INDUCTION OF THE PERMEABILITY TRANSITION CONTRIBUTES TO MITOCHONDRIAL INJURY AND ALTERED RESPIRATION DURING ENDOTOXEMIA 

E.D. Crouser, M.W. Julian and D.R. Pfeiffer
The Ohio State University, Columbus, Ohio

Altered O2 metabolism in systemic organs, characterized by impaired O2 extraction from the blood, is a hallmark of organ failure resulting from sepsis.  Our recent evidence suggests that mitochondrial injury, and not vascular dysregulation, is the primary cause of sepsis-induced alterations in O2 metabolism.  More specifically, ultrastructural analysis shows that mitochondrial swelling is a commonly seen feature of sepsis-induced organ injury.  We hypothesized that the permeability transition is involved and that inhibition of this phenomenon would protect against sepsis-associated injury.  To test this hypothesis we employed a well-established feline model of sepsis (i.e., intravenous lipopolysaccharide, LPS).  In three experimental groups, LPS (3 mg/kg, IV; n=7), LPS (3 mg/kg) pretreated with cyclosporin A (CsA, 6 mg/kg, n=7) or vehicle (Control; n=5), liver samples were obtained at 4 hours and simultaneous evaluations of mitochondrial ultrastructure and respiratory function were carried out.  Ultrastructural changes were most severe in the LPS treatment group as reflected by higher mitochondrial injury scores (2.8 ± 0.3 vs 1.3 ± 0.2; LPS vs Control, p < 0.001), whereas CsA pretreatment was partially protective (1.8 ± 0.6, p < 0.1 relative to both LPS alone and Controls).  LPS treatment was also associated with decreased state 3 respiration, and an increase in state 4 respiration apparently reflecting partial uncoupling of mitochondrial oxygen consumption from ATP production.  The magnitude of structural injury was closely correlated to the extent of functional impairment.  CsA pretreated animals demonstrated normal respiratory control in most cases, but a number of the preparations exhibited reduced respiration under state 3, state 4 and uncoupled conditions.  Under all three conditions the rates could be normalized by the addition of exogenous cytochrome c.  These findings suggest that the permeability transition occurs during sepsis and contributes significantly to the dysregulation of O2 metabolism that is observed.  The mechanism of cytochrome c depletion in the LPS + CsA pretreatment group is currently under investigation.

Supported by NIH (1 KO0 HL04355-01) and AHA (0051013B).

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