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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“NO acts as a free radical, and, depending on the microenvironment, it is oxidized, reduced or complexed with other biomolecules (Bloodsworth et al., 2000; Gaston et al., 1994; Radi, 2004).”
Background
A Novel Inhaled Organic Nitrate That Affects Pulmonary Vascular Tone in a Piglet Model of Hypoxia-Induced Pulmonary Hypertension
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Self-citation
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BackgroundInfluential
Capillary electrophoresis analysis of nitrite and nitrate in sub-microliter quantities of airway surface liquid
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Background
Pulmonary Hypertension and COVID-19
Castiglione, L., & Droppa, M. (2021) · Hämostaseologie · doi:10.1055/a-1661-0240 · Cited by 17
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“NO reacts with many molecular targets, including thiols (producing nitrosothiols, RS-NO), nitrogen-containing compounds (producing nitrosamines, RNH-NO), transition metals, oxygen, free radicals, enzymes, and heme-containing proteins, including hemoglobin, myoglobin, and cytochromes (57).”
Background
Regulation of asthmatic airway relaxation by estrogen and heat shock protein 90
Intapad, S., Dimitropoulou, C., Snead, C. M., Piyachaturawat, P., & Catravas, J. D. (2011) · Journal of Cellular Physiology · doi:10.1002/jcp.23045 · Cited by 17
“However, the role of eNOS- or nNOS-derived NO in asthma remains unclear because of the excessive iNOS-derived NO production detected in exhaled gas of asthmatic patients (Gaston et al., 1994).”
Background
Nitric oxide has no beneficial effects on ion transport defects in cystic fibrosis human nasal epithelium
Rückes-Nilges, C., Lindemann, H., Klimek, T., et al. (2000) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s004240000394 · Cited by 17
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Result
Hyperbaric oxygen increases plasma exudation in rat trachea: involvement of nitric oxide
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Background
Uptake of inhaled nitric oxide in acute lung injury
Westfelt, U. N., Lundin, S., & Stenqvist, O. (1997) · Acta Anaesthesiologica Scandinavica · doi:10.1111/j.1399-6576.1997.tb04794.x · Cited by 17
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“Epithelial cells and macrophages [3, 4, 7 , 10, 17] are the main sources of pulmonary NO, and inducible NOS (iNOS) is expressed in epithelial cells of the airways [8, 23].”
Background
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Background
The Controversy Persists: Is There a Qualification Criterion to Utilize Inhaled Nitric Oxide in Pre-term Newborns?
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“We cannot also exclude a difference between the two groups, regarding NO metabolism into peroxynitrite, S-nitrosyl or S-nitrosothiol compounds within the lungs (40, 41).”
Background
Site of action of endogenous nitric oxide on pulmonary vasculature in rats
Ferrario, L., Amin, H. M., Sugimori, K., et al. (1996) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s004240050165 · Cited by 16
“slower [11], and the half life of its activity becomes longer and thus its vasodilator effect may become potentiated.”
Background
Theoretical Gas Phase Mass Transfer Coefficients for Endogenous Gases in the Lungs
Condorelli, P., & George, S. C. (1999) · Annals of Biomedical Engineering · doi:10.1114/1.145 · Cited by 16
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“NO synthase (NOS) has been localized in mast cells of the human lung (Gaston et al. 1994) and the skin vascular endothelium (Abd-El-Aleem et al. 2000) suggesting that both of these sites are potential sources of NO in human skin.”
Background
Short-term effects of nCPAP on nasal mucociliary clearance and mucus transportability in healthy subjects
de Oliveira, L. R., Yagi, C. S. A., Figueiredo, A. C., Saldiva, P. H. N., & Lorenzi‐Filho, G. (2005) · Respiratory Medicine · doi:10.1016/j.rmed.2005.03.042 · Cited by 15
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Mupanemunda, R. H., & Edwards, A. D. (1995) · Archives of Disease in Childhood Fetal & Neonatal · doi:10.1136/fn.72.2.f131 · Cited by 15
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Ghosh, S., & ERZURUM, S. C. (2012) · Drug Discovery Today Disease Mechanisms · doi:10.1016/j.ddmec.2012.10.004 · Cited by 15
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Linnane, S. J., Thin, A. G., Keatings, V. M., et al. (2001) · European Respiratory Journal · doi:10.1183/09031936.01.00065701 · Cited by 15
“NO is a highly reactive gas that is rapidly oxidized by reaction with oxygen and superoxide radical at or close to its site of production [17].”
