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This Article Full Text Full Text (PDF) All Versions of this Article: 286/2/L275    most recent 00181.2003v1 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 (14) Citing Articles via Google Scholar Google Scholar Articles by Pagano, A. Articles by Barazzone Argiroffo, C. Search for Related Content PubMed PubMed Citation Articles by Pagano, A. Articles by Barazzone Argiroffo, C.

Mitochondrial cytochrome c release is a key event in hyperoxia-induced lung injury: protection by cyclosporin A

Departments of Pathology and Pediatrics, University of Geneva Medical School, 1211 Geneva 4, Switzerland

Submitted 6 June 2003 ; accepted in final form 21 September 2003

Hyperoxia is known to induce extensive alveolar cell death by still poorly defined mechanisms. In this study, the mitochondria-dependent cell death pathway was explored during hyperoxia-induced lung injury in mice. We observed a progressive release of cytochrome c from the mitochondria into the cytosol of alveolar cells. This release was accompanied by the translocation of the proapoptotic protein Bax from cytosol to mitochondria without detectable activation of caspase-3. As cytochrome c release can be induced by mitochondrial membrane alteration and permeability transition (MPT), mice were treated with cyclosporin A, which specifically inhibits MPT. Cyclosporin A treatment prevented mitochondrial release of cytochrome c during hyperoxia and concomitantly preserved mitochondria from extensive swelling and crista disorganization, as assessed by electron microscopy analysis of alveolar epithelial cells. These morphological and biochemical observations correlated with decreased lung tissue damage, as evaluated by morphological score and lung weight. In conclusion, mitochondrial damage and cytochrome c release are important linked events in hyperoxia-induced lung injury and can be efficiently blocked by cyclosporin A.

mice; apoptosis; mitochondria; type II epithelial cells; Bax

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