Cited by 918Nitric Oxide and Endothelin EffectsAsthma and respiratory diseasesRedox biology and oxidative stress

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The Biology of Nitrogen Oxides in the Airways

Gaston, B, Drazen, J M, Loscalzo, J, Stamler, J S·1994·American Journal of Respiratory and Critical Care Medicine

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Abstract

Nitrogen oxides (NOx), regarded in the past primarily as toxic air pollutants, have recently been shown to be bioactive species formed endogenously in the human lung. The relationship between the toxicities and the bioactivities of NOx must be understood in the context of their chemical interactions in the pulmonary microenvironment. Nitric oxide synthase (NOS) is a newly identified enzyme system active in airway epithelial cells, macrophages, neutrophils, mast cells, autonomic neurons, smooth muscle cells, fibroblasts, and endothelial cells. The chemical products of NOS in the lung vary with disease states, and are involved in pulmonary neurotransmission, host defense, and airway and vascular smooth muscle relaxation. Further, certain patients with pulmonary hypertension, adult respiratory distress syndrome and asthma may experience physiologic improvement with NOx therapy, including inhalation of nitric oxide (NO.) gas. Both endogenous and exogenous NOx react readily with oxygen, superoxide, water, nucleotides, metalloproteins, thiols, amines, and lipids to form products with biochemical actions ranging from bronchodilation and bacteriostasis (S-nitrosothiols) to cytotoxicity and pulmonary capillary leak (peroxynitrite), as well as those with frank mutagenic potential (nitrosamines). Recent discoveries demonstrating the relevance of these species to the lung have provided new insights into the pathophysiology of pulmonary disease, and they have opened a new horizon of therapeutic possibilities for pulmonary medicine.

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Crossref · 10.1164/ajrccm.149.2.7508323

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Background
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Charles, F.-G., Murray, L. J., Giordano, C. R., et al. (2019) · Canadian Journal of Anesthesia/Journal canadien d anesthésie · doi:10.1007/s12630-019-01449-x · Cited by 28
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BackgroundInfluential
Effect of Oral Arginine Supplementation on Exhaled Nitric Oxide Concentration in Sickle Cell Anemia and Acute Chest Syndrome
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“1 to 5 s) that is generated during the conversion of the amino acid L -arginine to L -citrulline by the enzyme NO synthase (NOS) in a reaction that requires nicotinamide adenine dinucleotide phosphate and molecular oxygen as cosubstrates, and tetrahydrobiopterin, thiol, and flavins (flavin adenine dinucleotide and fle…”
Background
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Background
Third Place—Resident Basic Science Award 1999 Elevated Nitric Oxide Metabolite Levels in Chronic Sinusitis
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Self-citation
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“In cells of the monocyte/macrophage lineage nitric oxide (NO) plays an important role as part of the non-specific defence mechanism (see Moncada et al. 1991; Barnes 1993; Gaston et al. 1994; Xie and Nathan 1994), as a signalling molecule between macrophages (MΦ) and other cells (see Barnes and Liew 1995) and as an int…”
Background
In vivo efficacy of telithromycin on cytokine and nitric oxide formation in lipopolysaccharide-induced acute systemic inflammation in mice
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“NITRIC OXIDE (NO) is a freely diffusible molecule that performs many regulatory functions, including smooth muscle relaxation, host defense, and inhibition of platelet aggregation and neurotransmission (23, 57).”
Background
Short-term effect of inhaled nitric oxide and prone positioning on gas exchange in patients with severe acute respiratory distress syndrome
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“NO may be formed and released by a variety of cells in the lung, including epithelial and endothelial cells, in¯ammatory cells and smooth muscle cells, and it exerts various functions in the airways (Gaston et al., 1994).”
Background
Online trapping and enrichment ultra performance liquid chromatography–tandem mass spectrometry method for sensitive measurement of “arginine-asymmetric dimethylarginine cycle” biomarkers in human exhaled breath condensate
Gangi, I. M. D., Pirillo, P., Carraro, S., et al. (2012) · Analytica Chimica Acta · doi:10.1016/j.aca.2012.09.032 · Cited by 27
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“…proteins (Lipton et al., 1993; Foster et al., 2003) and it is known that S-nitrosothiols within the brainstem (Lipton et al., 2001) and peripheral structures (Gaston et al., 1994, 2006; Stoyanovsky et al., 1997) exert positive effects on ventilatory function and pulmonary gas-exchange mechanisms.”
