Chlorine gas has been used as a terrorist weapon, in warfare and has injured many Americans in transportation or industrial accidents. Despite its devastating effects, no mechanism-based treatment has been developed. In this application, we hypothesize that targeting the TRPA1 ion channel post-exposure will ameliorate the acute pulmonary, cardiovascular and neurological effects of chlorine, leading to decreased morbidity and improved recovery. TRPA1 is a chemical irritant receptor eliciting pain, edema, vasodilation, cardiac arrhythmia, inflammation and leukocyte infiltration. Our preliminary studies in mice show that TRPA1 inhibitors, when administered post-chlorine exposure, prevent the chlorine-induced decline of blood oxygenation, improve pulmonary function and mitigate inflammation. Here, we propose to test the efficacy of a 3rd generation TRPA1 inhibitor, found to block mouse, human and porcine TRPA1, in mouse and pig models of chlorine inhalation injury, with the goal to develop this compound as a future human countermeasure. The following aims are proposed:
Aim 1 : Screen potential therapeutic effects of a 3rd generation TRPA1 inhibitor in mouse models of Cl2 gas inhalation injury.
Aim 2 : Determine the pharmacokinetic and toxicological properties of TRPA1 inhibitor in pigs.
Aim 3 : Test the TRPA1 inhibitor in a pig model of chlorine gas inhalation injury
Chlorine gas is a terrorism and warfare agent and, due to transport and industrial accidents, has injured many Americans. Currently, no effective treatment for chlorine gas injuries is available. Our proposal will test the therapeutic potential of an inhibitor of pain, lung injury and inflammation in mice and pigs for future development as a human treatment of this devastating injury.
