title: Abnormal permeability of inner and outer mitochondrial membranes contributes independently to mitochondrial dysfunction in the liver during acute endotoxemia.
abstract: OBJECTIVE
  This study was designed to determine the role played by the mitochondrial permeability transition in the pathogenesis of mitochondrial damage and dysfunction in a representative systemic organ during the acute phase of endotoxemia.
  
  
  METHODS
  A well-established, normotensive feline model was employed to determine whether pretreatment with cyclosporine A, a potent inhibitor of the mitochondrial permeability transition, normalizes mitochondrial ultrastructural injury and dysfunction in the liver during acute endotoxemia.
  
  
  METHODS
  The Ohio State University Medical Center research laboratory.
  
  
  METHODS
  Random source, adult, male conditioned cats.
  
  
  METHODS
  Hemodynamic resuscitation and maintenance of acid-base balance and tissue oxygen availability were provided, as needed, to minimize the potentially confounding effects of tissue hypoxia and/or acidosis on the experimental results. Treatment groups received isotonic saline vehicle (control; n = 6), lipopolysaccharide (3.0 mg/kg, intravenously; n = 8), or cyclosporine A (6.0 mg/kg, intravenously; n = 6) or tacrolimus (FK506, 0.1 mg/kg, intravenously; n = 4) followed in 30 mins by lipopolysaccharide (3.0 mg/kg, intravenously). Liver samples were obtained 4 hrs posttreatment, and mitochondrial ultrastructure, function, and cytochrome c, Bax, and ceramide contents were assessed.
  
  
  RESULTS
  As expected, significant mitochondrial injury was apparent in the liver 4 hrs after lipopolysaccharide treatment, despite maintenance of regional tissue oxygen availability. Namely, mitochondria demonstrated high-amplitude swelling and exhibited altered respiratory function. Cyclosporine A pretreatment attenuated lipopolysaccharide-induced mitochondrial ultrastructural abnormalities and normalized mitochondrial respiratory control, reflecting protection against inner mitochondrial membrane damage. However, an abnormal permeability of outer mitochondrial membranes to cytochrome c was observed in all lipopolysaccharide-treated groups and was associated with increased mitochondrial concentrations of Bax and ceramide.
  
  
  CONCLUSIONS
  These studies confirm that liver mitochondria are early targets of injury during endotoxemia and that inner and outer mitochondrial membrane damage occurs through different mechanisms. Inner mitochondrial membrane damage appears to relate to the mitochondrial permeability transition, whereas outer mitochondrial membrane damage can occur independent of the mitochondrial permeability transition. Preliminary evidence suggests that Bax may participate in lipopolysaccharide-induced outer mitochondrial membrane damage, but further investigations are needed to confirm this.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, The Ohio State University Medical Center, Columbus, OH, USA.
authors.forename: Elliott D
authors.initials: ED
authors.lastname: Crouser
authors.forename: Mark W
authors.initials: MW
authors.lastname: Julian
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Huff
authors.forename: Mandar S
authors.initials: MS
authors.lastname: Joshi
authors.forename: John A
authors.initials: JA
authors.lastname: Bauer
authors.forename: Martha E
authors.initials: ME
authors.lastname: Gadd
authors.forename: Mark D
authors.initials: MD
authors.lastname: Wewers
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Pfeiffer
mesh_terms: D000136:Acid-Base Equilibrium; D000208:Acute Disease; D000818:Animals; D002415:Cats; D016572:Cyclosporine / Q000494:pharmacology; D019446:Endotoxemia / Q000378:metabolism*; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D010539:Permeability / Q000187:drug effects
chemical_list: D008070:Lipopolysaccharides; D016572:Cyclosporine; D010100:Oxygen