BackgroundSelf-citation
Regulation of Airway Contractility by Plasminogen Activators through N-Methyl-D-Aspartate Receptor–1
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“NOS is present in the airway epithelial cells (37, 38).”
Background
Noninvasive Measurement of Exhaled Nitric Oxide in a Spontaneously Breathing Mouse
Weicker, S., KARACHI, T. A., Scott, J. A., McCormack, D., & MEHTA, S. (2001) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/ajrccm.163.5.2007025 · Cited by 29
“Furthermore, ENO levels in health and disease likely depend also on local conditions, including the pH, redox potential, the presence of NO-binding molecules (e.g., thiol groups), and the presence of reactive oxidant and antioxidant species ( 24 ).”
Background
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Ng, E. S. M., & Kubes, P. (2003) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/y03-078 · Cited by 27
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Background
Cytotoxic and Inflammatory Effects of Coarse and Fine Particulate Matter in Macrophages and Epithelial Cells
(2002) · The Annals of Occupational Hygiene · doi:10.1093/annhyg/46.suppl_1.203 · Cited by 27
“Another compound that has been linked to lung inflammation is the free radical nitric oxide (NO), which is formed during catalytic conversion of L-arginine by NO synthases (Gaston et al., 1994).”
Background
Insulin down‐regulates TRAIL expression in vascular smooth muscle cells both in vivo and in vitro
Corallini, F., Celeghini, C., Rizzardi, C., et al. (2007) · Journal of Cellular Physiology · doi:10.1002/jcp.21006 · Cited by 26
“However, the concept that endothelium-derived NO diffuses passively from the cytosol of its cells of origin into distant target cells to elicit a response (Gaston et al., 1994) is a subject of considerable debate from several years (Van Zwieten, 1997; Boulanger et al., 1998).”
Background
Nitric Oxide and its Metabolites in the Critical Phase of Illness: Rapid Biomarkers in the Making
Mian, A. I., Aranke, M., & Bryan, N. S. (2013) · The Open Biochemistry Journal · doi:10.2174/1874091x01307010024 · Cited by 26
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Skeletal muscle weakness, fatigue and sarcoidosis
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C57BL/6 and BALB/c Bronchoalveolar Macrophages Respond Differently to Exercise
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“In biologic systems or at air-aqueous interfaces, NO generation is marked by the formation of NO2 (nitrite) and NO3 (nitrate) (32).”
Background
Nitric Oxide: Diverse Actions in the Central and Peripheral Nervous Systems
Dawson, T. M., Gonzalez‐Zulueta, M., Kusel, J., & Dawson, V. L. (1998) · The Neuroscientist · doi:10.1177/107385849800400206 · Cited by 26
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Güzel, A., Guzel, A., Kanter, M., et al. (2008) · Pediatric Surgery International · doi:10.1007/s00383-008-2282-x · Cited by 25
“An iNOS enzyme whose expression in endothelium, epithelium, and inflammatory cells requires protein synthesis, is induced by cytokines and lipopolysaccharide, and produces large amounts of NO for extended periods of time [40].”
Background
Elemental and ion composition of exhaled AIR condensate in cystic fibrosis
Griese, M., Noss, J., & Schramel, P. (2003) · Journal of Cystic Fibrosis · doi:10.1016/s1569-1993(03)00062-6 · Cited by 25
Endothelial nitric oxide synthase is regulated by ERK phosphorylation at Ser602
Salerno, J. C., Ghosh, D. K., Razdan, R. K., Helms, K. A., Brown, C. C., McMurry, J. L., Rye, E. A., & Chrestensen, C. A. (2014) · Bioscience Reports · doi:10.1042/bsr20140015 · Cited by 25
Inability of rat alveolar macrophages to recycle l-citrulline to l-arginine despite induction of argininosuccinate synthetase mRNA and protein, and inhibition of nitric oxide synthesis by exogenous l-citrulline
Hammermann, R., Bliesener, N., Mössner, J., et al. (1998) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/pl00005300 · Cited by 25
“The synthesis and release of nitric oxide (NO) is an important effector system in the non-specific defense mechanism of macrophages (MΦ) including alveolar macrophages (AMΦ; see Moncada et al. 1991; Barnes 1993; Gaston et al. 1994; Xie and Nathan 1994).”
