Abstract
Sulfur mustard or mustard gas (HD) and its monofunctional analog, 2-chloroethyl ethyl sulfide (CEES), or “half-mustard gas,” are alkylating agents that induce DNA damage, oxidative stress, and inflammation. HD/CEES are rapidly absorbed in the skin causing extensive injury. We hypothesize that antioxidant liposomes that deliver both water-soluble and lipid-soluble antioxidants protect skin cells from immediate CEES-induced damage via attenuating oxidative stress. Liposomes containing water-soluble antioxidants and/or lipid-soluble antioxidants were evaluated using in vitro model systems. Initially, we found that liposomes containing encapsulated glutathione (GSH-liposomes) increased cell viability and attenuated production of reactive oxygen species (ROS) in HaCaT cells exposed to CEES. Next, GSH-liposomes were tested in a human epidermal model, EpiDerm. In the EpiDerm, GSH-liposomes administered simultaneously or 1 hour after CEES exposure (2.5 mM) increased cell viability, inhibited CEES-induced loss of ATP and attenuated changes in cellular morphology, but did not reduce caspase-3 activity. These findings paralleled the previously described in vivo protective effect of antioxidant liposomes in the rat lung and established the effectiveness of GSH-liposomes in a human epidermal model. This study provides a rationale for use of antioxidant liposomes against HD toxicity in the skin considering further verification in animal models exposed to HD.
Highlights
Sulfur mustard is a weapon of massdestruction that is relatively simple to synthesize; it is lethal in high doses and causes severe damage to skin, lungs, respiratory tract, and eyes [1]
We first performed a series of preliminary experiments testing the effect of various antioxidant liposome formulations in HaCaT keratinocytes exposed to chloroethyl ethyl sulfide (CEES)
Our studies with the human epidermal model, EpiDerm, showed that GSH, both “free” and “liposome encapsulated,” attenuated toxicity induced by CEES, a mustard gas analog
Summary
Sulfur mustard (military code HD) is a weapon of massdestruction that is relatively simple to synthesize; it is lethal in high doses and causes severe damage to skin, lungs, respiratory tract, and eyes [1]. The most prominent toxic effects of HD are to dermal tissues where it produces severe damage including extremely slow healing lesions and blisters, which can ulcerate and promote secondary infections [2, 3]. Despite the long military history of HD, the molecular mechanisms for its toxicity are not fully elucidated and an effective countermeasure has remained elusive. Both HD and CEES (a monofunctional analog of sulfur mustard) are alkylating agents that covalently react with nucleic acids, proteins, and intracellular glutathione (GSH). A considerable body of evidence supports the notion that oxidative stress is an important factor in promoting HD/CEES toxicity and that antioxidants such as GSH or NAC could be important countermeasures [5,6,7,8,9,10,11,12,13]
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