Direct lung injury, with pulmonary complications, accounted for most of the deaths following toxic chemical exposure in the Iran-Iraq- war, the accidental release of methyl isocyanate in Bhopal, India, the Tokyo subway sarin attack, and the hostage crisis in Moscow. These tragedies exemplify how susceptible human airways are to the effects of airborne chemicals and imply that respiratory management is most important and critical for saving life. Previous reports indicate that chemical injury is associated with direct chemical reaction followed by acute respiratory distress syndrome and late complications. A large number of civilians and an increasing number of children with pre-existing medical conditions such as asthma are more vulnerable to chemical threat agents. We propose to investigate the respiratory toxicity and lung injury following inhalation exposure to the deadly chemical threat agent sarin in animal models. Our recently developed micro-instillation technology of inhalation exposure will be used for sarin vapor exposure. Micro-instillation technology bypasses the detoxification of chemical threat agents in the airway of rodents, which have high levels of carboxylesterase and mucus. Thus, the chemical agents reach alveoli and mimics an exposure similar to human. The respiratory toxicity will be assessed by toxicological, biochemical, histopathological and respiratory functional analysis. The chronology of lung injury will be also assessed. We ill identify bronchoalveolar lavage, blood biomarkers or non-invasive respiratory parameters to diagnose the severity of exposure. A number of FDA-approved or in clinical trial as well as new therapeutic regimens will be evaluated to develop an effective medical countermeasure against pulmonary injury and its long-term consequences. We will also assess the respiratory toxicity of sarin in animals models of pre-existing medical conditions such as asthma. Potential therapeutics will be evaluated for protection against sarin exposure in asthma model. The proposed studies will define the biochemical mechanisms of respiratory toxicity and lung injury that play a central role in chemical threat agent induced toxicity and a major cause of death following exposure in normal and vulnerable populations with pre-existing medical conditions. Effective therapeutics to protect against pulmonary toxicity and its long-term consequences that can complement the existing modalities will be rapidly developed for a mass scenario. ? ? ?
