Changes in the glutathione system of lung cell lines after treatment with hydrocortisone.
Administration of anti-inflammatory glucocorticoids is a drug option in the therapy of acute respiratory distress syndrome (ARDS), according to present pathophysiological concepts. Surprisingly, glucocorticoids failed to show beneficial effects. This failure is not understood. In this investigation changes in the glutathione system due to hydrocortisone were found to consist of glutathione depletion and lowered glutathione reductase activities in alveolar epithelial type II cells, contrasted with unchanged activities in a fibroblast-like lung cell line. The glutathione system is thought to be the most important cellular antioxidative system and therefore alveolar epithelial type II cells might be more susceptible to oxidative stress after glucocorticoid treatment. As alveolar epithelial type II cells may be important targets in ARDS, because of their functions (stem cells of type I epithelial cells; surfactant synthesis), these changes might provide an explanation for the failure of glucocorticoids. In the present experiments the capability of hydrocortisone-treated alveolar epithelial type II cells to synthesise glutathione was found to be cysteine dependent at physiological concentrations. Transposing this observation to the in vivo situation, it might be expected that glucocorticoid efficacy in ARDS therapy requires co-administration of substances that increase glutathione synthesis, e.g. N-acetylcysteine.
Walther
Udo I
UI
Walther Straub-Institut für Pharmakologie und Toxikologie, Ludwig-Maximilians Universität München, Nussbaumstr. 26, 80336, Germany. udo.walther@lrz.uni-muenchen.de
D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002460:Cell Line; D048429:Cell Size / Q000187:drug effects; D002470:Cell Survival; D002712:Chlorides / Q000633:toxicity; D002855:Chromatography, Thin Layer; D004396:Coloring Agents; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005978:Glutathione / Q000096:biosynthesis / Q000378:metabolism*; D005980:Glutathione Reductase; D006801:Humans; D006854:Hydrocortisone / Q000008:administration & dosage / Q000494:pharmacology*; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013880:Thioredoxin-Disulfide Reductase; D014343:Trypan Blue; D017967:Zinc Compounds / Q000633:toxicity
D000893:Anti-Inflammatory Agents; D002712:Chlorides; D004396:Coloring Agents; D017967:Zinc Compounds; C016837:zinc chloride; D009247:NADH, NADPH Oxidoreductases; D005980:Glutathione Reductase; D013880:Thioredoxin-Disulfide Reductase; C424443:Txnrd3 protein, mouse; D005978:Glutathione; D014343:Trypan Blue; D006854:Hydrocortisone