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Lovelace-CRCE Research Project 4: Identification of Drugs for Treatment of SM Injury to Eye and Skin.
The blistering effect of Sulfur Mustard (SM) occurs in the eye and skin by a combination of SM-induced damage of epithelial cells (apoptosis and necrosis) and release of inflammatory cytokines. These processes lead to massive inflammation accompanied by edema and release of proteases that destroy the proteins attaching epithelial cells to their basement membrane in either the eye or the skin. This ultimately leads to sloughing (blistering) of the epithelial cell layer. Importantly, until now, no post-SM-exposure treatment has been proven to reduce the severity of the SM-induced acute or chronic injury.
In pilot experiments, we have found that the metalloprotease inhibitors, Ilomastat and doxycycline, dramatically reduced acute clinical symptoms and neovascularization of rabbit eyes exposed to SM vapor. In addition, Ilomastat totally blocked microvesication of organ-cultured human skin explants exposed to SM vapor, even when given 8 hours after SM exposure. We propose to extend these initial experiments to thoroughly evaluate the ability of these metalloprotease inhibitors and other selected lead drugs (indomethacin, diclofenac, dexamethasone, n-octyl homovanillamide) to reduce acute effects of SM exposure in rabbit eye and hairless guinea pig skin models.
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