Our previous studies and other published reports on the
chemical warfare agent sulfur mustard (SM) and its analog
2-chloroethyl ethyl sulfide (
CEES) have indicated a role of oxidative stress in skin
injuries caused by these vesicating agents. We examined the effects of the catalytic
antioxidant AEOL 10150 in the attenuation of
CEES-induced toxicity using our established skin injury models (skin epidermal cells and SKH-1 hairless mice) to validate the role of oxidative stress in the pathophysiology of mustard vesicating agents. Treatment of mouse epidermal JB6 and human HaCaT cells with
AEOL 10150 (50μM) 1h post-
CEES exposure resulted in significant (p < 0.05) reversal of
CEES-induced decreases in both cell viability and
DNA synthesis. Similarly,
AEOL 10150 treatment 1h after
CEES exposure attenuated
CEES-induced DNA damage in these cells. Similar
AEOL 10150 treatments also caused significant (p < 0.05) reversal of
CEES-induced decreases in cell viability in normal human epidermal keratinocytes. Cytoplasmic and mitochondrial
reactive oxygen species measurements showed that
AEOL 10150 treatment drastically ameliorated the
CEES-induced oxidative stress in both JB6 and HaCaT cells. Based on
AEOL 10150 pharmacokinetic studies in SKH-1 mouse skin, mice were treated with a topical formulation plus
subcutaneous injection (5mg/kg) of
AEOL 10150 1h after
CEES (4mg/mouse) exposure and every 4h thereafter for 12h. This
AEOL 10150 treatment regimen resulted in over 50% (p < 0.05) reversal of
CEES-induced skin bi-fold and epidermal thickness,
myeloperoxidase activity, and
DNA oxidation in mouse skin. Results from this study demonstrate the potential therapeutic efficacy of
AEOL 10150 against
CEES-mediated cutaneous lesions, supporting
AEOL 10150 as a medical countermeasure against SM-induced skin
injuries.