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This Article Full Text Full Text (PDF) All Versions of this Article: 292/5/L1211    most recent 00291.2006v2 00291.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by van der Toorn, M. Articles by Kauffman, H. F. Search for Related Content PubMed PubMed Citation Articles by van der Toorn, M. Articles by Kauffman, H. F.

Cigarette smoke-induced blockade of the mitochondrial respiratory chain switches lung epithelial cell apoptosis into necrosis

¹Laboratory of Allergology and Pulmonary Diseases, ²Department of Pulmonary Diseases, ³Department of Surgery, ⁴Department of Internal Medicine, and ⁵Groningen University Institute for Drug Exploration, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

Submitted 3 August 2006 ; accepted in final form 29 December 2006

Increased lung cell apoptosis and necrosis occur in patients with chronic obstructive pulmonary disease (COPD). Mitochondria are crucially involved in the regulation of these cell death processes. Cigarette smoke is the main risk factor for development of COPD. We hypothesized that cigarette smoke disturbs mitochondrial function, thereby decreasing the capacity of mitochondria for ATP synthesis, leading to cellular necrosis. This hypothesis was tested in both human bronchial epithelial cells and isolated mitochondria. Cigarette smoke extract exposure resulted in a dose-dependent inhibition of complex I and II activities. This inhibition was accompanied by decreases in mitochondrial membrane potential, mitochondrial oxygen consumption, and production of ATP. Cigarette smoke extract abolished the staurosporin-induced caspase-3 and -7 activities and induced a switch from epithelial cell apoptosis into necrosis. Cigarette smoke induced mitochondrial dysfunction, with compounds of cigarette smoke acting as blocking agents of the mitochondrial respiratory chain; loss of ATP generation leading to cellular necrosis instead of apoptosis is a new pathophysiological concept of COPD development.

chronic obstructive pulmonary disease; mitochondria

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