Exhaled Nitric Oxide Production by Nitric Oxide  Synthase–deficient Mice

Steudel, Wolfgang; Kirmse, Max; Weimann, Jörg; Ullrich, Robert C.; Hromi, Jonathan; Zapol, Warren M.

doi:10.1164/ajrccm.162.4.9909037

Cited by 29 publications

(24 citation statements)

References 41 publications

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“…In contrast to the present findings, in this study, exhaled NO concentration was comparable in iNOS-/-and wild-type mice using ambient air NO concentration in an airtight mouse housing chamber as an index of respiratory NO production [24]. An important limitation of this previous study, however, was that it did not allow determination of the fractional contributions of upper versus lower respiratory, and, possibly even more importantly, respiratory versus nonairway sources, to the measured NO production.…”

Section: Discussioncontrasting

confidence: 99%

Increased eNO and pulmonary iNOS expression in eNOS null mice

Cook¹,

Vollenweider²,

Ménard³

et al. 2003

Eur Respir J

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Increased eNO and pulmonary iNOS expression in eNOS null mice. S. Cook, P. Vollenweider, B. Ménard, M. Egli, P. Nicod, U. Scherrer. #ERS Journals Ltd 2003. ABSTRACT: Nitric oxide (NO) is a major regulatory molecule of the cardiovascular system; however, measurement of vascular NO synthesis in vivo represents a major challenge. NO stemming from the lower respiratory tract has been used as a marker of vascular endothelial function. Experimental evidence for this concept is lacking. Therefore, the aim of the present study was to investigate this relationship.Lower respiratory tract exhaled NO concentration, together with systemic and pulmonary artery pressure, was measured in endothelial nitric oxide synthase (NOS) (eNOS) null mice (eNOS-/-). Similar studies were performed in inducible NOS (iNOS) null mice (iNOS-/-).Defective endothelial NO synthesis in eNOS-/-mice (evidenced by systemic and pulmonary hypertension) was associated with augmented exhaled NO levels (12.5¡1.9 versus 9.8¡1.2 parts per billion (ppb), eNOS-/-versus wild type), whereas normal endothelial NO synthesis in iNOS-/-mice was associated with decreased exhaled NO levels (4.3 ¡ 1.5 ppb). Augmented exhaled NO levels in eNOS-/-mice were associated with upregulation of iNOS expression in the lung.These results indicate that inducible nitric oxide synthase is a major determinant of gaseous nitric oxide production in the lung, and lower respiratory tract exhaled nitric oxide does not always represent a marker of vascular endothelial nitric oxide synthesis. Since the late 1980s, nitric oxide (NO) has emerged as a major regulator of the cardiovascular system [1]. Measurement of vascular endothelial nitric oxide synthase (NOS) (eNOS) activity and its final product NO in vivo still represents a major challenge, because the small amount of NO produced by the endothelium is rapidly scavenged by haemoglobin and then inactivated. To date, the contribution of NO to the regulation of vascular tone has been assessed by indirect methods, examining specific modifications of physiological responses induced by NOS inhibitors and NO donors, and/or measuring levels of NO metabolites or cyclic guanosine monophosphate [2].NO is present in the exhaled air of many animal species and humans [3], but its origin and physiological function are incompletely understood. In the respiratory tract, all three NOS isoforms are expressed in tissues close to the airways. Although there is consensus that under normal conditions, a large proportion of the exhaled NO is synthesised by inducible NOS (iNOS) located in the epithelial cells of the upper respiratory tract [4,5], the origin and function of lower respiratory tract exhaled NO is incompletely understood. It has been claimed that exhaled NO stemming from the lower respiratory tract represents a marker of vascular endothelial NO synthesis [6][7][8][9][10][11][12]. Experimental evidence for this concept is lacking, however, and studies in humans, using pharmacological NOS inhibitors, suggest that eNOS barely albeit significantly, cont...

