Evaluation of protective effects of sodium thiosulfate, cysteine, niacinamide and indomethacin on sulfur mustard-treated isolated perfused porcine skin.

Sulfur mustard (bis(2-chloroethyl)sulfide, HD), a bifunctional alkylating agent, causes severe cutaneous injury, including cell death, edema and vesication. However, the mechanisms underlying HD-induced cutaneous toxicity remain undefined. The isolated perfused porcine skin flap (IPPSF) has been utilized to investigate dermal toxic compounds and pharmacological intervention. In this study, 4 compounds with different pharmacological mechanisms were tested for their ability to prevent the dark basal cell formation, vesication and vascular response charcteristic of exposure to HD in the IPPSF. Reduction of HD-induced dark basal cells was observed in IPPSFs perfused with sodium thiosulfate and cysteine, which are HD scavengers; niacinamide, a possible NAD+ stabilizer and an inhibitor of poly (ADP-ribose) polymerase; or indomethacin, a cyclooxygenase inhibitor, respectively. Treatments with niacinamide and indomethacin, but not sodium thiosulfate or cysteine, resulted in an inhibition of the vascular response in IPPSF exposed to HD. Microvesicles caused by HD were only partially prevented in the indomethacin-perfused IPPSFs. These data suggest that none of these agents alone would be successful antivesicant agents and different mechanisms are involved in production of HD-induced dark basal cells, microvesicles and the vascular response; unfortunately, blocking of the cellular toxicity as evidenced by dark basal cell formation did not prevent vesication, suggesting that other mechanisms must be operative and that there is a multistep, biochemical process that leads to a final lesion.