Sulfur mustard research--strategies for the development of improved medical therapy

Abstract

Objective: Sulfur mustard (SM) is a bifunctional alkylating substance being used as chemical warfare agent (vesicant). It is still regarded as a significant threat in chemical warfare and terrorism. Exposure to SM produces cutaneous blisters, respiratory and gastrointestinal tract injury, eye lesions, and bone marrow depression. Victims of World War I as well as those of the Iran-Iraq war have suffered from devastating chronic health impairment. Even decades after exposure, severe long-term effects like chronic obstructive lung disease, lung fibrosis, recurrent corneal ulcer disease, chronic conjunctivitis, abnormal pigmentation of the skin, and different forms of cancer have been diagnosed.

Methods: This review briefly summarizes the scientific literature and own results concerning detection, organ toxicity of SM, its proposed toxicodynamic actions, and strategies for the development of improved medical therapy.

Results: Despite extensive research efforts during the last century, efficient antidotes against SM have not yet been generated because its mechanism of action is not fully understood. However, deeper insights into these mechanisms gained in the last decade and promising developments of new drugs now offer new chances to minimize SM-induced organ damage and late effects.

Conclusion: Polymerase inhibitors, anti-inflammatory drugs, antioxidants, matrix metalloproteinase inhibitors, and probably regulators of DNA damage repair are identified as promising approaches to improve treatment.

Figure 1

Detection of sulfur mustard vapor with the sulfur mustard detector. Sulfur mustard was diluted in phosphate-buffered saline at indicated concentrations. Sulfur mustard detector was held above the fluid for 30 seconds (A). The sulfur mustard detector showed a red line as a positive result (B).

Figure 2

Sulfur mustard detector was used to detect environmental traces of sulfur mustard. Sulfur mustard detector was attached to an individual protective equipment before the soldier entered a cave with an open sulfur mustard grenade shell. Sulfur mustard detector was held over the shell for 5 seconds. After leaving the cave, the sulfur mustard detector showed red lines as positive results for the individual protective equipment as well as for the shell.

Figure 3

Pathways implicated in sulfur mustard-induced pathophysiology and possible targets (red) for therapeutic intervention. Sulfur mustard-induced direct and indirect (reactive oxygen species) DNA damage lead to polymerase (PARP) activation and nicotine adenine dinucleotide (NAD) depletion, which may result in necrotic cell death. Sulfur mustard exposure has also been demonstrated to activate the extrinsic and intrinsic pathway of apoptosis. Sulfur mustard-induced release of (pro)inflammatory cytokines has been linked to NFkB activation and prostaglandine release. Sulfur mustard has also been shown to upregulate matrix metalloproteases and serin proteases. The exact signal transduction for matrix metalloproteinase (MMP) activation has not been identified yet. In conclusion, PARP inhibitors, anti-inflammatory drugs, antioxidants, and MMP inhibitors are identified as promising pharmacological approaches to improve clinical outcome.