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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 TypeMiscellaneous
Year of Publication2016
AuthorsBalszuweit F., Menacher G., Schmidt A., Kehe K., Popp T., Worek F., Thiermann H., Steinritz D.
ISBN Number0378-4274 (Linking)
Accession Number26361990
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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