| Sulfur mustard (HD) is a vesicant agent, the repeated use of which in wars has demonstrated that it is powerfully destructive and is known as "the king of all CWAs(chemical warfare agents)". In history, sulfur mustard is a CWA used for military purpose by many countries, and both US and Russia keep stockpiles of this type of agent. The fact that many questions remain unanswered as to the mechanism of action, cytotoxicity, carcinogenicity, and vesicant properties of HD may explain why neither antidote nor prophylactics or therapeutic strategies are available for HD exposure. As a result, HD intoxication is chiefly handled by symptom-specific methods. Researchers worldwide have been showing great interest in the study of sulfur mustard, focusing on the establish of in vivo and in vitro model, mechanism of cutaneous vesication, the role of cytotoxicity, the screening of antidotes, as well as the characteristics of toxicokinetics, among which the mechanism of vesication is a focus of attention. Our research aims at an experimental study of HD induced cutaneous toxicity and a probe of the possible mechanism of cutaneous vesication, in the hope of furnishing a theoretical basis for further studies and screening of antidotes.1. The mouse ear model of cutaneous sulfur mustard injuryMouse ear edema to a single topical application of 5uL of 16,32,64 mg/mL HD was evaluated at 6, 12, 16, 20, 24, 30, 48, 72, 96h postexposure, and edema response was determined by weighing mouse ear. HD produced dose-and time-dependent changes in edema, with the severity dependent upon the dose and length of time of exposure. The first 24h marked an acute progression. Key light microscopic histopathologic changes assessed on the ear of exposure to 32 mg/mL HD at 3, 6, 12, 20, 24, 30, 48, 72, 96h, showed that sulfur mustard-related pathological changes covered a wide variety at different stages, such as edema, leukocytes infiltration, microvesicle, intracellular edema in the stratum basal cells, necrosis of stratum cells, vascular dilatation, hyperemia, hemorrhage, parakeratosis of stratum cells. The three endpoints of inflammation, microvesicle and necrosis were given particular attention, which suggested that the length of exposure was associated with severity of the 3 pathological changes, and that inflammation took place the earliest and necrosis the latest. Under transmission electron micrograph subcutaneous vesication and the disturbance of epidermal-dermal junction could be detected. These results indicated that the mouse ear exposure to a dose of 32mg/mL HD 5uL can establish mouse ear vesicant model and this model are optimal to screen pharmacological compounds that may protect against HD induced skin damage and to investigate the mechanism of cutaneous vesication.2. The antidotes for sulfur mustard cutaneous lesionThree compounds were administered as single topical treatments 10 min after HD challenge, including the 5% Povidone Iodine aqueous solution, the traditional Chinese medicine of Mei Bao Gao and anti-inflammatory compound of Clobetasol Propionate.Pharmacological modulation of HD injury in mouse ears was established by a reduction in edema or histopathology (epidermal necrosis and epidermal dermal separation, dermal inflammation) at 12,16,20, 24, 48, 72h following topical liquid HD exposure. Mei Bao Gao produced a slight reduction in edema, but produced significant reductions in epidermal necrosis and epidermal dermal separation within 24h. The Povidone Iodine was not involved in any way in the protective effects against HD-induced injury, and Clobetasol Propionate was shown to reduce slightly the dermal inflammation within 24h, but play no part in pharmacological modification of edema and other histopathological changes. These results demonstrate the unmistakable treatment effects of Mei Bao Gao against HD induced skin injury in an in vivo model as well as the feasibility of the use of the mouse ear vesicant model for evaluating medical countermeasures against HD.3. Mechanism of HD-induced cutan... |
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