Mechanism of Sulfur Mustard Induced Lung Injury Sulfur mustard (SM) is a powerful alkylating agent that was used extensively during the World War I and in 1980s' Iran-Iraq war, and analysts in the CIA, DOD, and the Congressional Research Service (CRS) have ranked SM as the highest probability agent to be used as a chemical weapon for terrorism. While exposure to high doses of SM may be lethal, sublethal exposures cause serious acute and chronic injuries primarily to the lung, skin and eyes and, to date, there is no effective treatment against SM. The respiratory consequences of acute SM exposure include throat pain, cough, and asthma-like symptoms, such as tachypnea, bronchospasms, and airway hyperresponsiveness, and the delayed effects, which might arise after months to years after SM exposure, comprise chronic bronchitis, asthma, bronchiectasis, and pulmonary fibrosis. Because the mechanism of SM-induced lung injury is not clear, it is a major hurdle in the development of rationale therapeutic interventions. Based on the published data, we propose that the lung injury associated with SM exposure results from its two properties: (a) SM is an extremely powerful alkylating agent that rapidly modifies cellular proteins, and we hypothesize that the major biological effects stem from the immunological consequences of these modifications. The early effects emerge from the activation of innate immunity (inflammation) and the associated cell death, and the delayed effects from the activation of the adaptive immune response directed to the modified (alkylated) self-antigens, leading to a chronic autoimmune status, (b) SM inhibits acetylcholinesterase that raises the synaptic level of acetylcholine causing acute bronchoconstriction, bronchospasms, and exacerbated asthma. Therefore, a combination of anti-inflammatory, immunosuppressive, anti-apoptotic, and anti-cholinergic drugs administered immediately after SM exposure might ameliorate both the early and the late respiratory effects of SM toxicity. To address the working hypothesis, we propose to: (1) evaluate the role of inflammation in SMinduced lung injury, (2), examine the effects of acute SM inhalation on airway resistance, (3) ascertain the effects of SM exposure on the development of adaptive immunity, and (4) examine the effects of potential therapeutic agents (particularly combination therapies) on the acute and chronic toxicities of SM exposure. These studies, we believe, will delineate the mechanism(s) of acute and chronic respiratory effects of SM exposure and provide a rationale approach to design and test the efficacy of therapeutic interventions.