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1 Laboratory of Allergology and Pulmonary diseases, University Medical Center Groningen, Groningen, Netherlands
2 Pulmonary Diseases, University Medical Center Groningen, Groningen, Netherlands
3 Surgery, University Medical Center Groningen, United States
4 Internal Medicine, University Medical Center Groningen, Groningen, Netherlands
5 Groningen University Institute for Drug Exploration, University Medical Center Groningen, Groningen, Netherlands
* To whom correspondence should be addressed. E-mail: d.j.slebos{at}int.umcg.nl.
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 hypothesised 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 activity 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, and loss of ATP generation leading to cellular necrosis in stead of apoptosis, is a new pathophysiological concept of COPD development.
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