Inhibition of mitochondrial permeability transition prevents sepsis-induced myocardial dysfunction and mortality.
OBJECTIVE
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.
Larche
Jérome
J
EA 2689, Université de Lille 2, Faculté de Médecine 1, Lille, France.
Lancel
Steve
S
Hassoun
Sidi Mohamed
SM
Favory
Raphael
R
Decoster
Brigitte
B
Marchetti
Philippe
P
Chopin
Claude
C
Neviere
Remi
R
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D020169:Caspases / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D004195:Disease Models, Animal; D007166:Immunosuppressive Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D007425:Intracellular Membranes / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism*; D009102:Multiple Organ Failure / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control; D009573:Nitrites / Q000097:blood; D010538:Peritonitis / Q000378:metabolism / Q000503:physiopathology*; D010539:Permeability / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D018805:Sepsis / Q000378:metabolism / Q000503:physiopathology*
D007166:Immunosuppressive Agents; D009573:Nitrites; D019253:Proto-Oncogene Proteins c-bcl-2; D016572:Cyclosporine; D020169:Caspases