Background
Expression of Nitric Oxide Synthases in Nasal Mucosa from a Mouse Model of Allergic Rhinitis
Oh, S. J., Min, Y., Lee, S., et al. (2003) · Annals of Otology Rhinology & Laryngology · doi:10.1177/000348940311201013 · Cited by 15
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“Several lines of evidence have indicated that the diffusible free radical nitric oxide (NO) plays a crucial role in the pathophysiology of airway disease and in the control of the airway inflammation.(11) NO is produced from L-arginine by a group of three distinct isoforms of nitric oxide synthase (NOS).”
Background
Exhaled nitric oxide measurements in the first 2 years of life: methodological issues, clinical and epidemiological applications
Gabriele, C., de Benedictis, F. M., & de Jongste, J. C. (2009) · The Italian Journal of Pediatrics/Italian journal of pediatrics · doi:10.1186/1824-7288-35-21 · Cited by 15
“Introduction Nitric oxide (NO) is formed in biological systems from Larginine and oxygen by the enzyme nitric oxide synthases (NOS), of which 3 isoforms have been described: type I and III, which are constitutive (cNOS) and type II which is inducible (iNOS) [1-3] (figure 1).”
Endogenous Nitric Oxide Production in the Airways of Preterm and Term Infants
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“At air–liquid interfaces in biological systems, NO may be converted to a number of toxic end products, including NO2 (Tannenbaum, 1997; Gaston et al., 1994).”
Background
Differential effects of inhaled nitric oxide and hyperoxia on pulmonary dysfunction in newborn guinea pigs
Gries, D. M., Tam, E. K., Blaisdell, J., et al. (2000) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.2000.279.5.r1525 · Cited by 15
“On the other hand, several studies suggest that NO could act as an antioxidant to counter the cytotoxic effects of reactive O2 species (8).”
Background
Hyperosmolarity reduces the relaxing potency of nitric oxide donors in guinea‐pig trachea
Hjoberg, J., Högman, M., & Hedenstierna, G. (1999) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0702569 · Cited by 15
“…cyclase might contribute to the e ect of the nitric oxide donor SNP on airway smooth muscle (Stuart-Smith & Vanhoutte, 1990; Stuart-Smith et al., 1994; Zhang et al., 1993; Fedan et al., 1995; Sadeghi-Hashjin et al., 1996; Wong et al., 1995; Zhou & Torphy, 1991; Diamond, 1993; Gaston et al., 1994a).”
Background
Safety aspects of delivery and monitoring of nitric oxide during mechanical ventilation
Westfelt, U. N., Lundin, S., & Stenqvist, O. (1996) · Acta Anaesthesiologica Scandinavica · doi:10.1111/j.1399-6576.1996.tb04437.x · Cited by 15
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“Finally, the dose of L-NMMA we employed has been used effectively in the past to inhibition NOS synthesis (16, 23), and, clearly, it worked here as well.”
BackgroundInfluential
Pulmonary hypertension: considerations in the liver transplant candidate
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“Decreased synthesis or release of thrombomodulin, heparan sulfate, and tissuetype plasminogen activator in conjunction with increased release of plasminogen activator inhibitor type 1 and tissue factor promote fibrin formation [7, 15 , 28, 55].”
BackgroundInfluential
Modulation of NF-κB and Hypoxia-Inducible Factor−1 by S -Nitrosoglutathione Does Not Alter Allergic Airway Inflammation in Mice
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Impact of Volume-Dependent Alveolar Diffusing Capacity on Exhaled Nitric Oxide Concentration
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Self-citation
Neonatal ECMO: Are Indications Changing?
Short, B. L. (1995) · The International Journal of Artificial Organs · doi:10.1177/039139889501801002 · Cited by 14
“With potential complications from nitric oxide use, including further lung injury from cytotoxic by-products and its carcinogenic potential during long-term use, use of nitric oxide should be tempered until studies are complete (16-17).”
