Treatment strategies for ocular toxicity from chloropicrin

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Project Summary Chloropicrin (Trichloronitromethane, CP), currently used as a soil fumigant and pesticide, was employed during World War I as a tear gas and choking agent and remains a potential agent for chemical terrorism. Its exposure causes severe ocular injury, especially to the corneal tissue; however, mechanisms of its injury are not well-defined and effective targeted treatments are elusive. The major goal of this application is to identify a novel targeted therapeutic approach, which can effectively mitigate acute and long-term ocular injuries from CP exposure, with a potential to be further tested against ocular injuries from other toxic chemical exposures. Data from our studies in corneal epithelial cells and ex vivo rabbit cornea demonstrate increased levels of nuclear erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), a critical target enzyme downstream of Nrf2, suggesting that the Nrf2 pathway, a key antioxidant and cytoprotective system, could be activated following CP exposure. Under this application, we propose to further asses the role of the Nrf2 pathway under CP-induced ocular injury using Nrf2 knockout (KO) mice. Nrf2 activity triggers cellular protective mechanisms against oxidative stress and inflammatory responses and is reported as a key target of new approaches for treating various oxidative stress-related ocular diseases/injuries. Hence, employing Nrf2 activators may be a novel approach for the treatment of ocular injuries due to CP exposure. Chemical ocular injury causes hypoxia that leads to tissue damage; oxygen therapy is reported to improve tissue preservation and enhance wound healing to mitigate ocular chemical and thermal burns. Our preliminary data shows the therapeutic potential of supersaturated oxygen emulsion (SSOE) therapy in reversing CP-induced acute toxicity in HCE cells and ex vivo rabbit corneas. Our hypothesis is that the Nrf2 signaling pathway is a key mediator in protecting against CP-induced corneal injury; activation of the Nrf2 pathway can inhibit CP-induced oxidative stress and inflammation, and simultaneous treatment with SSOE can increase tissue oxygen levels to improve tissue preservation and enhance wound healing, leading to a novel and more effective treatment strategy against CP- induced acute and long-term ocular injury. To test this hypothesis, the proposed aims are: Aim 1. To develop a CP-induced ocular injury model in mice and determine if the Nrf2-ARE pathway is a key mediator in CP- induced ocular injury using wild type and Nrf2 KO mice. Aim 2. To evaluate the efficacy of Nrf2 activators and supersaturated oxygen emulsion alone, or in combination, to identify an effective therapeutic strategy against CP-induced ocular injury. We anticipate that the outcomes from the above aims will establish a useful mouse ocular injury model with CP and ascertain if the Nrf2 signaling pathway is a novel target for therapeutic intervention to counteract CP-induced ocular injury. Successful completion of this project will identify a novel therapeutic approach that can more effectively mitigate acute and chronic ocular injuries from CP and lead to a better understanding of the mechanisms of CP-induced ocular toxicity.