Background
Nitric oxide, peroxynitrite, and lower respiratory tract inflammation
Robbins, R., Hadeli, K. O., Nelson, D., Sato, E., & Hoyt, J. C. (2000) · Immunopharmacology · doi:10.1016/s0162-3109(00)00220-4 · Cited by 25
Nitric oxide and β-adrenergic agonist-induced bronchial arterial vasodilation
Charan, N. B., Johnson, S. R., Lakshminarayan, S., Thompson, W. H., & Carvalho, P. (1997) · Journal of Applied Physiology · doi:10.1152/jappl.1997.82.2.686 · Cited by 23
Exopolysaccharides of Bifidobacterium longum subsp. infantis E4 on the immune and anti-inflammatory effects in vitro
Yue, Y., Wang, Y., Yang, R. F., Liu, D., Yang, C., Li, S., Sun, L., Li, B., & Huo, G. (2023) · Journal of Functional Foods · doi:10.1016/j.jff.2023.105699 · Cited by 25
Dexamethasone attenuated endotoxin-induced acute lung injury through inhibiting expression of inducible nitric oxide synthase
Yu, Z., Ouyang, J., & Li, Y. (2009) · Clinical Hemorheology and Microcirculation · doi:10.3233/ch-2009-1162 · Cited by 24
“…production of NO in lung is tightly regulated for short periods of time by two isoforms of constitutive nitric oxide synthases (NOS): endothelial NOS (eNOS) and neuronal NOS (nNOS) in airway epithelial cells pulmonary vascular endothelial cells, and noncholinergic, nonadren-ergic nerve ﬁbers [7].”
Association between the Type of Workplace and Lung Function in Copper Miners
Skoczyńska, A., Gruszczyński, L., Wojakowska, A., et al. (2016) · BioMed Research International · doi:10.1155/2016/5928572 · Cited by 24
“Endogenous nitric oxide (NO) plays key roles in lung biology, being involved in pulmonary neurotransmission, as well as host defense, airway and vascular smooth muscle relaxation, mucociliary clearance, airway mucus secretion, inflammation, and cytotoxicity [1, 2].”
Background
Endogenous nitric oxide in patients with chronic heart failure (CHF): relation to functional impairment and nitrate-containing therapies
Clini, E. M., Volterrani, M., Pagani, M., Bianchi, L. N. C., Porta, R., Gilè, L. S., Giordano, A., & Ambrosino, N. (2000) · International Journal of Cardiology · doi:10.1016/s0167-5273(00)00211-4 · Cited by 24
Exhaled nitric oxide during normoxic and hypoxic exercise in endurance athletes
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Nitric oxide and asthma.
Zoritch, B. (1995) · Archives of Disease in Childhood · doi:10.1136/adc.72.3.259 · Cited by 24
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“2002) and the subsequent increase in FENO (Gaston et al. 1994).”
Background
Effect of Arginase Inhibition on Pulmonary L-Arginine Metabolism in Murine Pseudomonas Pneumonia
Mehl, A., Ghorbani, P., Douda, D. N., Huang, H., Palaniyar, N., Ratjen, F. A., & Grasemann, H. (2014) · PLoS ONE · doi:10.1371/journal.pone.0090232 · Cited by 23
“While excessive NO production may have negative effects on inflammation, it is also possible that substrate limitation for NOS results in deleterious effects due to uncoupling of the enzyme resulting in superoxide radical formation [3,20–22].”
Background
Generation of purified nitric oxide from liquid N2O4 for the treatment of pulmonary hypertension in hypoxemic swine
Lovich, M. A., Fine, D. H., Denton, R. J., et al. (2014) · Nitric Oxide · doi:10.1016/j.niox.2014.02.001 · Cited by 23
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Background
Nickel Hexacyanoferrate‐Based Sensor Electrode for the Detection of Nitric Oxide at Low Potentials
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“have disadvantages and limitations (14).”
