Reactive aldehydes such as acrolein (2,3-propenal) are major components of air pollution and are proposed to contribute to the adverse effects of smoking in lung diseases such as chronic obstructive pulmonary disease (COPD). In addition, acrolein and similarly reactive aldehydes (such as 4- hydroxynonenal) are also generated endogenously, as presumed bioactive products of oxidative stress such as during inflammation. Acute and chronic lung diseases, including COPD, are often dominated by recruitment and activation of neutrophils, and tobacco smoke-derived aldehydes have been shown to alter several neutrophil properties, including stimulation of cytokine release, inhibition of the respiratory burst, and interference with constitutive neutrophil apoptosis. Overall, these various observations may help explain why smoking contributes to persistent airway inflammation, by increasing neutrophil recruitment and by interfering with neutrophil apoptosis, the latter a critical event in the termination of inflammatory processes. Preliminary studies in mice have shown that exposure to environmental tobacco smoke augments neutrophil inflammation by lipopolysaccharide, perhaps due to interference of tobacco smoke aldehydes with neutrophil apoptosis and clearance. Based on their chemical reactivity, these aldehydes react primarily with cellular GSH or with redox-sensitive cysteine residues in proteins, thereby altering cellular redox status and/or interfering with various cell signaling pathways. A better understanding of biochemical mechanisms by which these aldehydes modulate inflammatory processes may provide additional links between environmental/oxidative stress and inflammatory lung diseases such as COPD. Our hypothesis is that reactive aldehydes can contribute to chronic lung inflammation by interfering with granulocyte apoptosis, thereby increasing survival and/or necrosis, resulting in continued and increased inflammation.
We aim to explore the effects of aldehydes on pathways that regulate neutrophil survival and death pathways, and their consequences for neutrophil phagocytic clearance and/or release of toxic granule components. We plan to study this in freshly isolated human neutrophils (alone or in co-culture experiments with cultured macrophages or airway epithelial cells) and in a mouse model of acute transient airway inflammation. Finally, we aim to determine the major cellular targets for these aldehydes, using various derivatization strategies and proteomics approaches (2-D electrophoresis, MALDI mass spectrometry), in an attempt to relate specific protein modifications by these aldehydes to their cellular effects. We propose that thus identified cellular targets and its modifications could be used as mechanism-based biomarkers to explore a role of these aldehydes in the etiology of such diseases as COPD. ? ?
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