Chemical warfare agent sulfur mustard (HD) inflicts delayed blistering and incapacitating skin
injuries. To identify effective countermeasures against HD-induced skin
injuries, efficacy studies were carried out employing HD analog
2-chloroethyl ethyl sulfide (
CEES)-induced injury
biomarkers in skin cells and SKH-1 hairless mouse skin. The data demonstrate strong therapeutic efficacy of
silibinin, a natural
flavanone, in attenuating
CEES-induced skin injury and oxidative stress. In skin cells,
silibinin (10 µM) treatment 30 min after 0.35/0.5 mM
CEES exposure caused a significant (p<0.05) reversal in
CEES-induced decrease in cell viability, apoptotic and necrotic cell death, DNA damage, and an increase in oxidative stress.
Silibinin (1 mg) applied topically to mouse skin 30 min post-
CEES exposure (2 mg), was effective in reversing
CEES-induced increases in skin bi-fold (62%) and epidermal thickness (85%), apoptotic cell death (70%),
myeloperoxidase activity (complete reversal), induction of iNOS, COX-2, and MMP-9
protein levels (>90%), and activation of
transcription factors NF-κB and
AP-1 (complete reversal). Similarly,
silibinin treatment was also effective in attenuating
CEES-induced oxidative stress measured by
4-hydroxynonenal and 5,5-dimethyl-2-(8-octanoic acid)-1-pyrolline N-
oxide protein adduct formation, and 8-oxo-2-deoxyguanosine levels. Since our previous studies implicated oxidative stress, in part, in
CEES-induced toxic responses, the reversal of
CEES-induced oxidative stress and other toxic effects by
silibinin in this study indicate its pleiotropic therapeutic efficacy. Together, these findings support further optimization of
silibinin in HD skin toxicity model to develop a novel effective
therapy for skin
injuries by
vesicants.