MethodSelf-citation
Nitric oxide synthases are associated with bronchial dysplasia
Puhakka, A., Harju, T. H., Pääkkö, P. K., Soini, Y., & Kinnula, V. L. (2006) · Lung Cancer · doi:10.1016/j.lungcan.2005.11.005 · Cited by 23
“Recent studies suggest that reactive oxygen (ROS) and nitrogen species (RNS) are highly associated with the pathogenesis of cigarette smoke related lung diseases and that there is continuous oxidant burden in the airways of chronic smokers [5—12].”
Background
Complex Regulation of iNOS in Lung
Pitt, B. R., & Croix, C. M. S. (2002) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/ajrcmb.26.1.f224 · Cited by 23
“In a remarkably short period after the identification of nitric oxide (NO) as a novel signaling molecule in mammalian physiology, the critical role of L-arginine biosynthetic pathway in lung function became apparent (1).”
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“... that occurs during hyperpnea and recovery increases the permeability of a persistently inflamed vascular bed (8, 9). Because nitric oxide synthase expression has been identified in multiple elements of the tracheobronchial tree (i.e., the airway epithelium, the vascular endothelium, and the sensory nervous system)…”
Background
Evidence for the role of PI3-kinase-AKT-eNOS signalling pathway in secondary inflammatory process after spinal cord compression injury in mice
Paterniti, I., Esposito, E., Mazzon, E., Bramanti, P., & Cuzzocrea, S. (2011) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2011.07646.x · Cited by 22
Comparison of cadmium and enzyme-catalyzed nitrate reduction for determination of NO2−/NO3− in breath condensate
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INDUCTION OF INDUCIBLE NITRIC OXIDE SYNTHASE BY LIPOPOLYSACCHARIDE/INTERFERON GAMMA AND SEPSIS DOWN-REGULATES 5-LIPOXYGENASE METABOLISM IN MURINE ALVEOLAR MACROPHAGES
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“An inducible form of NOS (iNOS) is well known to be transcriptionally up-regulated by LPS [15, 16].”
Background
Role of Nitric Oxide on Diaphragmatic Contractile Failure in Escherichia coli Endotoxemic Rats
Sambe, A., Longrois, D., Danialou, G., Lanone, S., Bénessiano, J., Aubier, M., & Boczkowski, J. (1998) · Comparative Biochemistry and Physiology Part A Molecular & Integrative Physiology · doi:10.1016/s1095-6433(97)00422-4 · Cited by 22
Efficiency of inhaled nitric oxide as rescue therapy during severe ARDS: Survival and factors associated with the first response
Dupont, H., Corre, F. L., Fierobe, L., et al. (1999) · Journal of Critical Care · doi:10.1016/s0883-9441(99)90022-9 · Cited by 22
Potential Protective Properties of a Stable, Slow‐releasing Nitric Oxide Donor, GEA 3175, in the Lung
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Detection of nitric oxide in exhaled human breath: exercise and resting determinations.
Mantione, K. J., Esch, T., & Stefano, G. B. (2007) · PubMed · Cited by 22
Inducible Nitric Oxide Synthase mRNA and Immunoreactivity in the Lungs of Rats Eight Hours after Antigen Challenge
RENZI, P. M., Sebastiao, N., Assaad, A. S. A., Giaid, A., & Hamid, Q. A. (1997) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/ajrcmb.17.1.2307 · Cited by 22
Concentration of nitric oxide products in bronchoalveolar fluid obtained from infants who develop chronic lung disease of prematurity
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“26 27 Both these products may also be formed from nitrogen dioxide, low concentrations of which may be present if endogenous NO is produced in the inﬂammatory environment of infants who subsequently develop CLD.”