Background
Reaction of NO at low temperature by ACF loading urea and rare-earth element oxides (La2O3, CeO2)
Zeng, Z., Lu, P., Li, C., Zeng, G., & Jiang, X. (2012) · Journal of Coordination Chemistry · doi:10.1080/00958972.2012.686612 · Cited by 13
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“There are three kinds of NOS forms, two of which (NOS1, NOS 3) and constitutively expressed while the third NOS form (NOS2) is not normally present but can be produced by epithelial, endothelial, neutrophils, macrophages, fibroblasts, and smooth muscle cells when inflammatory cytokines, endotoxin, and viral infection…”
Background
OGG1 in Lung—More than Base Excision Repair
Ma, X., Ming, H., Liu, L., Zhu, J., Pan, L., Chen, Y., & Xiang, Y. (2022) · Antioxidants · doi:10.3390/antiox11050933 · Cited by 13
“Oxidative stress can exacerbate airway infl mmatory responses by which asthma, chr nic obstru tive pulmonary disease (COPD) and ther invasive pulmonary diseases are accompanied [22,23].”
Background
Pulmonary infection, and not systemic inflammation, accounts for increased concentrations of exhaled nitric oxide in patients with septic shock
ten Oever, J., Mandon, J., Netea, M. G., van Deuren, M., Harren, F. J. M., Cristescu, S. M., & Pickkers, P. (2013) · Journal of Breath Research · doi:10.1088/1752-7155/7/3/036003 · Cited by 13
“After synthesis, NO can react with other molecules as oxygen, superoxide, transition metals, nitrogen and sulfur, preventing it to stay in measurable form [34].”
Background
Clinical Significance of the Increased Peak Levels of Exhaled Nitric Oxide in Patients with Bronchial Asthma.
Satouchi, M., Maeda, H., Yu, Y., & Yokoyama, M. (1996) · Internal Medicine · doi:10.2169/internalmedicine.35.270 · Cited by 13
The effect of low-dose inhaled fluticasone propionate on exhaled nitric oxide in asthmatic patients and comparison with oral zafirlukast
Lanz, M. J., Lanz, M. J., Eisenlohr, C. P., et al. (2001) · Annals of Allergy Asthma & Immunology · doi:10.1016/s1081-1206(10)62241-7 · Cited by 13
Free nitric oxide diffusion in the bronchial microcirculation
Condorelli, P., & George, S. C. (2002) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00003.2002 · Cited by 13
Exhaled nitric oxide in paediatric asthma
Ratnawati, R., & Thomas, P. S. (2005) · Chronic Respiratory Disease · doi:10.1191/1479972305cd73ra · Cited by 13
Exchange dynamics of nitric oxide in the human nose
Chambers, D. C., Carpenter, D. A., & Ayres, J. G. (2001) · Journal of Applied Physiology · doi:10.1152/jappl.2001.91.5.1924 · Cited by 13
“NO produced by NOS in airway walls may be excreted into the lumen in the gas phase, or it may diffuse submucosally, where it will combine avidly with heme (17) and other reactants (9).”
Background
Nitric oxide-related products and myeloperoxidase in bronchoalveolar lavage fluids from patients with ALI activate NF-kappa B in alveolar cells and monocytes
Nys, M., Preiser, J., Deby-Dupont, G. P., Habraken, Y., Mathy-Hartert, M., Damas, P., & Lamy, M. (2005) · Vascular Pharmacology · doi:10.1016/j.vph.2005.08.007 · Cited by 12
Biphasic effects of free radical scavengers against bleomycin-induced pulmonary fibrosis
Fujita, M., Mizuta, Y., Ikegame, S., Ouchi, H., Ye, Q., Harada, E., Inoshima, I., Yoshimi, M., Watanabe, K., & Nakanishi, Y. (2008) · Pulmonary Pharmacology & Therapeutics · doi:10.1016/j.pupt.2008.06.006 · Cited by 11
Exhaled nitric oxide in single and repetitive prolonged exercise
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“Furthermore, it has been proposed that a decreased exhaled NO after strenuous exercise may contribute to the alteration of immune function (Gaston et al., 1994), but whether a lowered NO availability contributes to the decreased immune function reported in athletes (Nieman, 2000) after prolonged intensive exercise rem…”
BackgroundInfluential
Photocatalysis as a method for reduction of ambient NOx in deep underground mines
Banasiewicz, A., Janicka, A. B., Michalak, A., et al. (2022) · Measurement · doi:10.1016/j.measurement.2022.111453 · Cited by 12
Impairment of Airway Mucociliary Transport in Patients with Sinobronchial Syndrome: Role of Nitric Oxide
Tamaoki, J., Taira, M., Nishimura, K., et al. (2000) · Journal of Aerosol Medicine · doi:10.1089/jam.2000.13.239 · Cited by 12
Nitric oxide in the breath of bottlenose dolphins: Effects of breath hold duration, feeding, and lung disease
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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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