title: Cyclosporin A ameliorates mitochondrial ultrastructural injury in the ileum during acute endotoxemia.
abstract: OBJECTIVE
  This study was designed to determine the role, if any, of the mitochondrial permeability transition in the pathogenesis of mitochondrial injury 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 cyclosporin A, a potent inhibitor of the mitochondrial permeability transition, reduces the severity of mitochondrial injury in the ileum during acute endotoxemia.
  
  
  METHODS
  The Ohio State University Medical Center research laboratory. SUBJECTS Adult, male conditioned cats.
  
  
  METHODS
  Volume 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. Following isotonic saline vehicle (control; n = 6), lipopolysaccharide (3.0 mg/kg, intravenously; n = 10), or cyclosporin A (6 mg/kg, intravenously; n = 7) followed in 60 mins by lipopolysaccharide (3.0 mg/kg, intravenously) administration, ileal samples were obtained at 4 hrs posttreatment, and mitochondrial ultrastructure was assessed. Objective comparisons of mitochondrial ultrastructural morphology were performed by using digital image analyses.
  
  
  RESULTS
  As expected, significant mitochondrial injury was apparent in the ileal tissues by 4 hrs following LPS treatment, despite maintenance of regional tissue oxygen availability. Objective evaluation of mitochondrial morphology demonstrated characteristics consistent with high-amplitude swelling. Cyclosporin A pretreatment protected against the development of these LPS-induced mitochondrial ultrastructural abnormalities, an effect not attributable to the suppression of lipopolysaccharide-induced tumor necrosis factor-alpha production.
  
  
  CONCLUSIONS
  These investigations are the first to demonstrate a protective effect of cyclosporin A against mitochondrial injury in a representative systemic organ during acute endotoxemia. We propose that mitochondrial injury likely related to induction of the mitochondrial permeability transition may participate in the pathogenesis of systemic organ injury and organ failures during acute sepsis.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, The Ohio State University Medical Center, 201F Davis Heart & Lung Research Institute, 473 West Twelfth Avenue, Columbus, OH 43210-1252, USA. Crouser-1@medctr.osu.edu
authors.forename: Elliott D
authors.initials: ED
authors.lastname: Crouser
authors.forename: Mark W
authors.initials: MW
authors.lastname: Julian
authors.forename: Mandar S
authors.initials: MS
authors.lastname: Joshi
authors.forename: John A
authors.initials: JA
authors.lastname: Bauer
authors.forename: Mark D
authors.initials: MD
authors.lastname: Wewers
authors.forename: Judith M
authors.initials: JM
authors.lastname: Hart
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Pfeiffer
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002415:Cats; D016572:Cyclosporine / Q000493:pharmacokinetics; D019446:Endotoxemia / Q000188:drug therapy / Q000503:physiopathology; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism*; D008070:Lipopolysaccharides; D008297:Male; D008854:Microscopy, Electron; D008928:Mitochondria / Q000187:drug effects / Q000648:ultrastructure*; D028361:Mitochondrial Diseases / Q000188:drug therapy / Q000503:physiopathology*; D009102:Multiple Organ Failure / Q000188:drug therapy / Q000503:physiopathology*; D010539:Permeability; D011897:Random Allocation; D013053:Spectrophotometry
chemical_list: D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D016572:Cyclosporine