Abstract
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.
Highlights
Skin injuries inflicted by vesicating chemical warfare agent sulfur mustard [HD, bis(2-chloroethyl) sulfide)] can be acute, excruciating and last for several years [1,2,3,4]
HD is a bifunctional alkylating agent that reacts with cellular targets including lipids, proteins and DNA, and mechanistic aspects of HD-induced skin injuries include oxidative stress, DNA damage and cell cycle pathways, caspase and poly (ADP–ribose) polymerases (PARP), mitogen activated protein kinases (MAPKs) and Akt pathways, transcription factors activator protein-1 (AP-1) and nuclear factor- kB (NF-kB), matrix metalloprotease-9 (MMP9), inflammatory mediators cyclooxygenase-2 (COX-2), inducible nitric oxide synthase, cytokines, and calcium signaling [5,6,10,11,12,13,14,15,16,17]
Agents that can target HD-induced oxidative stress are important therapeutic options because oxidative stress is reported as an immediate key consequence of HD exposure, which can lead to the activation of intricate signaling pathways [14,18]
Summary
Skin injuries inflicted by vesicating chemical warfare agent sulfur mustard [HD, bis(2-chloroethyl) sulfide)] can be acute, excruciating and last for several years [1,2,3,4]. Agents that can target HD-induced oxidative stress are important therapeutic options because oxidative stress is reported as an immediate key consequence of HD exposure, which can lead to the activation of intricate signaling pathways [14,18]. Several antioxidants such as GSH, Nacetyl cysteine (NAC), sulforaphane, zinc oxide, zinc chloride, butylated hydroxyanisole (BHA), ebselen, desferrioxamine, Lthiocitrulline (L-TC) have shown beneficial effects in reducing vesicant-induced skin injuries [14,18,19]; most of them exhibit stronger protective effect than therapeutic potential [14,18,19,20]. In this study, we focused our efforts on the identification of effective mechanism-based pleiotropic or multifunctional rescue therapy to target the complex pathways triggered by vesicant exposure that lead to incapacitating skin injuries
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
