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 imp...

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Published in:Pulmonary pharmacology & therapeutics 2012-10, Vol.25 (5), p.407-412
Main Authors: Siore, Amsel M, Parker, Richard E, Cuppels, Chris, Thorn, Natalie, Hansen, Jason M, Stecenko, Arlene A, Brigham, Kenneth L
Format: Article
Language:English
Subjects:
Animals
Cytokines - secretion
Endotoxins - toxicity
Liver - physiology
Medical Education
Mitochondria
Mitochondria - metabolism
Oxidant stress
Oxidation-Reduction
Pulmonary Edema - etiology
Pulmonary/Respiratory
Sepsis
Swine
Vascular Resistance
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Summary: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.
ISSN:1094-5539
1522-9629
DOI:10.1016/j.pupt.2012.08.002