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Protective effects of the thiol compounds GSH and NAC against sulfur mustard toxicity in a human keratinocyte cell line

TitleProtective effects of the thiol compounds GSH and NAC against sulfur mustard toxicity in a human keratinocyte cell line
Publication TypeJournal Article
Year of Publication2016
AuthorsBalszuweit F., Menacher G., Schmidt A., Kehe K., Popp T., Worek F., Thiermann H., Steinritz D.
JournalToxicol Lett
Date PublishedFeb 26
ISBN Number1879-3169 (Electronic)0378-4274 (Linking)
KeywordsAcetylcysteine/*pharmacology, Antidotes/*pharmacology, Apoptosis/drug effects, Cell Line, Chemical Warfare Agents/*toxicity, Cytoprotection, Cytotoxicity, Dose-Response Relationship, Drug, Glutathione/*pharmacology, GSH, Humans, Inflammation Mediators/metabolism, Interleukin-6/metabolism, Interleukin-8/metabolism, KERATINOCYTES, Keratinocytes/*drug effects/metabolism/pathology, Mustard Gas/*toxicity, Nac, NECROSIS, Pro-inflammatory cytokines, Sulfhydryl Compounds/*pharmacology, Sulfur Mustard, Thiol compounds, Time Factors

Sulfur mustard (SM) is a chemical warfare agent causing blistering, inflammation and ulceration of the skin. Thiol compounds such as glutathione (GSH) and N-acetylcysteine (NAC) have been suggested as potential antidotes. We investigated SM toxicity in a human keratinocyte cell line (HaCaT) and used GSH and NAC to counteract its cytotoxic effects. Cells were treated with 1, 5 or 10mM GSH or NAC and exposed to 30, 100 or 300muM SM. Different treatment regimens were applied to model extra- and intra-cellular GSH/NAC effects on SM toxicity. Necrosis, apoptosis and interleukin-6 and -8 levels were determined 24h post-exposure. Necrosis and apoptosis increased with SM dose. Interleukin-6 and -8 production peaked at 100muM and decreased at 300muM probably due to reduced ability for interleukin biosynthesis. Intracellular GSH/NAC diminished necrosis induced by 100muM SM. Extracellular GSH/NAC protected against necrosis and apoptosis induced by 100 and 300muM SM. Interleukin-6 and -8 production, induced by 100muM SM was reduced by GSH/NAC. However, low-dose GSH/NAC treatment of cells exposed to 300muM SM led to increased interleukin production. Thus, moderately poisoned cells are mostly responsible for SM-induced secretion of pro-inflammatory cytokines. GSH and NAC treatment can reduce SM-induced toxic effects. Protective effects were more pronounced by extracellular GSH or NAC administration. Rescue of severely poisoned cells may result in a strong secretion of pro- inflammatory cytokines. In summary, thiol compounds such as GSH or NAC constitute a promising approach to improve the therapy for SM injury. Additional intervention to prevent adverse effects of interleukin production might be beneficial.


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