Iyer Smita S, Jones Dean P, Brigham Kenneth L, Rojas Mauricio
Department of Medicine, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA.
Am J Respir Cell Mol Biol. 2009 Jan;40(1):90-8. doi: 10.1165/rcmb.2007-0447OC. Epub 2008 Jul 29.
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.
多条证据表明，细胞外硫醇/二硫键氧化还原环境的紊乱与急性肺损伤（ALI）的进展和严重程度相关。半胱氨酸（Cys）及其二硫键胱氨酸（CySS）构成血浆中最丰富的低分子量硫醇/二硫键氧化还原对，在对感染和损伤的炎症反应中，Cys的体内平衡受到不利影响。虽然人们非常关注谷胱甘肽（GSH）和谷胱甘肽二硫化物（GSSG），但对于ALI中Cys/CySS对的调节知之甚少。本研究的目的是确定内毒素给药是否会导致Cys减少和/或血浆Cys/CySS氧化还原状态（E(h)Cys/CySS）的氧化，并确定这些变化是否与血浆E(h)GSH/GSSG的变化相关。小鼠腹腔注射内毒素，并在已知与内毒素诱导的肺损伤进展相关的时间点测量GSH和Cys的氧化还原状态。通过高效液相色谱法和能斯特方程，使用Cys、CySS、GSH和GSSG值计算mV中的E(h)。我们观察到内毒素在急性期对GSH和Cys氧化还原系统有不同的影响；血浆E(h)Cys/CySS在对内毒素的早期反应中被选择性氧化，而E(h)GSH/GSSG保持不变。出乎意料的是，E(h)GSH/GSSG和E(h)Cys/CySS随后的氧化是内毒素诱导的厌食症的结果。综上所述，结果表明，Cys氧化增强、Cys和CySS转运改变以及食物摄入量减少均导致内毒素血症中血浆Cys/CySS氧化还原状态的氧化。
