Cannabinoid-2 receptor signaling in vesicant induced lung injury

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Sulfur mustard (SM), a vesicant that is one of the most lethal chemical warfare agents, remains as a great threat in modern times. Exposure to SM and its mono-functional analog 2-chloroethyl ethyl sulfide (CEES) induces deleterious effects on the lung. Oxidative stress and uncontrolled inflammation are considered as the major mechanisms of SM toxicity on the lung. Currently, there are no effective medical countermeasures to mitigate the vesicant induced lung damage. Therefore, it is essential to expand our understanding of the molecular mechanisms and to identify effective measures, including pharmacological interventions, to alleviate the inflammation and oxidative stress induced by SM. Cannabinoid-2 receptors (CB2R), expressed mainly in the immune cells, have shown promising anti-inflammatory and anti-injury potential without any adverse psychotic effects. Our preliminary findings indicated a significant reduction of CEES- induced acute lung injury and immune cell infiltration by pharmacological activation of CB2R, while the genetic deletion of CB2R worsened the lung injury. Moreover, CB2R ligands show marked functional selectivity, suggesting CB2R can be a good target for developing counter measures to CEES. Given these promising indications, this project aims to further investigate how CB2R activation attenuates CEES-induced acute lung injury, using pharmacological activation and genetic deletion approach in the following specific aims: 1) To determine the extent to which CB2R regulates the CEES-induced acute lung injury, inflammatory response, and oxidative stress. 2) To delineate the mechanism of the protective role of CB2R in CEES-induced lung injury, inflammatory response, and oxidative stress. These efforts will reveal a novel mechanism of endocannabinoid signaling through CB2R in CEES-induced lung injury and would assist in translational strategies for the development of therapeutic agent against vesicant-induced lung damage.