The long-term goal of this project is to develop an effective treatment for mustard gas induced injury This project will focus on the use of small molecular weight catalytic antioxidants to help understand the role o reactive oxygen species and their formation in 2-chloroethyl ethyl sulfide (CEES)-induced lung and derma injury. CEES is a strong electrophile that readily reacts with cellular macromolecules and depletes endogenous antioxidants. In addition, CEES stimulates a strong inflammatory response that is characterized by neutrophi influx. Mustard exposure is often associated with producing adult respiratory distress syndrome (ARDS) tha requires supplemental oxygen therapy to maintain adequate tissue oxygenation. Recent studies have suggested that CEES-induced lung injury could be attenuated by exogenous instillation of catalytic antioxidants such as superoxide dismutase and catalase. My laboratory has extensively studied manganese porphyrins anc demonstrated them to be efficient scavengers of superoxide, hydrogen peroxide, lipid peroxides and peroxynitrite. Manganese porphyrins are highly effective against a variety of intracellular and extracellula oxidative stress models. We currently have developed a lead metalloporphyrin that is in phase I human clinica trials. Recently we found that the breakdown products of these metalloporphyrins to also possess poten antioxidant activity. This discovery has lead to the development of metalloporphyrin analogs (metallated lineai tetrapyrroles) that have high activity. We propose to test the efficacy of catalytic antioxidants that include AEOL 10150 and the metallated linear tetrapyrroles for the treatment of mustard gas-induced lung and derma injury. We will 1) determine the efficacy of catalytic antioxidants in rat and human models of CEES-induced lunc injury;2) determine the efficacy of catalytic antioxidants in mouse and human models of CEES-induced derma injury;and 3) develop and characterize a new class of catalytic antioxidants, the linear tetrapyrroles. We wil correlate changes in injury responses to markers of oxidative stress. The significance of these studies are that they have the possibility to provide rapid relief and prevent life threatening injury to comba troops and/or civilians that may become exposed to a mustard gas attack.
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