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Nitrogen Oxides and cigarette smoke-induced injury

Institution: University of California, Davis
Investigator(s): Albert van der Vliet, Ph.D.
Award Cycle: 1998 (Cycle 7) Grant #: 7RT-0167 Award: $304,118
Subject Area: Pulmonary Disease
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
Cigarette smoking is a major risk factor in chronic obstructive lung disease (e.g., bronchitis, emphysema), cardiovascular disease and various cancers. Cigarette smoke (CS) contains over 1000 compounds, many of which are extremely reactive with biological targets. Inhalation of tobacco smoke has been demonstrated to cause oxidative stress, which is due in part to the many oxidants within CS itself, and is a consequence of the inflammatory response induced by smoking. These oxidative processes are known to contribute to cell and tissue injury and decreased organ function, and are believed to be involved in tobacco-related disease. One important class of compounds in CS are nitrogen oxides, of which the primary form is nitric oxide (NO). Further oxidation of NO occurs in CS to produce highly toxic nitrogen oxides, as well as many reactive organic radicals that also contribute to the toxicity of CS. Nitric oxide itself is not necessarily toxic (e.g., NO is produced in the body by many cell types as a physiological messenger molecule, and by inflammatory cells as part of the defense mechanism against invading organisms). However, the relatively high concentration of NO present in tobacco smoke may render it toxic. Indeed, NO is known to be toxic to cells at high concentrations, which most likely involves further oxidation of NO to more deleterious compounds. As part of an inflammatory response, certain white blood cells are activated to produce a number of compounds, including various oxidants, that are thought to contribute to tissue injury and decreased organ function during chronic inflammatory disorders. Recently, some of these have been shown to interact with NO to form various reactive nitrogen oxides that can cause specific modifications to cellular components (e.g. proteins and their constituent amino acids). A specific example of this is the product of nitrogen oxides reacting with the amino acid tyrosine, producing “3-nitrotyrosine”. In many recent studies, formation of 3-nitrotyrosine has been associated with a many diseases, including those associated with inflammation in lung airways. We propose that 3-nitrotyrosine is generated within the lung after inhalation of tobacco smoke, which may result in inactivation of many enzymes and represent a biological pathway by which normal cell function may be impaired. It is our hypothesis that cigarette smoking or exposure to environmental tobacco smoke contributes to oxidative injury in the lung and subsequently leads to decreased lung function. Moreover, we hypothesize that the combination of exposure to CS with ongoing inflammation in the respiratory tract (such as in patients with asthma or adult respiratory distress syndrome) results in increased production of reactive nitrogen oxides, causing NO-dependent irreversible modifications in cell constituents. The specific aims of this research proposal are (1) to define the chemical interactions between nitrogen oxides in CS and inflammatory-derived oxidants, (2) to investigate the contribution of nitrogen oxides to the injury (to the cells lining the surfaces of the lung) induced by tobacco smoke, and (3) to identify specific protein modification products that are characteristic of various reactive nitrogen oxides in lung specimens from human subjects, in order to correlate the presence of specific NO-dependent protein modifications to cigarette smoking. It is anticipated that these studies will further our understanding of the pathophysiology of tobacco-related disease.
Publications

Peroxynitrite induces covalent dimerization of epidermal growth factor receptors in A431 epidermoid carcinoma cells
Periodical: Journal of Biological Chemistry Index Medicus:
Authors: van der Vliet A, Hristova M, Cross CE, Eiserich JP, Goldkorn T ART
Yr: 1998 Vol: 273 Nbr: Abs: Pg: 31860-31866

Cigarette smokers and oxidant stress .... a continuing mystery
Periodical: American Journal of Clinical Nutrition Index Medicus:
Authors: Cross CE, van der Vliet A, Eiserich JP ART
Yr: 1998 Vol: 67 Nbr: Abs: Pg: 184-185

Analysis of aromatic nitration, chlorination, and hydroxylation by gas chromatography-mass spectrometry
Periodical: Methods in Enzymology Index Medicus:
Authors: van der Vliet A, Jenner A, Eiserich JP, Cross CE, Halliwell B ART
Yr: 1999 Vol: 301 Nbr: Abs: Pg: 471-483

Substance P primes the formation of hydrogen peroxide and nitric oxide in human neutrophils
Periodical: Journal of Leukocyte Biology Index Medicus:
Authors: Sterner-Kock A, Braun RK, van der Vliet A, et al ART
Yr: 0 Vol: Nbr: Abs: Pg:

Micronutrient antioxidants and smoking.
Periodical: British Medical Bulletin Index Medicus:
Authors: Cross CE, Traber M, Eiserich J, van der Vliet A ART
Yr: 1999 Vol: 55 Nbr: Abs: Pg: 691-704

