Published ahead of print on July 29, 2008, doi:10.1165/rcmb.2007-0447OC Am. J. Respir. Cell Mol. Biol., Volume 40, Number 1, January 2009, 90-98 A more recent version of this article appeared on January 1, 2009
Submitted on December 11, 2007 Oxidation of Plasma Cysteine/Cystine Redox State in Endotoxin-Induced Lung InjurySmita S Iyer1,1 Nutrition and Health Sciences Program, Emory University, Atlanta, GA, USA; Center for Translational Research in the Lung, Emory University, Atlanta, GA, USA; Clinical Biomarkers Laboratory, Department of Medicine, Emory University, Atlanta, GA, USA, 2 Nutrition and Health Sciences Program, Emory University, Atlanta, GA, USA; Division of Pulmonary, Allergy, and Critical Care Medicine, Emory University, Atlanta, GA, USA; Clinical Biomarkers Laboratory, Department of Medicine, Emory University, Atlanta, GA, USA, 3 Division of Pulmonary, Allergy, and Critical Care Medicine, Emory University, Atlanta, GA, USA; Center for Translational Research in the Lung, Emory University, Atlanta, GA, USA; McKelvey Center for Lung Transplantation, Emory University, Atlanta, GA, USA * To whom correspondence should be addressed. 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 (Eh Cys/CySS) and to determine whether these changes were associated with changes in plasma Eh 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. Eh in mV was calculated using Cys, CySS, GSH and GSSG values by HPLC and the Nernst equation. We observed distinct effects of endotoxin on the GSH and Cys redox systems during the acute phase; plasma Eh Cys/CySS was selectively oxidized early in response to endotoxin, while Eh GSH/GSSG remained unchanged. Unexpectedly, subsequent oxidation of Eh GSH/GSSG and Eh 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.
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