The biology of nitrogen oxides in the airways
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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The hallmark feature of PAH and other forms of PH is reduced bioavailability of NO signaling and poor endothelial responsiveness to triggers of vasodilatation.
“The hallmark feature of PAH and other forms of PH is reduced bioavailability of NO signaling and poor endothelial responsiveness to triggers of vasodilatation[28–34].”
From Enterosalivary nitrate metabolism and the microbiome: Intersection of microbial metabolism, nitric oxide and diet in cardiac and pulmonary vascular health (2017) · cites this paper as [28]
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“After exposure to various inflammatory stimuli such as lipopolysaccharide (LPS), tumor necrosis factor (TNF ), or interleukin (IL)-1 , an inducible form of NOS (iNOS) is expressed by many cells within the lung parenchyma.(12) Studies involving the use of mice deficient in specific NOS isoforms has shed some light on t…”
BackgroundRole of Inducible Nitric Oxide Synthase in Pulmonary Microvascular Protein Leak in Murine Sepsis
Wang, L. F., Patel, M., Razavi, H. M., Weicker, S., JOSEPH, M. G., McCormack, D. G., & Mehta, S. (2002) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.2110017 · Cited by 172 · see citing works
Correlation of Systemic Superoxide Dismutase Deficiency to Airflow Obstruction in Asthma
COMHAIR, S. A. A., Ricci, K. S., Arroliga, M. E., Lara, A., Dweik, R. A., Song, W., Hazen, S. L., Bleecker, E. R., Busse, W. W., Chung, K. F., et al. (2005) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200502-180oc · Cited by 167 · see citing works
Self-citationIncreased exhaled nitric oxide in patients with stable chronic obstructive pulmonary disease
Corradi, M., Majori, M., Cacciani, G., Consigli, G. F., de'Munari, E., & Pesci, A. (1999) · Thorax · doi:10.1136/thx.54.7.572 · Cited by 167 · see citing works
“In the past, nitric oxide (NO) was regarded exclusively as an atmospheric contaminant. Currently, however, it is thought to play an important endogenous signalling role in the physiological control of airway function and in the pathophysiology of airway diseases.”
BackgroundExhaled nitric oxide in childhood asthma: a review
Pijnenburg, M. W. H., & de Jongste, J. C. (2007) · Clinical & Experimental Allergy · doi:10.1111/j.1365-2222.2007.02897.x · Cited by 163 · see citing works
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Nasal nitric oxide is increased in allergic rhinitis
Arnal, J., Didier, A. P., RAMI, J., M’Rini, C., Charlet, J.-P., Serrano, É., & Jp, B. (1997) · Clinical & Experimental Allergy · doi:10.1111/j.1365-2222.1997.tb00719.x · Cited by 163 · see citing works
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“seems due to the effects of these drugs on the iNOS gene ( 11 ).”
BackgroundNitric oxide and reactive nitrogen species in airway epithelial signaling and inflammation
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“It has been suggested that upregulation of NO synthesis in asthma serves to counterbalance bronchoconstrictor stimuli [69], although NO is a rather weak bronchodilator compared to its vasodilator properties.”
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Vascular smooth muscle and nitric oxide synthase
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“Thus, the EDRF concept implied that NO diffuses passively from the cytosol of its cell of origin into distant target cells to elicit a response (20).”
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Increased nitric oxide metabolites in exhaled breath condensate after exposure to tobacco smoke
Bálint, B., Donnelly, L., Hanazawa, T., Kharitonov, S., & Barnes, P. J. (2001) · Thorax · doi:10.1136/thorax.56.6.456 · Cited by 150 · see citing works
“3 5–8 Cigarette smoke not only contains oxidants, but also generates an increased release of oxidants from neutrophils and macrophages.”
BackgroundAirway epithelium as an effector of inflammation: molecular regulation of secondary mediators
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“Nitric oxide also has the potential to react quickly with the large quantities of superoxide and protein thiols available to form peroxynitrite or nitrosothiols [63], which may also serve as secondary mediators of inflammation.”
BackgroundNitric oxide metabolites in cystic fibrosis lung disease
Grasemann, H., IOANNIDIS, I., Tomkiewicz, R. P., de GROOT, H., Rubin, B. K., & Ratjen, F. A. (1998) · Archives of Disease in Childhood · doi:10.1136/adc.78.1.49 · Cited by 146 · see citing works
Total nitrite/nitrate in expired breath condensate of patients with asthma
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Asymmetric Dimethylarginine Induces Oxidative and Nitrosative Stress in Murine Lung Epithelial Cells
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Oxidative stress in asthma: Part of the puzzle
Şahiner, Ü. M., Birben, E., ERZURUM, S. C., Saçkesen, C., & Kalaycı, Ö. (2018) · Pediatric Allergy and Immunology · doi:10.1111/pai.12965 · Cited by 145 · see citing works
The airway cholinergic system: physiology and pharmacology
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Modulation of cytokine and nitric oxide by mesenchymal stem cell transfer in lung injury/fibrosis
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“NO reacts rapidly with oxygen-centered superoxide radicals to form peroxynitrite, a potent oxidizer that may contribute to tissue injury in ALI and fibrosis [29,30].”
BackgroundRole of Nitric Oxide Carried by Hemoglobin in Cardiovascular Physiology
Premont, R. T., Reynolds, J. D. H., Zhang, R., & Stamler, J. S. (2019) · Circulation Research · doi:10.1161/circresaha.119.315626 · Cited by 142 · see citing works
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“NO is a free radical species that possesses a reactive unpaired electron (16, 17).”
BackgroundExhaled breath condensate biomarkers in COPD
Borrill, Z., Roy, K. C., & Singh, D. (2008) · European Respiratory Journal · doi:10.1183/09031936.00116107 · Cited by 135 · see citing works
- Authors
- Gaston, B., Drazen, J. M., Loscalzo, J., & Stamler, J. S.
- Affiliations
- Boston Children's Hospital (US)
- 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
- 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
- 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 › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Physiology › 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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