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Review
. 2010 Mar;114(1):5-19.
doi: 10.1093/toxsci/kfp253. Epub 2009 Oct 15.

Mechanisms mediating the vesicant actions of sulfur mustard after cutaneous exposure

Michael P Shakarjian  1 , Diane E Heck, Joshua P Gray, Patrick J Sinko, Marion K Gordon, Robert P Casillas, Ned D Heindel, Donald R Gerecke, Debra L Laskin, Jeffrey D Laskin
Affiliations
Review

Mechanisms mediating the vesicant actions of sulfur mustard after cutaneous exposure

Michael P Shakarjian et al. Toxicol Sci. 2010 Mar.

Abstract

Sulfur mustard (SM), a chemical weapon first employed during World War I, targets the skin, eyes, and lung. It remains a significant military and civilian threat. The characteristic response of human skin to SM involves erythema of delayed onset, followed by edema with inflammatory cell infiltration, the appearance of large blisters in the affected area, and a prolonged healing period. Several in vivo and in vitro models have been established to understand the pathology and investigate the mechanism of action of this vesicating agent in the skin. SM is a bifunctional alkylating agent which reacts with many targets including lipids, proteins, and DNA, forming both intra- and intermolecular cross-links. Despite the relatively nonselective chemical reactivity of this agent, basal keratinocytes are more sensitive, and blistering involves detachment of these cells from their basement membrane adherence zones. The sequence and manner in which these cells die and detach is still unresolved. Much has been discovered over the past two decades with respect to the mechanisms of SM-induced cytotoxicity and the intracellular and extracellular targets of this vesicant. In this review, the effects of SM exposure on the skin are described, as well as potential mechanisms mediating its actions. Successful therapy for SM poisoning will depend on following new mechanistic leads to develop drugs that target one or more of its sites of action.

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Figures

FIG. 1.
FIG. 1.
Structures of SM and related analogs, chloroethyl ethyl sulfide (CEES, half-mustard), and mechlorethamine (nitrogen mustard, HN2). All three agents induce blistering of the skin. Sulfur mustard is the most potent of these agents followed by HN2 and CEES (Fox and Scott, 1980; Goldenberg and Begleiter, 1980; Goldenberg et al., 1971; Sharma et al., 2008).
FIG. 2.
FIG. 2.
Time course of pathophysiological changes that occur after dermal exposure to SM. A latency period of variable length precedes erythema, the first sign of injury. Vesiculation commences between 13 and 22 h after exposure and develops over the course of 48 h to form large blisters. A second round of blistering may also be observed. Necrosis and eschar formation occurs after blisters collapse. Healing is prolonged, taking 2–3 weeks for vesicating lesions and several weeks for full-thickness erosions (Balali-Mood and Hefazi, 2005; Papirmeister et al., 1991).
FIG. 3.
FIG. 3.
Mechanism of mustard-induced alkylation. Example of an alkylation reaction between SM and a 2-deoxyguanosine base. One chloroethyl side chain undergoes a first-order (SN1) intramolecular cyclization, releasing chloride and forming a positively charged ethylsulfonium ring. This intermediate reacts rapidly (through carbonium ion or formation of a transition complex intermediate) with nucleophilic groups, such as the N7 of 2-deoxyguanosine. The remaining choloroethyl side chain will then also cyclize and react with another nearby nucleophilic group or with water (Calabresi and Chabner, 1990).
FIG. 4.
FIG. 4.
Mechanisms of cutaneous injury induced by SM. SM alkylates DNA, proteins, and small molecules in the skin. DNA damage can lead directly to cell death or activate PARP and other repair enzymes; cells may be rescued or progress to death by apoptosis or necrosis. Protein alkylation of cytoskeletal, hemidesmosomal, and ECM proteins can impair anchoring of basal keratinocytes to the basement membrane, leading to cell detachment and anoikis. Alkylation of intracellular GSH increases tissue susceptibility to oxidative stress. SM exposure also results in increased expression of a number of proinflammatory proteins in the skin, including iNOS, matrix-degrading proteases, COX-2, cytokines, and chemokines. NO generated by iNOS can combine with other oxidants generating more long-lived and cytotoxic species such as peroxynitrite. Proteases can destroy epidermal-basement membrane connections. Prostaglandins generated via COX-2 increase membrane permeability and together with cytokines and chemokines participate in recruitment of circulating leukocytes, thereby amplifying inflammation and tissue injury. Weakening of the connections between basal keratinocytes and their basement membrane connections through these various mechanisms will result in epidermal-dermal separation and frank vesication.
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