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Section: Discussioncontrasting

confidence: 99%

Increased eNO and pulmonary iNOS expression in eNOS null mice

Cook¹,

Vollenweider²,

Ménard³

et al. 2003

Eur Respir J

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“…This would suggest that iNOS activity is the principal source of ex-NO in rats under normal conditions, although an impact of the exposure to aerosol- ized, endotoxin-free saline cannot be ruled out. These data concur with similar findings published by Steudel et al (2000) using knockout mice. Aerosolized LPS caused a significant rise in airway neutrophilia that was inhibited by both L-NAME and 1400W, which would suggest that the iNOS-derived NO plays an inflammatory role in this model.…”

Section: Nos Inhibitors and Rat Airway Inflammation 629supporting

confidence: 93%

Nitric Oxide as a Noninvasive Biomarker of Lipopolysaccharide-Induced Airway Inflammation: Possible Role in Lung Neutrophilia

McCluskie

Birrell²,

Wong³

et al. 2004

J Pharmacol Exp Ther

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Lipopolysaccharide (LPS) is known to generate nitric oxide (NO) in the airway through the activation of nitric-oxide synthase (NOS). The functional consequences of this on the inflammatory response are not clear, with conflicting data published. In the clinic, exhaled NO (ex-NO) is used as a noninvasive biomarker to assess the extent of airway inflammation. It is proposed that monitoring levels of ex-NO could be a useful guide to determining the effectiveness of disease modifying therapies. The aim was, using pharmacological tools, to determine the role of NO in an aerosolized LPSdriven animal model of airway inflammation by assessment of ex-NO, neutrophilia, and inflammatory biomarkers, using a nonselective NOS inhibitor, N G -nitro-L-arginine methyl ester (L-NAME), and a selective inducible NOS (iNOS) inhibitor,

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“…2). As expected, NOS2 mRNA was undetectable in LPS-treated NOS2 Ϫ/Ϫ or wild-type mice were quite similar and may largely originate from other NOS isoforms (NOS1 or NOS3) (47). Quantitative RT-PCR analysis of lung tissue mRNA showed expression of NOS3 and (to a lesser degree) NOS1, and expression of these NOS isozymes was similar in NOS2 Ϫ/Ϫ and wild-type mice (data not shown).…”

Section: Lps-induced Airway Neutrophilia Is Reduced In Nos2supporting

confidence: 74%

Multiple contributing roles for NOS2 in LPS-induced acute airway inflammation in mice

Okamoto¹,

Gohil²,

Finkelstein³

et al. 2004

American Journal of Physiology-Lung Cellular and Molecular Phys

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Acute lung inflammation and injury were induced by intranasal instillation of lipopolysaccharide (LPS) in normal and type 2 nitric oxide synthase (NOS2)-deficient (NOS2 Ϫ/Ϫ ) C57BL/6 mice. LPS-induced increases in extravasated airway neutrophils and in lung lavage fluid of TNF-␣ and macrophage inflammatory protein-2 were markedly lower in NOS2 Ϫ/Ϫ than in wild-type mice, indicating that NOS2-derived nitric oxide (NO⅐) participates in inflammatory cytokine production and neutrophil recruitment. Instillation of LPS also increased total lung lavage protein and induced matrix metalloproteinase-9 and mucin 5AC, as indexes of lung epithelial injury and/or mucus hyperplasia, and increased tyrosine nitration of lung lavage proteins, a marker of oxidative injury. All these responses were less pronounced in NOS2 Ϫ/Ϫ than in wild-type mice. Inhibition of NOS activity also suppressed production of TNF-␣ and macrophage inflammatory protein-2 by LPS-stimulated mouse alveolar MH-S macrophages, and this was restored by NO⅐ donors, illustrating involvement of NO⅐ in macrophage cytokine signaling. Oligonucleotide microarray (GeneChip) analysis of global lung gene expression revealed that LPS inhalation induced a range of transcripts encoding proinflammatory cytokines and chemokines, stress-inducible factors, and other extracellular factors and suppressed mRNAs encoding certain cytoskeletal proteins and signaling proteins, responses that were generally attenuated in NOS2 Ϫ/Ϫ mice. Comparison of both mouse strains revealed altered expression of several cytoskeletal proteins, cell surface proteins, and signaling proteins in NOS2 Ϫ/Ϫ mice, changes that may partly explain the reduced responsiveness to LPS. Collectively, our results suggest that NOS2 participates in the acute inflammatory response to LPS by multiple mechanisms: involvement in proinflammatory cytokine signaling and alteration of the expression of various genes that affect inflammatory-immune responses to LPS.

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Exhaled Nitric Oxide Production by Nitric Oxide Synthase–deficient Mice

Cited by 29 publications

References 41 publications

Increased eNO and pulmonary iNOS expression in eNOS null mice

Increased eNO and pulmonary iNOS expression in eNOS null mice

Nitric Oxide as a Noninvasive Biomarker of Lipopolysaccharide-Induced Airway Inflammation: Possible Role in Lung Neutrophilia

Multiple contributing roles for NOS2 in LPS-induced acute airway inflammation in mice

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