The Mustard Consortium's Elucidation of the Pathophysiology of Sulfur Mustard and Antidote Development

Abstract : The Mustards Consortium has utilized both in vivo and in vitro models simultaneously to continue to elucidate mustard gas pathophysiology. In previous work done by the MC it was found that CEES, the mustard analogue, induced oxidative stress and was its primary mechanism of action. Consequently, NAC (N-acetyl cystiene) was found to be protective as a prophylaxis and treatment. A combination of a water and fat soluble antioxidant encapsulated in a liposome (STIMAL) was found to have the best ameliorative effect against CEES. We have initiated development of next generation STIMAL, in order to optimize its ameliorative effect. The mechanism of action of the antioxidants is suspected to be primarily by their effect on redox regulated pathways. In an effort to elucidate the mechanism of action of the antioxidants and the pathophysiology of mustards, profiles are being developed for: gene expression and antioxidant levels, as well as biochemical pathways. The first known histological comparison between CEES and sulfur mustard was carried out. Two new rat lung models were developed for the administration of sulfur mustards in preparation for efficacy testing of STIMAL against sulfur mustards. Pulmonary fibrosis was demonstrated in both guinea pig and rat lung models.