Myeloperoxidase and protein oxidation in cystic fibrosis
Periodical: American Journal of Physiology Index Medicus:
Authors: van der Vliet A, Nguyen MN, Shigenaga MK, Eiserich JP, Marelich GP, Cross CE ART
Yr: 2000 Vol: 279 Nbr: Abs: Pg: L537-L546

Tobacco-related diseases: is there a role for antioxidant micronutrient supplementation?
Periodical: Clinics in Chest Medicine Index Medicus:
Authors: Traber MG, van der Vliet A, Reznick AZ, Cross CE ART
Yr: 2000 Vol: 21 Nbr: Abs: Pg: 173-187

Nitrotyrosine formation in vivo. How, where and why?
Periodical: Free Radical Biology and Medicine Index Medicus:
Authors: van der Vliet A ART
Yr: 2000 Vol: Nbr: Abs: Pg:

Oxidants, nitrosants, and the lung
Periodical: American Journal of Medicine Index Medicus:
Authors: van der Vliet A, Cross CE ART
Yr: 2000 Vol: 109 Nbr: Abs: Pg: 398-421

Cigarette smoke impairs neutrophil respiratory burst activation by aldehyde-induced thiol modifications
Periodical: Toxicology Index Medicus:
Authors: Nguyen H, Finkelstein E, Reznick A, Cross CE, van der Vliet A ART
Yr: 2001 Vol: 160 Nbr: Abs: Pg: 207-217

Inhibition of neutrophil apoptosis by acrolein: a contributing factor in tobacco-related inflammatory disease?
Periodical: American Journal of Physiology Index Medicus:
Authors: Finkelstein EI, Nardini M, van der Vliet A ART
Yr: 2001 Vol: 281 Nbr: Abs: Pg: L732 - L739

Nitric oxide: a proinflammatory mediator in lung disease?
Periodical: Respiratory Research Index Medicus:
Authors: van der Vliet A, Eiserich JP, Cross CE ART
Yr: 2000 Vol: 1 Nbr: Abs: Pg: 67-72

Cigarettes, cancer, and carotenoids: a continuing, unresolved antioxidant paradox
Periodical: American Journal of Clinical Nutrition Index Medicus:
Authors: van der Vliet A ART
Yr: 2000 Vol: 72 Nbr: Abs: Pg: 1421-1423

Inactivation of glutathione S-transferase by nitric oxide-derived oxidants. Exploring a role for tyrosine nitration.
Periodical: Archives of Biochemistry and Biophysics Index Medicus:
Authors: Wong PS, Elserich JP, Lopez CL, Jones AD, Reddy S, Cross CE, and van der Vliet A ART
Yr: 2001 Vol: 394 Nbr: Abs: Pg: 216 - 228

Susceptibility to ozone-induced acute lung injury in iNOS-deficient mice.
Periodical: American Journal of Physiology Index Medicus:
Authors: Kenyon NJ, van der Vliet A, Schock BC, Okamoto T, McGrew GM, and Last JA ART
Yr: 2002 Vol: 282 Nbr: Abs: Pg: L540 - L545

Acrolein-induced cytotoxicity in cultured human bronchial epithelial cells. Modulation by alpha-tocopherol and ascorbic acid.
Periodical: Toxicology Index Medicus:
Authors: Nardini M, Finkelstein EI, Reddy S, Valacchi G, Traber M, Cross CE, and van der Vliet A ART
Yr: 2002 Vol: 170 Nbr: Abs: Pg: 173 - 185

S-nitrosothiols inhibit cytokine-mediated induction of MMP-9 in airway epithelial cells.
Periodical: American Journal of Respiratory Cell and Molecular Biology Index Medicus:
Authors: Okamoto T, Valacchi G, Gohil K, Akaike T, and van der Vliet A ART
Yr: 2002 Vol: 27 Nbr: Abs: Pg: 463 - 473

Identification of glutathione modifications by cigarette smoke.
Periodical: Free Radical Biology and Medicine Index Medicus:
Authors: Reddy S, Finkelstein EI, Wong PS, Phung A, Cross CE, and van der Vliet A ART
Yr: 2002 Vol: Nbr: Abs: Pg:

Innate antioxidant defense systems in the respiratory tract.
Periodical: BioFactors Index Medicus:
Authors: van der Vliet A, and Cross CE ART
Yr: 2001 Vol: 15 Nbr: Abs: Pg: 83 - 86

Cigarette smokers and oxidant stress...a continuing mystry.
Periodical: American Journal of Clinical Nutrition Index Medicus:
Authors: Cross CE, van der Vliet A, and Eiserich JP ART
Yr: 1998 Vol: 67 Nbr: Abs: Pg: 184 - 185

Peroxidanses wheesing their way into asthma.
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Cross CE, van der Vliet A, and Elserich JP ART
Yr: 2001 Vol: 104 Nbr: Abs: Pg: 1102 - 1103