| Inhibition of mitochondrial permeability transition prevents sepsis-induced myocardial dysfunction and mortality. | |
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MedLine Citation:
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PMID: 16843190 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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OBJECTIVES: The purpose of this study was to test whether mitochondrial dysfunction is causative of sepsis sequelae, a mouse model of peritonitis sepsis induced by cecal ligation and perforation. Inhibition of mitochondrial permeability transition was achieved by means of pharmacological drugs and overexpression of the antiapoptotic protein B-cell leukemia (Bcl)-2. BACKGROUND: Sepsis is the leading cause of death in critically ill patients and the predominant cause of multiple organ failure. Although precise mechanisms by which sepsis leads to multiple organ dysfunction are unknown, growing evidence suggests that perturbations of key mitochondrial functions, including adenosine triphosphate production, Ca2+ homeostasis, oxygen-derived free radical production, and permeability transition, might be involved in sepsis pathophysiology. METHODS: Heart and lung functions were evaluated respectively by means of isolated heart preparation, bronchoalveolar lavage fluid protein concentration, lung wet/dry weight ratio, lung homogenate myeloperoxidase activity, and histopathologic grading. Respiratory fluxes, calcium uptake, and membrane potential were evaluated in isolated heart mitochondria. RESULTS: Peritonitis sepsis induced multiple organ dysfunction, mitochondrial abnormalities, and increased mortality rate, which were reduced by pharmacological inhibition of mitochondrial transition by cyclosporine derivatives and mitochondrial Bcl-2 overexpression. CONCLUSIONS: Our study provides strong evidence that mitochondrial permeability transition plays a critical role in septic organ dysfunction. These studies demonstrate that mitochondrial dysfunction in sepsis is causative rather than epiphenomenal and relevant in terms of vital organ function and outcome. Regarding the critical role of heart failure in the pathophysiology of septic shock, our study also indicates a potentially new therapeutic approach for treatment of sepsis syndrome. |
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Authors:
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Jérome Larche; Steve Lancel; Sidi Mohamed Hassoun; Raphael Favory; Brigitte Decoster; Philippe Marchetti; Claude Chopin; Remi Neviere |
Publication Detail:
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Type: In Vitro; Journal Article; Research Support, Non-U.S. Gov't Date: 2006-06-22 |
Journal Detail:
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Title: Journal of the American College of Cardiology Volume: 48 ISSN: 1558-3597 ISO Abbreviation: J. Am. Coll. Cardiol. Publication Date: 2006 Jul |
Date Detail:
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Created Date: 2006-07-17 Completed Date: 2006-08-22 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 8301365 Medline TA: J Am Coll Cardiol Country: United States |
Other Details:
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Languages: eng Pagination: 377-85 Citation Subset: AIM; IM |
Affiliation:
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EA 2689, Université de Lille 2, Faculté de Médecine 1, Lille, France. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Bronchoalveolar Lavage Fluid Caspases / metabolism Cyclosporine / pharmacology Disease Models, Animal Immunosuppressive Agents / pharmacology Intracellular Membranes / drug effects* Mice Mice, Inbred C57BL Mice, Transgenic Mitochondria, Heart / drug effects*, metabolism* Multiple Organ Failure / metabolism Myocardial Reperfusion Injury / prevention & control Nitrites / blood Peritonitis / metabolism, physiopathology* Permeability / drug effects Proto-Oncogene Proteins c-bcl-2 / metabolism* Sepsis / metabolism, physiopathology* |
| Chemical | |
Reg. No./Substance:
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0/Immunosuppressive Agents; 0/Nitrites; 0/Proto-Oncogene Proteins c-bcl-2; 59865-13-3/Cyclosporine; EC 3.4.22.-/Caspases |
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