Elevated levels of exhaled nitric oxide in bronchiectasis.

Kharitonov, Sergei A.; Wells, Adrian; O’Connor, Brian; Cole, Peter; Hansell, D.M.; Logan-Sinclair, R.; Barnes, Peter J.

doi:10.1164/ajrccm.151.6.7767536

Cited by 281 publications

(161 citation statements)

References 23 publications

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“…Exhaled NO has been demonstrated to be elevated in airway inflammatory diseases, suci asthma and bronchiectasis (Kharitonov et al, 1995(Kharitonov et al, 1996, but the precise cellular source of exhaled N In the present study, we have provided direct evider ence and distribution of NOS in lung tissues and f production of nitrite from AM in patients with cancer. The iNOS expression of AM was up-regul with primary lung cancer compared with that subjects.…”

Section: Discussionmentioning

confidence: 53%

Increased level of exhaled nitric oxide and up-regulation of inducible nitric oxide synthase in patients with primary lung cancer

Liu

Wang²,

Chen³

et al. 1998

Br J Cancer

144

111

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Summary Monocyte-macrophage series have an important role in host surveillance against cancer. The cytotoxic/cytostatic activity of macrophages is, to a great extent, attributed to the up-regulation of inducible nitric oxide synthase (iNOS) and production of nitric oxide (NO). Here, in 28 patients with primary lung cancer and 20 control subjects, we measured the concentration of exhaled NO and nitrite in epithelial lining fluid (ELF) using a chemiluminescence NO analyser, and studied NOS expression in alveolar macrophages (AM) and lung tissues by flow cytometry; immunohistochemical analysis was also undertaken. The mean fluorescence intensity (Fl) of iNOS expression in AM was significantly increased in patients with lung cancer (tumour side 263.5 ± 15.2 Fl, normal side 232.4 ± 18.6 Fl; n = 28) compared with that in control subjects (27.3 ± 3.2 Fl; n = 20, P< 0.001). The level of exhaled NO from cancer patients (16.9 ± 0.9 p.p.b.; n = 28) was significantly higher than that in the control group (6.0 ± 0.5 p.p.b.; n = 20, P < 0.001). The level of nitrite was also significantly higher in ELF from cancer patients (tumour side 271.1 ± 28.9 nm and normal side 257.4 ± 19.6 nm vs control subjects 32.9 + 4.1 nM; P< 0.001). The intensity of iNOS expression in AM was correlated with the level of exhaled NO (rS = 0.73, n = 76, P < 0.001) and the nitrite released in ELF (r, = 0.56, n = 76, P < 0.001). The nitrite generation of cultured AM from patients with lung cancer was significantly enhanced compared with that of control subjects after culture for 24 h (tumour side 5.75 ± 0.69 and normal side 5.68 ± 0.58 gM per 106 cells vs control group 38.3 + 3.6 nm per 106 cells; P< 0.001). The distribution of iNOS was identified in AM, tumour-associated macrophages, endothelium, chondrocytes, airway epithelium of both lungs and malignant cells (adenocarcinoma and alveolar cell carcinoma) of cancer patients. cNOS was labelled in alveolar macrophages, endothelial cells and nerve elements from lung tissue. Our results indicate that, in patients with primary lung cancer, the production of NO from alveolar macrophages was increased as a result of the up-regulation of iNOS activity. The increased NO production was not specific to the tumour side and might be attributed to the tumour-associated non-specific immunological and inflammatory processes of the host.Keywords: lung cancer; alveolar macrophage; nitric oxide; nitric oxide synthase; nitrite; cytotoxicity The host defence mechanism is important in the development and growth of tumours. The incidence of malignancy is reported to be increased in subjects with compromised immunity (Penn, 1986). The complex defence and immunological mechanisms against cancer contain several types of cells, including macrophages (Fidler et al, 1988) and mediators, such as nitric oxide (NO) (Farias-Eisner et al, 1996).Macrophages have a role in host surveillance against cancer (Hibbs et al, 1978). Macrophages can be activated both in vivo and in vitro to kill tumour cells. The oncolytic activity of macrophag...

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Section: Discussionmentioning

confidence: 53%

Increased level of exhaled nitric oxide and up-regulation of inducible nitric oxide synthase in patients with primary lung cancer

Liu

Wang²,

Chen³

et al. 1998

Br J Cancer

144

111

View full text Add to dashboard Cite

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“…The exhaled NO concentration is increased in airway inflammation 12,36,37 and is suppressed in substances may interact with NO is not presently known.…”

Section: Discussionmentioning

confidence: 97%

Exhaled nitric oxide and oxygenation abnormalities in hepatic cirrhosis

et al. 1997

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Impaired arterial oxygenation, ranging from increased alImpaired arterial oxygenation, ranging from increased alveolar-arterial oxygen gradient (AaDo 2 ) to hypoxemia, is veolar-arterial oxygen gradient (AaDo 2 ) to hypoxemia, is comcommonly reported in patients with cirrhosis. 1 In the absence monly present in patients with cirrhosis. Nitric oxide (NO), of overt mechanical dysfunction of the lung, it has been through pulmonary vasodilatation, may play a major role in suggested that oxygenation abnormalities of cirrhotic pathe oxygen abnormalities of cirrhosis. Our aim was to study tients may be a consequence of ventilation/perfusion misthe relationship between NO production and O 2 abnormalities match and intrapulmonary shunting. 2-4 Intrapulmonary vasin 45 nonsmoking patients with cirrhosis and without major cular dilatations and artero-venous communications are cardiovascular and respiratory diseases. Intrapulmonary thought to be the pathological bases of the physiological shunting was detected by contrast-enhanced (CE) echocardimechanisms of oxygenation abnormalities. 5,6 ography. Lung volumes and diffusion, arterial blood gas analy-The vascular dilatations can result in severe hypoxemia, sis, serum NO 0 2 /NO 0 3 , NO output in the exhaled air, and which, at variance from that caused by intrapulmonary cardiac index by the echocardiographic method were detershunts, may respond normally to supplemental oxygen. mined in all patients. Twenty-seven (60%) patients had anIncreased circulation of a pulmonary vasodilator seems abnormally increased (ú15 mm Hg) AaDo 2 . The mean values to be the favored mechanism for intrapulmonary vascular of exhaled NO output and serum NO 0 2 /NO 0 3 were significantly dilatations in cirrhosis, and nitric oxide (NO) has recently higher in cirrhotic patients than in controls (252 { 117 vs.ascended to the top of the list of possible substances. 6,7 75.2 { 19 nL/min/m 2 , P õ .0001; and 47.5 { 29.4 vs. 32.9NO is a powerful local vasodilator of endothelial origin, { 10.1 mmol/L, P õ .02, respectively). In all patients, there which contributes to the normally low pulmonary vascular was a significant correlation between exhaled NO and AaDo 2 tone. 8 NO has been shown to play an important role in regulat-(r Å .78, P õ .0001). Twelve patients (26.6%) were found to ing the vasomotor tone in experimental cirrhosis. 9,10 It is now have CE-echocardiographic evidence of intrapulmonary possible to measure NO produced in the lung by measuring its shunting (positive CE-echo). Nine patients were considered concentration in exhaled air. 11,12 Recently, increased NO output to have hepatopulmonary syndrome (HPS) on the basis of an in exhaled air has been reported in patients with advanced AaDo 2 ú 15 mm Hg and positive CE-echo. These 9 patients cirrhosis, in whom exhaled NO was associated with systemic had a mean value of exhaled NO significantly higher than circulatory disturbances. 13 Exhaled NO was reported to be patients without HPS (331 { 73.2 vs. 223 { 118.4 nL/min/ raised almost threefold in t...

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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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Elevated levels of exhaled nitric oxide in bronchiectasis.

Cited by 281 publications

References 23 publications

Increased level of exhaled nitric oxide and up-regulation of inducible nitric oxide synthase in patients with primary lung cancer

Increased level of exhaled nitric oxide and up-regulation of inducible nitric oxide synthase in patients with primary lung cancer

Exhaled nitric oxide and oxygenation abnormalities in hepatic cirrhosis

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

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