Mitochondrial cytochrome c release is a key event in hyperoxia-induced lung injury: protection by cyclosporin A.
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.
Pagano
Alessandra
A
Department of Pathology, Centre médical universitaire, 1211 Geneva 4, Switzerland.
Donati
Yves
Y
Métrailler
Isabelle
I
Barazzone Argiroffo
Constance
C
D000818:Animals; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology*; D045304:Cytochromes c / Q000378:metabolism*; D005260:Female; D018496:Hyperoxia / Q000188:drug therapy / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008171:Lung Diseases / Q000188:drug therapy / Q000378:metabolism* / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D011650:Pulmonary Alveoli / Q000378:metabolism; D051028:bcl-2-Associated X Protein
C494827:Bax protein, mouse; D007166:Immunosuppressive Agents; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D016572:Cyclosporine; D045304:Cytochromes c; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases