Sulfur mustard toxicity following dermal exposure: role of oxidative stress, and antioxidant therapy

Abstract

Objective: Sulfur mustard (bis-2-(chloroethyl) sulfide) is a chemical warfare agent (military code: HD) causing extensive skin injury. The mechanisms underlying HD-induced skin damage are not fully elucidated. This review will critically evaluate the evidence showing that oxidative stress is an important factor in HD skin toxicity. Oxidative stress results when the production of reactive oxygen (ROS) and/or reactive nitrogen oxide species (RNOS) exceeds the capacity of antioxidant defense mechanisms.

Methods: This review will discuss the role of oxidative stress in the pathophysiology of HD skin toxicity in both in vivo and in vitro model systems with emphasis on the limitations of the various model systems. Evidence supporting the therapeutic potential of antioxidants and antioxidant liposomes will be evaluated. Antioxidant liposomes are effective vehicles for delivering both lipophilic (incorporated into the lipid bilayers) and water-soluble (encapsulated in the aqueous inner-spaces) antioxidants to skin. The molecular mechanisms interconnecting oxidative stress to HD skin toxicity are also detailed.

Results: DNA repair and inflammation, in association with oxidative stress, induce intracellular events leading to apoptosis or to a programmable form of necrosis. The free radical, nitric oxide (NO), is of considerable interest with respect to the mechanisms of HD toxicity. NO signaling pathways are important in modulating inflammation, cell death, and wound healing in skin cells.

Conclusions: Potential future directions are summarized with emphasis on a systems biology approach to studying sulfur mustard toxicity to skin as well as the newly emerging area of redox proteomics.

Figure 1

Distribution and accumulation of HD via circulation after dermal/inhalation exposure.

Figure 2

Schematic representation of the hypothesized molecular mechanisms of HD toxicity in skin cells.

Figure 3

LPS (100 ng/mL) enhances the cytotoxicity of CEES (500 μM). Means not sharing a common letter are significantly different (P < .05). Cytotoxicity was measured after 24 hours by the MTT assay.

Figure 4

CEES inhibits NO production in LPS stimulated RAW 264.7 macrophages. Cells were simultaneously treated with various levels of CEES (as indicated) and low doses of LPS (as indicated). NO production was monitored as the concentration of nitrite in the culture media after 24 hours.