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PRECLINICAL STUDIES

Inhibition of Mitochondrial Permeability Transition Prevents Sepsis-Induced Myocardial Dysfunction and Mortality

Jérome Larche, MD^_*,, Steve Lancel, PhD^_*,, Sidi Mohamed Hassoun^_*,, Raphael Favory, MD^_*,, Brigitte Decoster, PhD^_*,, Philippe Marchetti, MD, PhD, Claude Chopin, MD^_* and Remi Neviere, MD, PhD^_*,,_*

^_* EA 2689, Université de Lille 2
Département de Physiologie
INSERM U459, Faculté de Médecine 1, Lille, France

Manuscript received November 9, 2005; revised manuscript received February 17, 2006, accepted February 28, 2006.

^_* Reprint requests and correspondence: Dr. Remi Neviere, Département de Physiologie, Faculté de Médecine 1, Place Verdun, Lille 59045 Lille, France (Email: rneviere{at}univ-lille2.fr).

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.

Abbreviations and Acronyms   BALF = bronchoalveolar lavage fluid   Bcl = B-cell leukemia   CLP = cecal ligation and puncture   CsA = cyclosporine A   m = mitochondrial transmembrane potential   MPO = myeloperoxidase   NIM811 = N-methyl-4-isoleucine cyclosporine   RCR = respiratory control ratio   TNF = tumor necrosis factor   TPP+ = tetraphenylphosphonium