Targeting the endocannabinoid signaling in chemical threat agents-induced lung injury - Summary: The U.S. Department of Homeland Security (DHS) has identified over 200 chemicals of concern (CoCs) that threaten public health, with approximately 25% posing respiratory risks. Notably, nitrogen mustard (NM) and ammonia (NH3) are significant contributors to lung injury. Currently, there are no effective medical countermeasures to mitigate NM- or NH3-induced lung damage, therefore, the search for an effective therapeutic or prophylactic treatment persists. The endocannabinoids and their lipid-related mediators contribute to the modulation of oxidative stress and lipid peroxidation and 2- Arachidonoylglycerol (2-AG), is the most abundant endocannabinoid. 2-AG is produced ‘on demand’ and rapidly degraded, and monoacylglycerol lipase (MAGL or MgII) is the main enzyme responsible for 2-AG catabolism. The hydrolysis of 2-AG by MAGL terminates the activation of CB receptors, releasing free AA that serves as a precursor for the synthesis of pro-inflammatory eicosanoids. Enhancing the 2-AG signaling displays an anti-inflammatory response to proinflammatory and mechanical insults. Our preliminary findings indicate that acute exposure to NM or NH3 results in a significant increase in MAGL in mouse lung tissue. The NM-induced increase in MAGL was significantly higher in lung immune cells compared to alveolar epithelial and endothelial cells. A similar increase in MAGL was observed in human alveolar macrophages (HAMs) in response to NM exposure. Furthermore, our pilot study showed that the administration of JZL184, a potent and highly selective inhibitor of MAGL, resulted in a significant reduction in NM- and NH3-induced acute lung injury and immune cell infiltration in mice. Given these promising indications, this project aims to further investigate how augmenting the 2-AG signaling by inactivation of MAGL could confer protection against NM- or NH3-induced lung injury. Aim 1: To determine the extent to which MAGL inactivation/inhibition changes NM- or NH3-induced lung injury, inflammatory response, and toxicity. Aim 2: To determine the cellular and molecular responses of MAGL inactivation on NM or NH3-induced lung injury and inflammatory response. Aim 3: To delineate the mechanism by which MAGL inhibition/inactivation exerts the protective effects in NM or NH3-induced acute lung injury and inflammatory response.
