CHAPTER 4:Mustard: Pathophysiology and Therapeutic Approaches

Sulfur mustard (SM) is a highly reactive compound that was discovered in the 19th century and has repeatedly been used as a chemical warfare agent. Despite decades of medical research, no causative treatment against SM exists. This is largely due to the highly complex pathophysiology at the cellular and intercellular level. This chapter describes the clinical symptoms with particular regard to the skin, eyes and respiratory systems. SM exerts its toxicity both through its primary effect, i.e. DNA and protein alkylation, and secondary mechanisms, including excessive inflammation, formation of reactive oxygen species (ROS) and reactive nitrogen species (RNS), and poly(ADP-ribose) polymerase (PARP) overactivation. Loss of the phagocytotic ability of immune cells reduces the clearance of apoptotic bodies and necrotic cell debris. Cell migration is also impaired, negatively affecting immune cells and early endothelial cells, with adverse effects on wound healing. Regarding medical countermeasures against SM injury, this chapter outlines symptomatic therapy and describes the specific requirements and strategies in the search for novel antidotes. Corresponding to mechanisms of SM toxicity, current and potential therapeutic interventions are discussed, including direct scavenging of SM, anti-oxidative and anti-inflammatory therapy, limitation of extrinsic apoptosis and, theoretically, PARP inhibition. Some of the—currently most promising—compounds to treat SM injuries counteract multiple aspects of its toxicity: silibinin provides membrane stabilization, limits radical formation and enhances protein biosynthesis, whereas macrolide antibiotics limit necrosis and inflammation, and restore migratory and phagocytotic abilities of immune cells. For some compounds, including phytopharmaceuticals, no precise mechanism of action is currently known. Cell therapies are in their early experimental stages, but some approaches have been highly successful in animal studies and grafts of limbal corneal stem cells have even proven their clinical efficacy to counteract severe, long term effects of SM exposure. In summary, the current treatment of SM toxicity is mostly reliant on symptomatic interventions. A better understanding of its pathophysiology is likely to result in therapeutic advances in the near to medium term future. Pharmacological and cell therapeutic interventions both have a role in providing the best possible therapy for victims of SM exposure.