title: The role of mitochondrial oxidation in endotoxin-induced liver-dependent swine pulmonary edema.
abstract: We reported previously studies in an in situ perfused swine preparation demonstrating that endotoxemia induced lung injury required the presence of the liver and that the response was accompanied by oxidative stress. To determine whether lung and liver mitochondrial oxidative stress was important to the response, we compared the effects of equimolar amounts of two antioxidants, n-acetylcysteine, which does not replenish mitochondrial glutathione, and procysteine which does, on endotoxemia induced lung injury in the swine preparation. In a swine perfused liver-lung preparation, we measured physiologic, biochemical and cellular responses of liver and lung to endotoxemia with and without the drugs. Endotoxemia caused oxidation of the mitochondria-specific protein, thioredoxin-2, in both the lungs and the liver. Procysteine reduced thioredoxin-2 oxidation, attenuated hemodynamic, gas exchange, hepatocellular dysfunction, and cytokine responses and prevented lung edema. n-acetylcysteine had more modest effects and did not prevent lung edema.
  
  
  CONCLUSIONS
  We conclude that mitochondrial oxidation may be critical to the pathogenesis of endotoxemia-induced liver-dependent lung injury and that choices of antioxidant therapy for such conditions must consider the desired subcellular target in order to be optimally effective.
authors.affiliation: Center for Translational Research in the Lungs, McKelvey Center for Lung Transplantation, Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine and Predictive Health Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Amsel M
authors.initials: AM
authors.lastname: Siore
authors.forename: Richard E
authors.initials: RE
authors.lastname: Parker
authors.forename: Chris
authors.initials: C
authors.lastname: Cuppels
authors.forename: Natalie
authors.initials: N
authors.lastname: Thorn
authors.forename: Jason M
authors.initials: JM
authors.lastname: Hansen
authors.forename: Arlene A
authors.initials: AA
authors.lastname: Stecenko
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Brigham
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004731:Endotoxins / Q000633:toxicity*; D008099:Liver / Q000502:physiology*; D008928:Mitochondria / Q000378:metabolism*; D010084:Oxidation-Reduction; D011654:Pulmonary Edema / Q000209:etiology*; D013552:Swine; D014655:Vascular Resistance
chemical_list: D016207:Cytokines; D004731:Endotoxins