Cigarette smoke impairs neutrophil respiratory burst activation by aldehyde-induced thiol modifications

Exposure to airborne pollutants such as tobacco smoke is associated with in creased activation of inflammatory-immune processes and is thought to contr ibute to the incidence of respiratory tract disease. We hypothezised that c igarette smoke (CS) could synergize with activated inflammatory/immune cell s to cause oxidative injury or result in the formation of unique reactive o xidants. Isolated human neutrophils were exposed to gas-phase CS, and the p roduction of nitrating and chlorinating oxidants following neutrophil stimu lation was monitored using the substrate 4-hydroxyphenylacetate (HPA). Stim ulation of neutrophils in the presence of CS resulted in a reduced oxidatio n and chlorination of HPA, suggesting inhibition of NADPH oxidase or myelop eroxidase (MPO), the two major enzymes involved in inflammatory oxidant for mation. Peroxidase assays demonstrated that neutrophil MPO activity was not significantly affected after CS-exposure, leaving the NADPH oxidase as a l ikely target. The inhibition of neutrophil oxidant formation was found to c oincide with depletion of cellular GSH, and a similar modification of criti cal cysteine residues, such as those in NADPH oxidase components, might be involved in reduced respiratory burst activity. As ol,P-unsaturated aldehyd es such as acrolein have been implicated in thiol modifications by CS, we e xposed neutrophils to acrolein prior to stimulation, and observed inhibitio n of NADPH oxidase activation in relation to GSH depletion. Additionally, t ranslocation of the cytosolic components of NADPH oxidase to the membrane, a necessary requirement for enzyme activation, was inhibited. Protein adduc ts of acrolein (or related aldehydes) could be detected in several neutroph il proteins, including NADPH oxidase components, following neutrophil expos ure to either CS or acrolein. Alterations in neutrophil function by exposur e to (environmental) tobacco smoke may affect inflammatory/infectious condi tions and thereby contribute to tobacco-related disease. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.