Abnormal permeability of inner and outer mitochondrial membranes contributes independently to mitochondrial dysfunction in the liver during acute endotoxemia*

作者：Elliott D. Crouser, M Julián, Jennifer E. Huff, Mandar Joshi, John Anthony Bauer, Martha E. Gadd, Mark D. Wewers, Douglas R. Pfeiffer · 发表于：Critical Care Medicine · 年份：2004 · DOI：10.1097/01.ccm.0000109449.99160.81 · 被引用次数：87 · 研究领域：Immune Response and Inflammation、Mitochondrial Function and Pathology、Liver Disease and Transplantation

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. DESIGN: 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. SETTING: The Ohio State University Medical Center research laboratory. SUBJECTS: Random source, adult, male conditioned cats. INTERVENTIONS: 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. MEASUREMENTS AND MAIN RESULTS: As expected, significant mitochondrial injury was apparent in the liver 4 hrs after lipopolysaccharide treatment...