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Published ahead of print on May 14, 2003, doi:10.1165/rcmb.2002-0235OC

Am. J. Respir. Cell Mol. Biol., Volume 29, Number 5, November 2003, 562-570

A more recent version of this article appeared on November 1, 2003
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Submitted on November 6, 2002
Revised on May 13, 2003

Cigarette smoke prevents apoptosis through inhibition of caspase activation and induces necrosis

Julie A Wickenden1, Murray C Clarke2, Adriano G Rossi3, Irfan Rahman1, Stephen P Faux4, Kenneth Donaldson1, and William MacNee1*

1 ELEGI/Colt Laboratories, MRC Centre for Inflammation Research, University of Edinburgh Medical School, Edinburgh, United Kingdom, 2 Phagocyte Laboratories, MRC Centre for Inflammation Research, University of Edinburgh Medical School, Edinburgh, United Kingdom, 3 MRC Laboratories, MRC Centre for Inflammation Research, University of Edinburgh Medical School, Edinburgh, United Kingdom, 4 Institute of Occupational Medicine, Edinburgh, United Kingdom; ELEGI/Colt Laboratories, MRC Centre for Inflammation Research, University of Edinburgh Medical School, Edinburgh, United Kingdom

* To whom correspondence should be addressed. E-mail: w.macnee{at}ed.ac.uk.

Emphysema is characterised 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 anti-apoptogenic 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.




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