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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[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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“THE SIGNALING MOLECULE nitric oxide (NO), generated by NO synthase (NOS), plays a critical role in physiological processes in the pulmonary epithelium (6, 16).”
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Exhaled Nitric Oxide in Human Lung Transplantation: A Noninvasive Marker of Acute Rejection
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BackgroundMolecular mechanisms of nitrogen dioxide induced epithelial injury in the lung.
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“It is important to recognize that under physiological conditions, NOz has a half-life of only seconds (14), but the assay for accumulated nitrite is an indication of the total NOz production over time.”
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“It has been postulated that the induction of inducible NO synthase (iNOS),(3) the high-output form of NO synthase (NOS), is responsible for increased levels of NO and its oxidation products in the expired breath (1, 2).”
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“Excessive production of NO in the pulmonary vasculature via iNOS is thought to be a key mechanism in the pronounced systemic vasodilation of sepsis (Gaston et al, 1994, Moncada et al, 1991; Ullrich et al, 1999) and has also been implicated in sepsis-associated pulmonary edema via cytotoxic…”
BackgroundInfluentialSkloot, G. S., & Togias, A. G. (2003) · Clinical Reviews in Allergy & Immunology · doi:10.1385/criai:24:1:55 · Cited by 75
“Many studies have demonstrated that exhaled NO is increased in asthma ( 94 ,95).”
BackgroundNitric oxide metabolism in asthma pathophysiology
Ghosh, S., & ERZURUM, S. C. (2011) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2011.06.009 · Cited by 79
“RSNO are present at lower than normal levels in the tracheal aspirates of children with acute asthma exacerbations [149,160] as well as in the bronchoalveolar lavage fluid of well-controlled asthmatic individuals [14].”
Roles of iNOS and nNOS in sepsis-induced pulmonary apoptosis
Rudkowski, J. C., Barreiro, E., Harfouche, R., et al. (2004) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00266.2003 · Cited by 75
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Response of premature infants with severe respiratory failure to inhaled nitric oxide
Meurs, K. P. V., Rhine, W. D., Asselin, J. M., Durand, D. J., & Preemie NO Collaborative Group (1997) · Pediatric Pulmonology · doi:10.1002/(sici)1099-0496(199711)24:5 · Cited by 112
Relaxin Counteracts Asthma-Like Reaction Induced by Inhaled Antigen in Sensitized Guinea Pigs*
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“oxide has been shown to cause relaxation of lung airways and blood vessels and, hence, to improve asthmatic symptoms and favor lung perfusion (14).”
BackgroundInhaled Nitric Oxide Decreases Hyperoxia-Induced Surfactant Abnormality in Preterm Rabbits
Issa, A., Lappalainen, U., Kleinman, M., Bry, K., & Hallman, M. (1999) · Pediatric Research · doi:10.1203/00006450-199902000-00016 · Cited by 72
Meurs, H., Hamer, M. A. M., Pèthe, S., et al. (2000) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0703488 · Cited by 73
“It is now well established that nitric oxide (NO) is importantly involved in the regulation of airway tone as well as in asthmatic in¯ammation (Barnes & Belvisi, 1993; Gaston et al., 1994; Barnes & Liew, 1995).”
BackgroundNitrite/ nitrate and cytokine levels in bronchoalvelar lavage fluid of lung cancer patients
Arias‐Díaz, J., Vara, E., Torres-Melero, J., Garcı́a, C., Baki, W., Ramσrez-Armengol, J. A., & Balibrea, J. L. (1994) · Cancer · doi:10.1002/1097-0142(19940901)74:5 · Cited by 73
Hoffman, G. M., Ross, G. A., Day, S. E., et al. (1997) · Critical Care Medicine · doi:10.1097/00003246-199702000-00026 · Cited by 73
Kawamoto, H., Takeno, S., & Yajin, K. (1999) · The Laryngoscope · doi:10.1097/00005537-199912000-00023 · Cited by 72
Shay, A. H., Choi, R., Whittaker, K., Salehi, K. K., Kitchen, C. M. R., Tashkin, D. P., Roth, M. D., & Baldwin, G. C. (2003) · The Journal of Infectious Diseases · doi:10.1086/368370 · Cited by 71
“number of regulatory and protective functions [10].”
Nonlinearity of respiratory mechanics during bronchoconstriction in mice with airway inflammation
Wagers, S. S., Lundblad, L. K. A., Moriya, H. T., et al. (2002) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00883.2001 · Cited by 72
Nitrogen Dioxide Promotes Allergic Sensitization to Inhaled Antigen
Bevelander, M., Mayette, J., Whittaker, L. A., et al. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.179.6.3680 · Cited by 71
“NO2 is a toxic-free radical gas that is a component of air pollution (1, 3) and is also formed in the lung during inflammation (4).”
BackgroundEiserich, J. P., Vossen, V., O’neill, C. A., Halliwell, B. B., Cross, C. E., & van der Vliet, A. (1994) · FEBS Letters · doi:10.1016/0014-5793(94)01011-0 · Cited by 71
An organic field effect transistor as a selective NOx sensor operated at room temperature
Marinelli, F., Dell’Aquila, A., Torsi, L., Tey, J. N., Suranna, G. P., Mastrorilli, P., Romanazzi, G., Nobile, C. F., Mhaisalkar, S. G., Cioffi, N., et al. (2009) · Sensors and Actuators B Chemical · doi:10.1016/j.snb.2009.04.035 · Cited by 70
Metadata
- 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 (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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