Inhibition of neutrophil apoptosis by acrolein: a mechanism of tobacco-related lung disease?
Cigarette smoking is known to contribute to inflammatory diseases of the respiratory tract by promoting recruitment of inflammatory-immune cells such as neutrophils and perhaps by altering neutrophil functional properties. We investigated whether acrolein, a toxic unsaturated aldehyde found in cigarette smoke, could directly affect neutrophil function. Exposure of freshly isolated human neutrophils to acrolein markedly inhibited spontaneous neutrophil apoptosis as indicated by loss of membrane asymmetry and DNA fragmentation and induced increased neutrophil production of the chemokine interleukin-8 (IL-8). Acrolein (1--50 microM) was found to induce marked activation of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinases (MAPKs), and inhibition of p38 MAPK activation by SB-203580 prevented acrolein-induced IL-8 release. However, inhibition of either ERK or p38 MAPK did not affect acrolein-dependent inhibition of apoptosis. Acrolein exposure prevented the activation of caspase-3, a crucial step in the execution of neutrophil apoptosis, presumably by direct inhibition of the enzyme. Our results indicate that acrolein may contribute to smoke-induced inflammatory processes in the lung by increasing neutrophil recruitment and reducing neutrophil clearance by apoptosis.
Finkelstein
E I
EI
Center for Comparative Respiratory Biology and Medicine, Department of Internal Medicine, School of Medicine, University of California, Davis, California 95616, USA.
Nardini
M
M
van der Vliet
A
A
D000171:Acrolein / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D061945:Caspase Inhibitors; D004789:Enzyme Activation; D005978:Glutathione / Q000037:antagonists & inhibitors; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis; D007425:Intracellular Membranes / Q000378:metabolism; D008171:Lung Diseases / Q000209:etiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology*; D012907:Smoking / Q000009:adverse effects
D061945:Caspase Inhibitors; D016209:Interleukin-8; D000171:Acrolein; D019255:NADPH Oxidases; D020928:Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D005978:Glutathione