2-arachidonoylglycerol signaling in nitrogen mustard-induced lung injury

The Department of Health and Human Services National Institutes of Health Office of the Director awarded Old Dominion University $458,144 on June 23, 2026, under the Trans-NIH Research Support program (CFDA 93.310) to investigate 2-arachidonoylglycerol signaling as a therapeutic target for nitrogen mustard-induced lung injury.

The research aims to assess the efficacy of monoacylglycerol lipase (MAGL) inhibition in protecting against nitrogen mustard-induced acute lung injury, inflammatory response, and oxidative stress, and to delineate the protection mechanisms. Nitrogen mustard, a potent cytotoxic vesicant, causes acute lung injury and potentially chronic conditions including fibrosis, emphysema, and bronchiolitis obliterans, with no existing medical countermeasures. Preliminary findings indicate that acute nitrogen mustard exposure increases MAGL levels in mouse lung tissues, immune cells, and human alveolar macrophages, and that JZL184, a MAGL inhibitor, reduces nitrogen mustard-induced acute lung injury and immune cell infiltration in mice. The project will build on this foundation to investigate how augmenting 2-arachidonoylglycerol signaling through MAGL inactivation confers protection.

Performance occurs in Norfolk, Virginia. The period of performance runs from June 23, 2026, through June 22, 2028. Old Dominion University Research Foundation (Odurf) serves as the fiscal and administrative agent for the award.

Abstract

Nitrogen mustard (NM), a potent cytotoxic vesicant, can cause acute lung injury and potentially lead to chronic conditions like fibrosis, emphysema, and bronchiolitis obliterans. NM remains a significant chemical threat due to its ease of synthesis and weaponization. Currently, there are no effective medical countermeasures to mitigate NM-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 indicated that acute exposure to NM resulted in a significant increase in magl in mouse lung tissues, immune cells, and human alveolar macrophages. Furthermore, our pilot study showed that the administration of JZL184, a potent inhibitor of magl resulted in a significant reduction in NM-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-induced lung injury. Aim 1: to assess the efficacy of magl inhibition/inactivation in protection against NM-induced acute lung injury, inflammatory response, and oxidative stress. Aim 2: to delineate the mechanism of protection by magl inhibition/inactivation in NM-induced acute lung injury, inflammatory response, and oxidative stress. These efforts would assist in translational strategies for the development of therapeutic agents against NM-induced lung damage.