Cytochrome C limits oxidative stress and decreases acidosis in a rat model of hemorrhagic shock and reperfusion injury.

BACKGROUND: Hemorrhagic shock and reperfusion (HSR) injury leads to a cascade of reactive oxygen species (ROS) production and mitochondrial dysfunction, which results in energy failure, cell death and multiple organ dysfunction. Cytochrome c (cyt c) is the final electron carrier in the mitochondrial electron transport chain providing the electrochemical force for ATP production. We sought to determine whether exogenous cyt c administration would improve parameters of organ dysfunction and/or mitochondrial stability in a rat model of HSR. METHODS: Male rats were hemorrhaged to a mean arterial pressure (MAP) of 33 +/- 2.0mmHg for 1 hour prior to resuscitation. Saline or cyt c (0.8mg [HSR-LoCC] or 3.75mg [HSR-HiCC]) was administered (iv) 30 minutes prior to resuscitation. Rats were euthanized by cardiac puncture 2 hours post-surgery and tissue collected and analyzed for lipid peroxidation, endogenous antioxidant activity (glutathione peroxidase (GPx) and catalase), TNF-[alpha] expression, mitochondrial function (complex-I activity) and circulating mitochondrial DNA (mtDNA). RESULTS: Cyt c administration improved lactate clearance, decreased hepatic lipid peroxidation, increased hepatic GPx activity, restored pulmonary TNF-[alpha] to sham activity levels and increased hepatic complex-I activity. Furthermore, addition of exogenous cyt c decreased circulating levels of mtDNA CONCLUSIONS: These studies demonstrate that cyt c reduces markers of physiologic stress, decreases oxidative stress, and lowers levels of circulating mtDNA. The impact of cytochrome c is organ specific. Further studies remain to determine the sum of the effects of cytochrome c on overall outcome. (C) 2016 Lippincott Williams & Wilkins, Inc.

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