l-Arginine is not the limiting factor for nitric oxide synthesis by human alveolar macrophages<i>in vitro</i>

Muijsers, Richard B.R.; Hacken, Nick H. T. ten; Ark, Ingrid van; Folkerts, Gert; Nijkamp, Frans P.; Postma, D.S.

doi:10.1183/09031936.01.00101301

Cited by 20 publications

(11 citation statements)

References 18 publications

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“…However, this finding of high FeNO in patients with severe asthma maintained on high doses of corticosteroids was also observed in other studies [18, 19]. The enzyme inducible nitric oxide synthase (iNOS/NOS2), which catalyzes the generation of NO, is strongly induced by type 2 cytokines, and thus would be expected to be responsive to treatment [20]. However, NOS2 is also induced in human airway epithelial cells by the type I cytokine IFN-γ [21].…”

Section: Type 2 and Non-type 2 Asthma And The Association Of Neutrophsupporting

confidence: 63%

Neutrophilic Inflammation in Asthma and Association with Disease Severity

Ray

Kolls

2017

Trends in Immunology

388

307

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Asthma is a chronic inflammatory disorder of the airways. While the local infiltration of eosinophils and mast cells, and their role in the disease, have long been recognized, neutrophil infiltration has also been assessed in many clinical studies. In these studies, airway neutrophilia was associated with asthma severity. Importantly, neutrophilia also correlates with asthma that is refractory to corticosteroids, the mainstay of asthma treatment. However, it is now increasingly recognized that neutrophils are a heterogeneous population, and a more precise phenotyping of these cells may help delineate different subtypes of asthma. Here, we review the current knowledge on the role of neutrophils in asthma and highlight future avenues of research in this field.

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Section: Type 2 and Non-type 2 Asthma And The Association Of Neutrophsupporting

confidence: 63%

Neutrophilic Inflammation in Asthma and Association with Disease Severity

Ray

Kolls

2017

Trends in Immunology

388

307

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“…In contrast to murine macrophages, it was found that human mononuclear phagocytes did not release large amounts of NO, despite the presence of iNOS (309,444). However, the lack of NO synthesis in these experiments is probably an in vitro artifact.…”

Section: A Formation Of Rnsmentioning

confidence: 74%

Nitric Oxide in Health and Disease of the Respiratory System

Ricciardolo¹,

Sterk²,

Gaston³

et al. 2004

Physiological Reviews

792

649

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During the past decade a plethora of studies have unravelled the multiple roles of nitric oxide (NO) in airway physiology and pathophysiology. In the respiratory tract, NO is produced by a wide variety of cell types and is generated via oxidation of l-arginine that is catalyzed by the enzyme NO synthase (NOS). NOS exists in three distinct isoforms: neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS). NO derived from the constitutive isoforms of NOS (nNOS and eNOS) and other NO-adduct molecules (nitrosothiols) have been shown to be modulators of bronchomotor tone. On the other hand, NO derived from iNOS seems to be a proinflammatory mediator with immunomodulatory effects. The concentration of this molecule in exhaled air is abnormal in activated states of different inflammatory airway diseases, and its monitoring is potentially a major advance in the management of, e.g., asthma. Finally, the production of NO under oxidative stress conditions secondarily generates strong oxidizing agents (reactive nitrogen species) that may modulate the development of chronic inflammatory airway diseases and/or amplify the inflammatory response. The fundamental mechanisms driving the altered NO bioactivity under pathological conditions still need to be fully clarified, because their regulation provides a novel target in the prevention and treatment of chronic inflammatory diseases of the airways.

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“…The divergent behavior of rodent and human AM is not caused by limited availability of extracellular L-arginine, since the supplementation of the culture medium with the cationic amino acid does not trigger NO production in human AM (41). However, from studies in rodent cells, it is known that, at variance with other cells (42), macrophages markedly depend upon the transport of extracellular arginine to the intracellular compartment through the inducible transporter SLC7A2/CAT2B for NOS2-dependent NO synthesis (8).…”

Section: Discussionmentioning

confidence: 99%

Alveolar Macrophages from Normal Subjects Lack the NOS-Related System y⁺for Arginine Transport

Rotoli

DallˈAsta

Barilli

et al. 2007

Am J Respir Cell Mol Biol

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Systems y+ and y+L represent the main routes for arginine transport in mammalian cells. While system y+ activity is needed for the stimulated NO production in rodent alveolar macrophages (AM), no information is yet available about arginine transport in human AM. We study here arginine influx and genes for arginine transporters in AM from bronchoalveolar lavage of normal subjects. These cells express the y+ -related genes SLC7A1/CAT1 and SLC7A2/CAT2B, as well as the y+L genes SLC7A7/y+LAT1 and SLC7A6/y+LAT2. However, compared with human endothelial cells, AM express much less SLC7A2 mRNA and higher levels of SLC7A7 mRNA. Granulocyte macrophage colony-stimulating factor or IFN-gamma do not change the expression of any transporter gene, while lipopolysaccharide induces SLC7A2/CAT2B. Under all the conditions tested, leucine inhibits most of the arginine transport in the presence of Na+ and N-ethylmaleimide, an inhibitor of system y+, is completely ineffective, indicating that system y+L operates most of the arginine influx. Comparable results are obtained in AM from patients with interstitial lung disease, such as Nonspecific Interstitial Pneumonia (NSIP), although these cells have a higher SLC7A1 and a lower SLC7A7 expression than AM from normal subjects. It is concluded that AM from normal subjects or patients with NSIP lack a functional transport system y+, a situation that may limit arginine availability for NO synthesis. Moreover, since mutations of SLC7A7/y+LAT1 cause Lysinuric Protein Intolerance, a disease often associated with AM impairment and alveolar proteinosis, the high SLC7A7 expression observed in human AM suggests that y+LAT1 activity is important for the function of these cells.

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l-Arginine is not the limiting factor for nitric oxide synthesis by human alveolar macrophagesin vitro

Cited by 20 publications

References 18 publications

Neutrophilic Inflammation in Asthma and Association with Disease Severity

Neutrophilic Inflammation in Asthma and Association with Disease Severity

Nitric Oxide in Health and Disease of the Respiratory System

Alveolar Macrophages from Normal Subjects Lack the NOS-Related System y⁺for Arginine Transport

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l-Arginine is not the limiting factor for nitric oxide synthesis by human alveolar macrophagesin vitro

Cited by 20 publications

References 18 publications

Neutrophilic Inflammation in Asthma and Association with Disease Severity

Neutrophilic Inflammation in Asthma and Association with Disease Severity

Nitric Oxide in Health and Disease of the Respiratory System

Alveolar Macrophages from Normal Subjects Lack the NOS-Related System y+for Arginine Transport

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Alveolar Macrophages from Normal Subjects Lack the NOS-Related System y⁺for Arginine Transport