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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. |
