ReviewMolecular toxicology of sulfur mustard-induced cutaneous inflammation and blistering
Introduction
Sulfur mustard (SM; 2,2′-dichloroethyl sulfide; CASRN: 505-60-2) is a strongly alkylating agent, which can react with all constituents of the skin. Schematically, the process of SM-induced skin pathology can be divided in three overlapping stages: erythema, blister formation and ulceration (Smith et al., 1919). Skin hyperpigmentation is a frequently observed finding accompanying all SM skin lesions (Balali-Mood and Hefazi, 2005). Typical erythema and skin oedema formation occurs several hours after skin contact, which is followed by subepidermal blisters (Aasted et al., 1987). Erythema can frequently be observed 4–8 h after SM exposure at a threshold dose (vapour: 100–300 mg min/m3, liquid: 10–20 μg/cm2) while blister formation occurs at higher doses (vapour: 1000–2000 mg min/m3, liquid: 40–100 μg/cm2) (Kehe and Szinicz, 2005). The blisters are characterized by small vesicles, which coalesce at a later point in time to gross blisters or large bullae (Balali-Mood and Hefazi, 2006). Exposure to higher concentrations of SM results in ulcers penetrating dermal structures of the skin. These three major skin pathologic findings (erythema, blister, and ulcer) have been linked to a variety of molecular mechanisms (Kehe et al., 2008).
The histopathology of SM affected skin shows vasodilatation and neutrophil infiltrate, which indicates that various vasoactive and chemoattractant mediators are produced in the exposed area (Smith et al., 1997).
The aim of this article is to describe the current knowledge of underlying pathophysiological mechanisms of acute epithelial lesions following SM exposure. Based on this concept rational targets for therapeutical intervention are presented.
Section snippets
Tissue destruction (blister and ulcer)
SM-induced blisters are thin-walled and filled with an amber-coloured fluid. A positive Nikolsky sign was frequently described, which means that rubbing of the skin will produce more blistering. Skin blistering may last for several days to weeks after a single SM exposure (Kehe et al., 2004). These blisters are clinical signs of dermal–epidermal separation of skin layers. Histopathologic analysis reveals marked keratinocyte cell death in the basal layer with signs of a massive inflammatory
PARP signaling
Poly(ADP-ribosyl)ation of cellular proteins in combination with marked depletion of nicotine adenine dinucleotide (NAD+) and adenosine triphosphate (ATP) has been observed after SM exposure (Bhat et al., 2000, Meier et al., 1987) and depends on SM-induced activation of poly(ADP-ribose) polymerases (PARPs) (Fig. 2). PARPs modulate SM-induced cell death and thereby blister formation. This mechanism has been extensively reviewed in this issue of Toxicology (Debiak et al., 2009). PARP-1 and PARP-2
Apoptosis
SM induces concentration-dependent necrotic and apoptotic cell death (Rosenthal et al., 1998, Rosenthal et al., 2001). Necrosis causes cytoplasmatic swelling and cellular rupture with release of intracellular contents which results in damage of surrounding cells and a massive inflammatory response. Even though recent findings also describe necrosis as a well orchestrated process (Festjens et al., 2006), it remains distinct from apoptosis, which needs longer time to be completed, follows a
Calcium signaling and calmodulin
Intracellular Ca++ is mainly stored in the endoplasmatic reticulum (ER). Ca++ release from this store is essential in many cellular signaling pathways. Toxicants can cause significant ER stress with changes in Ca++ homeostasis and induction of cell death e.g. apoptosis (Berridge et al., 2000). Interestingly, SM induces a rise of intracellular levels of free Ca++ in adult and neonatal keratinocytes (Mol and Smith, 1996, Sawyer and Hamilton, 2000). The rise in free Ca++ was moderate in these
Nitric oxide signaling and oxidative stress
Ca++ and the calmodulin proteins have been identified to play an essential role in the formation of nitric oxide. Interestingly, reactive nitrogen species (RNS) and peroxynitrite (ONOO–) have recently been proposed as key mediators of SM-induced cytotoxicity (Korkmaz et al., 2006, Yaren et al., 2007, Sawyer et al., 1996). Nitric oxide is produced by nitrogen oxide synthases (NOSs), which convert the amino acid l-arginine into NO and l-citrullin. There are three types of NOSs: endothelial NOS
Inflammation
The histopathology of SM damaged skin showed a marked inflammatory response (Smith et al., 1998), which indicates the production or release of various vasoactive and chemoattractant mediators in the affected area. Keratinocytes as the first cells in contact with SM are believed to have a central role in the first phase of initiating this response. As of now, several pathways have been identified to be involved in the release and regulation of gene expression of proinflammatory mediators.
NF-κB pathway and MAPKs
The transcription factor NF-κB (nuclear factor kappa-B) family members share structural homology with the retroviral oncoprotein v-Rel (Rel). NF-κB is composed of the five NF-κB/Rel family members p50 (NF-κB1), p52 (NF-κB2), RelA (p65), RelB and c-Rel, which form homo- or heterodimers. NF-κB, most often composed of p50 and p65/RelA, is involved in several cellular responses related to cellular stress and is a crucial mediator of inflammatory processes (Karin and Greten, 2005) (Fig. 4). NF-κB
Matrix-metalloproteases
Large blister formation after SM injury shares some similarities with epidermolysis bullosa (Monteiro-Riviere et al., 1999). A recent study revealed that 24 h after SM exposure epidermal–dermal separation was associated with a discontinuous pattern of laminin 5 and type VII collagen (Greenberg et al., 2006). Hemidesmosomes contain the two proteins BP230 and BP180 that can be used to characterize the blister plane. The intracellular protein BP230 (also known as BPAG1) associates the
Conclusions
In summary, a huge body of data has accumulated in the past century of research to understand the pathophysiology of SM poisoning (Fig. 5). Several pathways have been identified as playing major roles in signaling SM mediated cytotoxic effects. However, many questions are still open and coordinated research is needed to fill the gaps. With respect to our present knowledge about SM-induced pathophysiology anti-inflammatory drugs (e.g. inhibitors of p38), anti-oxidants (e.g. N-acetylcysteine),
Conflict of interest
The authors declare that there are no competing interests.
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