Our long term goal is to develop the catalytic antioxidant AEOL10150 as medical countermeasure for sulfur mustard gas-induced acute lung injury. Sulfur mustard gas is a commonly stockpiled chemical warfare agent that has been deployed on military personnel and in civilian populations producing mass casualties. Currently there are no effective treatments for sulfur mustard gas exposure. AEOL10150 uniquely targets reactive oxygen and nitrogen species that have been implicated in cellular and tissue damage produced by alkylating agents such and sulfur and nitrogen mustards. We have previously shown that AEOL10150 can protect the lung against several chemical agent exposures including chlorine, phosgene, soman, and sulfur mustard gases in rodent models. AEOL10150 is in advanced development as a mitigator of radiation-induced lung injury by Aeolus Pharmaceuticals. AEOL10150 is in advanced drug development with completed GLP chronic safety studies in mice and monkeys, completed Chemistry, Manufacturing, and Control (CMC), and a phase 1A clinical safety trials in humans. The purpose of this UO1 grant is to optimize AEOL10150 dose and delivery in a swine model of SM-induced acute lung injury as part of the requirements of the FDA Animal Rule. We will achieve this goal through 3 specific aims. The first aim will establish a swine sulfur mustard inhalation model that produces acute respiratory injury and mortality within 24 to 48 hours. The second aim will optimize AEOL10150 pharmacodynamics in the swine sulfur mustard inhalation model. And the third aim will determine the efficacy of AEOL10150 in a swine model of SM-induced acute lung injury while mitigating mortality. These studies will allow AEOL10150 to move forward and help design the pivotal safety and efficacy studies needed for regulatory FDA approval of AEOL10150 under the animal rule. AEOL10150 has the potential to be a broad spectrum medical counteragent against traditional chemical warfare agents and toxic industrial chemicals that inflict a lung toxidrome.