title: Cigarette smoke-induced blockade of the mitochondrial respiratory chain switches lung epithelial cell apoptosis into necrosis.
abstract: 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.
authors.affiliation: Laboratory of Allergology and Pulmonary Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Marco
authors.initials: M
authors.lastname: van der Toorn
authors.forename: Dirk-Jan
authors.initials: DJ
authors.lastname: Slebos
authors.forename: Harold G
authors.initials: HG
authors.lastname: de Bruin
authors.forename: Henri G
authors.initials: HG
authors.lastname: Leuvenink
authors.forename: Stephan J L
authors.initials: SJ
authors.lastname: Bakker
authors.forename: Rijk O B
authors.initials: RO
authors.lastname: Gans
authors.forename: Gerard H
authors.initials: GH
authors.lastname: Koëter
authors.forename: Antoon J M
authors.initials: AJ
authors.lastname: van Oosterhout
authors.forename: Henk F
authors.initials: HF
authors.lastname: Kauffman
mesh_terms: D002478:Cells, Cultured; D006801:Humans; D007700:Kinetics; D008928:Mitochondria / Q000378:metabolism*; D008933:Mitochondrial Swelling / Q000502:physiology*; D009336:Necrosis; D010101:Oxygen Consumption / Q000502:physiology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology / Q000473:pathology*; D020545:Respiratory Mucosa / Q000166:cytology* / Q000473:pathology* / Q000502:physiology*; D012906:Smoke / Q000009:adverse effects*; D012907:Smoking / Q000009:adverse effects*
chemical_list: D012906:Smoke