Novel therapeutics for vesicants and toxic inhaled chemicals (U54)

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PROJECT SUMMARY (See instructions): Denver's CounterACT program was formed to develop models of sulfur mustard (SM) toxicity to lung and skin, understand injury pathogenesis, and evaluate novel antioxidants to rescue SM-mediated injuries. SM analog CEES (2-chloroethyl ethylsulfide) caused inflammation, DNA damage (8-hydroxydeoxy-guanosine accumulation; comet assay; ATM/ATR activation and downstream signaling) and lipid peroxidation (4- hydroxynonenal) in tissues, as well as inflammation. In lung, CEES caused bronchial vascular injury/leak. Airway obstructive fibrin-containing casts formed after inhalation exposures to CEES or SM, and similar lesions were apparent after chlorine (400 ppm). Catalytic antioxidant AEOL10150, which scavenges superoxide, hydrogen peroxide, lipid peroxides, and peroxynitrite, rescued: a) upper (nasal) and lower airway injuries by CEES; b) lower airway injury by SM; c) oxidative stress, inflammation and methacholine reactivity due to chlorine; and d) skin injuries by CEES such as inflammation and neutrophil infiltration. A natural dietary supplement silibinin also rescued skin injuries by CEES. New data showed: a) AEOL10150 efficacy to limit injury by escalated CEES and SM exposures, as well as acute lung injury by higher (250 ppm) chlorine concentrations, b) coagulation activation in the CEES inhalation and chlorine models, and c) efficacy of tPA (tissue-type plasminogen activator) in late rescue, starting 4h after CEES inhalation. Next cycle, Denver CounterACT will: a) establish early anticoagulant and/or late fibrinolytic agent efficacies in airways obstruction by CEES, SM and chlorine, b) evaluate AEOL10150 in profound airway injuries by these agents (both alone and combined with anticoagulant and/or fibrinolytic approaches), and c) evaluate AEOL10150 and flavonoid silibinin to rescue skin injuries by CEES, nitrogen mustard (NM), and SM. Effective anticoagulant and/or fibrinolytic agents will be cross-checked to verify lack of exacerbation of skin injuries. Endpoints of oxidative stress, inflammation, increased permeability, and, for lungs, airway obstruction, will be evaluated. Agent(s) found effective for CEES/NM would be evaluated in skin injury by SM. These approaches will identify promising rescue agents for skin and lung injury by toxic gases.