Phosgene is a common toxic industrial chemical used in the manufacture of plastics and industrial materials. Exposure to phosgene gas causes acute lung injury (ALI) that primarily targets alveoli, resulting in acute pulmonary edema and fatal acute respiratory distress syndrome. In this respect, it is similar to other agents that target alveoli such as chloropicrin and perfluoroisobutylene. No effective therapies currently exist to treat phosgene-induced ALI, and it is considered a significant chemical threat risk. The Angiopoietin (Ang)-1/Tie2 signaling pathway is one of the most potent mediators of vascular integrity and prevention of vascular leak induced by a variety of stimuli, including inflammation, vascular endothelial growth factor (a.k.a., vascular permeability factor), serotonin, and histamine, suggesting that this pathway non-specifically inhibits vascular permeability. Ang-1/Tie2 signaling is negatively regulated by the naturally occurring antagonistic ligand, Ang-2. Substantial evidence now demonstrates that upregulation of Ang-2 plays a key role in promoting pulmonary vascular leak in a variety of pathological conditions, such as sepsis, and inhibition of Ang-2 or activation of Ang-1/Tie2 can prevent pulmonary vascular permeability and reduce mortality in sepsis models. Recently, Ang- 2 expression has been shown to be increased in phosgene-induced ALI, highlighting the Angiopoietin/Tie2 pathway as a potential therapeutic target in chemical-induced lung injury. In addition to Ang-2, Tie2 is negatively regulated by vascular endothelial protein tyrosine phosphatase (VE-PTP). Preliminary studies from our group demonstrate that inhibition of VE-PTP with highly selective small molecule compounds results in dramatic Tie2 activation and enhanced endothelial barrier function. In a mouse model of pulmonary vascular leak that causes a high incidence of shock and death, administration of a small molecule inhibitor of VE-PTP completely blocks these adverse effects. Based on these results, we hypothesize that activation of Tie2 using highly selective and potent small molecule inhibitors of VE-PTP will prevent phosgene-induced vascular leakage, pulmonary edema, and mortality. To test this hypothesis, the Specific Aims of this proposal are to: 1) Develop and characterize a mouse model of phosgene-induced acute lung injury;2) Identify the most potent VE-PTP inhibitors with the greatest efficacy in vitro;and 3) Determine the efficacy of VE-PTP inhibitors in preventing phosgene-induced pulmonary vascular leak, pulmonary edema, hypoxia, and mortality in a mouse model. Completion of these Aims will lead to the identification of potentially therapeutic small molecules that can be advanced to subsequent pharmacology/toxicology testing and development as treatments for acute lung injury resulting from the inhalation of phosgene and similar toxic industrial chemicals.
Phosgene is a common and widely used industrial chemical. Exposure to phosgene gas causes a highly lethal acute lung injury characterized by a rapid and dramatic leakage of fluid into the lungs for which no effective treatments currently exist. Thus, phosgene represents a significant chemical threat, as accidental or intentional (e.g., terrorist) exposure of large populations to phosgene gas would have disastrous consequences. This application will test whether novel chemical inhibitors of vascular leak will prevent phosgene-induced lung injury. If successful, these studies would provide an important and effective treatment for this significant chemical threat risk.