Cyclosporin A ameliorates mitochondrial ultrastructural injury in the ileum during acute endotoxemia

Elliott D. Crouser, Mark W. Julian, Mandar S. Joshi, John A. Bauer, Mark D. Wewers, Judith M. Hart, Douglas R. Pfeiffer

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

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. Design: 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. Setting: The Ohio State University Medical Center research laboratory. Subjects: Adult, male conditioned cats. Interventions: 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. Measurements and Main 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-α 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.

Original languageEnglish
Pages (from-to)2722-2728
Number of pages7
JournalCritical Care Medicine
Volume30
Issue number12
DOIs
StatePublished - Dec 1 2002

Keywords

  • Electron microscopy
  • Feline
  • Permeability transition
  • Sepsis
  • Spectrophotometry

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

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