Background
Derivation of Mass Transfer Coefficients for Transient Uptake and Tissue Disposition of Soluble and Reactive Vapors in Lung Airways
Asgharian, B., Price, O. T., Schroeter, J., et al. (2011) · Annals of Biomedical Engineering · doi:10.1007/s10439-011-0274-9 · Cited by 21
“Equation ( 10 ) was used by Bush et al. 4 to calcu-”
Method
NO–Steroids: Potent Anti-inflammatory Drugs with Bronchodilating Activity in Vitro
Tallet, D., Soldato, P. D., Oudart, N., & Burgaud, J. (2002) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2001.6192 · Cited by 21
Recent Marijuana Use and Associations With Exhaled Nitric Oxide and Pulmonary Function in Adults in the United States
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An Intratracheal Instillation Bioassay System for Detection of Lung Toxicity Due to Fine Particles in F344 Rats
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Gas-phase Disproportionation of Nitric Oxide at Elevated Pressures
Tsukahara, H., Ishida, T., Todoroki, Y., et al. (2003) · Free Radical Research · doi:10.1080/1071576021000036489 · Cited by 21
Assaying all of the nitrogen oxides in breath modifies the interpretation of exhaled nitric oxide
Nguyen, T.-A., Woo-Park, J., Hess, M., et al. (2005) · Vascular Pharmacology · doi:10.1016/j.vph.2005.08.003 · Cited by 21
Therapeutic Gases for Neonatal and Pediatric Respiratory Care
Myers, T. R. (2003) · Respiratory Care · doi:10.4187/respcare.03480399 · Cited by 21
Extended Nitric Oxide Measurements in Exhaled Air of Cystic Fibrosis and Healthy Adults
Höfer, M., Mueller, L., Rechsteiner, T. J., et al. (2009) · Lung · doi:10.1007/s00408-009-9160-8 · Cited by 21
“The suspected causes of decreased FeNO in CF are numerous and can be summarized as follows: (1) decreased NO production secondary to impaired iNOS expression/activity or L-arginine deficiency [24–29], (2) increased bacterial, enzymatic, or chemical NO consumption [4, 30–33], and (3) slower NO diffusion through the hig…”
Background
Glutathione Peroxidase‐Based Amperometric Biosensor for the Detection of S‐Nitrosothiols
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Lung Carcinogenesis by Diesel Exhaust Particles and the Carcinogenic Mechanism Via Active Oxygens
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Authors: Gaston, B., Drazen, J. M., Loscalzo, J., & Stamler, J. S.
Affiliations: Boston Children's Hospital (US)
ORCID: Gaston, B
Drazen, J M
Loscalzo, J
Stamler, J S
Venue: American Journal of Respiratory and Critical Care Medicine
Publisher: Oxford University Press (OUP)
Published: 1994-02-01
Volume: 149
Issue: 2
Pages: 538-551
ISSN: 1073-449X (ISSN-L)
1535-4970
DOI: 10.1164/ajrccm.149.2.7508323
OpenAlex: W2054510493
Cited by: 918
References: 0
Citations by year: 2025: 6 · 2024: 4 · 2023: 4 · 2022: 10 · 2021: 13 · 2020: 5 · 2019: 6 · 2018: 10 · 2017: 9 · 2016: 15 · 2015: 16 · 2014: 19 · 2013: 27 · 2012: 16
FWCI: 37.13
Type: journal article
Language: en
Open access: closed
Licence: academic.oup.com/pages/standard-publication-reuse-rights (vor)
Locations: American Journal of Respiratory and Critical Care Medicine (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (5r01hl040411-02, 5p50hl019170-20, 5r01hl043344-04)
National Heart, Lung, and Blood Institute (HL43344, HL-40411, HL 19170)
Topics: Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Asthma and respiratory diseases
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Keywords: nitrogen oxides, nitric oxide, nitric oxide synthase, airway epithelial cells, S-nitrosothiols, peroxynitrite, nitrosamines, pulmonary hypertension, acute respiratory distress syndrome, asthma, nitric oxide inhalation therapy, bronchodilation, host defense, smooth muscle relaxation
MeSH terms: Amino Acid Oxidoreductases, Animals, Humans, Lung, Lung Diseases, Nitric Oxide, Nitrogen Oxides, Nitrous Oxide, Nitric Oxide Synthase

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The Biology of Nitrogen Oxides in the Airways

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