New Approaches towards the Elucidation of Epidermal-Dermal Separation in Sulfur Mustard-Exposed Human Skin and Directions for Therapy

摘要

This study sought to broaden knowledge about therapies for sulfur mustard (HD agent) exposure by examining the compound's mechanism of action. Results of experiments with a human skin ex vivo model show that apoptosis and metalloprotease activity are key elements in HD-induced skin pathogenesis, and that intervention in these two processes is successful in resisting microvesication and impairment of epidermal cells. The observation that pancaspase and metalloprotease inhibitors can prevent microvesication in the human skin ex vivo model if applied 6 hours and 18 hours, respectively, after exposure to HD opens possibilities for nonurgent cure of HD casualties. The results indicate that microvesication in HD-exposed human skin ex vivo is not caused by MMP-2 activity or by reduced expression of the adhesion molecule laminin-5. The application of a proteomic approach in the search for mechanisms of action of HD has proven to be a valuable tool: involvement of apoptosis and of phosphorylated HSP27 in the cellular response towards HD was discovered. Furthermore, keratins appear to be predominant targets for alkylation by HD. Only a few other proteins are alkylated. In conclusion, the current studies using the human skin ex vivo model yielded general mechanistic themes that also will apply to injuries induced by HD in other organs and will contribute to progress in the search for medical countermeasures against HD-damage in multiple organs.