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Cigarette Smoke Prevents Apoptosis through Inhibition of Caspase Activation and Induces Necrosis

ELEGI/Colt, Phagocyte, and MRC Laboratories, Centre for Inflammation Research, University of Edinburgh Medical School; and Institute of Occupational Medicine, Roxburgh Place, Edinburgh, Scotland, United Kingdom

Address correspondence to: Prof. W. MacNee, ELEGI/Colt Research Laboratories, Wilkie Building, University of Edinburgh Medical School, Teviot Place, Edinburgh EH8 9AG, UK. E-mail: w.macnee{at}ed.ac.uk

Emphysema is characterized by enlargement of the distal airspaces in the lungs due to destruction of alveolar walls. Alveolar endothelial and epithelial cell apoptosis induced by cigarette smoke is thought to be a possible mechanism for this cell loss. In contrast, our studies show that cigarette smoke condensate (CSC) induces necrosis in alveolar epithelial cells and human umbilical vein endothelial cells. Furthermore, study of the cell death pathway in a model system using Jurkat cells revealed that in addition to inducing necrosis, CSC inhibited apoptosis induced by staurosporine or Fas ligation, with both effects prevented by the antioxidants glutathione and dithiothreitol. Time course experiments revealed that CSC inhibited an early step in the caspase cascade, whereby caspase-3 was not activated. Moreover, cell-free reconstitution of the apoptosome in cytoplasmic extracts from CSC-treated cells, by addition of cytochrome-c and dATP, did not result in activation of caspases-3 or -9. Thus, smoke treatment may alter the levels of pro- and antiapoptogenic factors downstream of the mitochondria to inhibit active apoptosome formation. Therefore, unlike previous studies, cell death in response to cigarette smoke by necrosis and not apoptosis may be responsible for the loss of alveolar walls and inflammation observed in emphysema.

Abbreviations: calcium magnesium-free phosphate-buffered saline, CMF-PBS • chronic obstructive pulmonary disease, COPD • cigarette smoke condensate, CSC • dithiothreitol, DTT • glutathione, GSH • glutathione disulphide, GSSG • lactate dehydrogenase, LDH • human umbilical vein endothelial cells, HUVECs • poly (ADP-ribose) polymerase, PARP • reactive oxygen species, ROS • staurosporine, SS

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