?Development of antidotes for toxic gases? The goal of this Program is to create a systematic process for developing antidotes against toxic gaseous chemicals by capitalizing on the proven track record of a team of physician-scientists backed by accomplished basic scientists. We will examine two acute pulmonary and cardiopulmonary toxidromes caused by the gaseous chemicals sharing common injury mechanisms: 1) alkylating agents, sulfur mustard (SM) and methyl isocyanate (MIC), that cause DNA crosslinking/damage, apoptosis, airway epithelial and endothelial injury, acute lung injury, and fibrosis, and 2) rapidly absorbed gases, methylmercaptan (CH3SH) and cyanide (HCN), that cause systemic mitochondrial failure. These toxic chemicals were chosen based on: 1) capacity to cause critical illness and death, 2) perceived threat(s), 3) recent and/or important past exposures, and 4) priorities of the NIH/CounterACT, BARDA, DoD, and international community. Therapies being advanced in Projects 1, 3, and 4 are intended as rescue countermeasures for mass casualty scenarios. Two of these (Projects 1 and 3) are intended to be for acute inhalation accidents or disasters. In Project 1, for MIC, three classes of therapies directed at receptor-mediated (TRP channel antagonist(s)), coagulation-related (plasminogen activator(s)), and biochemical (thiol compounds) events will be investigated in a new preclinical acute inhalation model. Therapies would be for immediate/delayed treatment, with intramuscular, airway, and enteral and/or intravenous delivery for TRP channel antagonists, plasminogen activators, and thiol compounds, respectively. In Project 2, the anti-fibrotic drugs pirfenidone and nintedanib will be evaluated via oral/airway delivery in a fibrotic chronic lung disease model in rats following sublethal SM exposure. In Project 3, the vitamin B12 analog cobinamide and sodium thiosulfate, both of which react directly with methyl mercaptan, will be tested as countermeasures against this acutely toxic gas in mice, rabbits, and pig models. In Project 4, a nanoparticle- associated cobinamide (Cbn) will be evaluated as acute rescue countermeasure for oral NaCN intoxication in rabbit and pig models. Because oral NaCN is absorbed as a gas (HCN) at the gastric mucosa, and since victims often will not be conscious, gastric lavage delivery will be used. The Specific Aims are: 1) Determine potential of TRP channel antagonists, plasminogen activators, and thiols to decrease airway injury and lethality after MIC inhalation; 2) Define the efficacy of pirfenidone and other anti-fibrotic drugs against airway and parenchymal lung fibrosis after SM inhalation; 3) Establish efficacy of Cbn and thiosulfate for rescuing animals from lethal methylmercaptan exposures and 4) test the potential efficacy of nonabsorbable nano preparations of Cbn versus other Cbn preparations and routes in an oral NaCN poisoning and lethality model. Successful therapies from each project will be ready for advanced development and attain pre-IND status at or before the end of the cycle.