Therapeutic approaches to dermatotoxicity by sulfur mustard - I. Modulation of sulfur mustard-induced cutaneous injury in the mouse ear vesicant model

The mouse ear edema model is recognized for its usefulness in studying skin responses and damage following exposure to chemical irritants, and for eva luating pharmacological agents against chemically induced skin injury. We r ecently modified the mouse ear edema model for use with sulfur mustard (HD) and used this model to study the protective effect of 33 topically applied compounds comprising five pharmaceutical strategies (anti-inflammatories, protease inhibitors, scavengers/chelators, poly(ADP-ribose) polymerase (PAR P) inhibitors, calcium modulators/chelators) against HD-induced dermatotoxi city, Pharmacological modulation of HD injury in mouse ears was established by a reduction in edema or histopathology (epidermal necrosis and epiderma l-dermal separation) at 24 h following topical liquid HD exposure, Ten of t he 33 compounds administered as single topical pretreatments up to 2 h prio r to HD challenge produced significant reductions in edema, Five of these t en also produced significant reductions in histological endpoints, Three ca ndidates (olvanil, indomethacin, hydrocortisone) showing protection at 24 h were evaluated further for 'extended protection' at 48 and 72 h after HD c hallenge and showed significant modulation of edema at 48 h but not at 72 h , Olvanil also showed significant reductions in histology at 48 and 72 h, O lvanil and indomethacin were shown to reduce significantly the edema at 24 h post-exposure when administered topically 10 min after HD challenge, with olvanil additionally protecting against epidermal necrosis, These results demonstrate prophylactic and treatment effects of pharmacological agents ag ainst HD-induced skin injury in an in vivo model and support the continued use of the mouse ear vesicant model (MEVM) for evaluating medical counterme asures against HD.