a median of 0.5 mM. Condensate amylase levels did not correlate with the nitrite value obtained (r=0.31). IL-8 was detected in 33% of CF samples.Breath condensate is an acceptable method of sample collection in children. Nitrite was raised in breath condensate from patients with cystic fibrosis when compared with control subjects. Eur Respir J 2000; 15: 955±957. Pulmonary inflammation in children with cystic fibrosis (CF) begins soon after birth [1], and arresting this progressive inflammation is central to CF research. It would be desirable therefore to identify a measure of pulmonary inflammation (single or combined), that is more sensitive than pulmonary function testing, noninvasive, repeatable and applicable to young children. The assessment of exhaled breath in CF has not been fruitful: nitric oxide levels are normal [2], or reduced [3] in CF when compared with control subjects, and exhaled pentane is raised in CF, but prone to gastrointestinal contamination [4].The measurement of inflammatory mediators in breath condensate (exhaled aerosolized bronchoalveolar lining fluid), might provide a noninvasive, direct assessment of pulmonary inflammation. Condensate is capable of carrying molecules <65 kDa [5]: that could include the majority of pro-inflammatory pulmonary cytokines that are increased in CF. Nitrite This technique, however, has not been applied to children with CF, and the aim of the current study was therefore to evaluate the reliability and acceptability of this technique, assessing whether children with CF have raised nitrite (like their adult counterparts [6]), and to assess for the first time whether IL-8, a dominant pro-inflammatory cytokine in CF [8], is found in measurable quantities in exhaled condensate. MethodsThe study was performed at the authors' regional paediatric CF centre (Edinburgh, Scotland, UK). Control samples were collected from children who were either staff relatives or attending fracture clinic with single stable fractures and no history of chronic respiratory illness. Children with CF were clinically stable at the time of assessment.The equipment for condensate collection has previously been used successfully in adults, ...

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Decreased concentration of exhaled nitric oxide (NO) in patients with cystic fibrosis

Cited by 191 publications

References 37 publications

Nitric oxide production by polymorphonuclear leucocytes in infected cystic fibrosis sputum consumes oxygen

Nitric oxide production by polymorphonuclear leucocytes in infected cystic fibrosis sputum consumes oxygen

Mechanisms of NOS2 regulation by Rho GTPase signaling in airway epithelial cells

Measurement of inflammatory markers in the breath condensate of children with cystic fibrosis

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