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

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.