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Oxidation of Plasma Cysteine/Cystine Redox State in Endotoxin-Induced Lung Injury

¹ Nutrition and Health Sciences Program, ² Division of Pulmonary, Allergy, and Critical Care Medicine, ³ Center for Translational Research in the Lung, ⁴ McKelvey Center for Lung Transplantation, and ⁵ Clinical Biomarkers Laboratory, Department of Medicine, Emory University, Atlanta, Georgia

Correspondence and requests for reprints should be addressed to Mauricio Rojas, M.D., Dept. of Medicine/Pulmonary, Whitehead Research Building, Suite 205J, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322. E-mail: mrojas{at}emory.edu

Several lines of evidence indicate that perturbations in the extracellular thiol/disulfide redox environment correlate with the progression and severity of acute lung injury (ALI). Cysteine (Cys) and its disulfide Cystine (CySS) constitute the most abundant, low-molecular-weight thiol/disulfide redox couple in the plasma, and Cys homeostasis is adversely affected during the inflammatory response to infection and injury. While much emphasis has been placed on glutathione (GSH) and glutathione disulfide (GSSG), little is known about the regulation of the Cys/CySS couple in ALI. The purpose of the present study was to determine whether endotoxin administration causes a decrease in Cys and/or an oxidation of the plasma Cys/CySS redox state (E_h Cys/CySS), and to determine whether these changes were associated with changes in plasma E_h GSH/GSSG. Mice received endotoxin intraperitoneally, and GSH and Cys redox states were measured at time points known to correlate with the progression of endotoxin-induced lung injury. E_h in mV was calculated using Cys, CySS, GSH, and GSSG values by high-performance liquid chromatography and the Nernst equation. We observed distinct effects of endotoxin on the GSH and Cys redox systems during the acute phase; plasma E_h Cys/CySS was selectively oxidized early in response to endotoxin, while E_h GSH/GSSG remained unchanged. Unexpectedly, subsequent oxidation of E_h GSH/GSSG and E_h Cys/CySS occurred as a consequence of endotoxin-induced anorexia. Taken together, the results indicate that enhanced oxidation of Cys, altered transport of Cys and CySS, and decreased food intake each contribute to the oxidation of plasma Cys/CySS redox state in endotoxemia.

Key Words: lipopolysaccharide • oxidative stress • thiol/disulfide redox state • anorexia • acute lung injury

CLINICAL RELEVANCE Our findings suggest a distinct role for oxidation of Cys/CySS redox state in acute lung injury (ALI). Understanding how oxidized Cys/CySS can potentiate the inflammatory response to injury may help in the optimization of strategies for controlling ALI.

 

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